A pan‐tumor review of the role of poly(adenosine diphosphate ribose) polymerase inhibitors

Abstract

Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors, such as olaparib, talazoparib, rucaparib, and niraparib, comprise a therapeutic class that targets PARP proteins involved in DNA repair. Cancer cells with homologous recombination repair defects, particularly BRCA alterations, display enhanced sensitivity to these agents because of synthetic lethality induced by PARP inhibitors. These agents have significantly improved survival outcomes across various malignancies, initially gaining regulatory approval in ovarian cancer and subsequently in breast, pancreatic, and prostate cancers in different indications. This review offers a comprehensive clinical overview of PARP inhibitor approvals, emphasizing their efficacy across different cancers based on landmark phase 3 clinical trials.

INTRODUCTION

One of the major pathways in human cancer development and progression is genomic instability, characterized by a high frequency of mutations. ¹ Typically, human cells attempt to maintain genomic integrity by using at least five active DNA‐repair pathways: homologous recombination, base excision repair, mismatch repair, nucleotide excision repair, and nonhomologous end joining. ²

In the last decade, poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors (PARPi) have been approved across different tumor types harboring alterations in homologous recombination. The PARP family includes 17 proteins, and the two major ones involved in single‐strand DNA‐repair mechanisms are PARP1 and PARP2. ³ PARP1 binds DNA breaks and forms poly(adenosine diphosphate ribose) (PAR) chains, known as PARylation, which serve as attachment sites for additional repair proteins at the site of DNA damage, facilitating DNA repair. Moreover, the auto‐PARylation of PARP itself promotes its dissociation from the repaired DNA, maintaining the overall genomic stability of the cell. ⁴ PARPi act by trapping PARP1 on DNA and inhibiting normal auto‐PARylation, thus terminating the progression of the replication fork. ⁴ Moreover, the inhibition of PARP1 by PARPi leads to double‐strand breaks, activating the homologous recombination repair (HRR) mechanism in normal HRR‐proficient cells, leading to cell survival. In tumor cells lacking this repair mechanism, they may use alternative pathways, such as nonhomologous end joining, which can also potentially induce cell death through error‐prone DNA‐repair mechanisms (Figure 1). ⁵ This process of inhibiting a secondary DNA repair pathway in cells with existent homologous recombination deficiency (HRD) results in a phenomenon known as synthetic lethality. ⁶

FIGURE 1.

Mechanism of action of PARPi and FDA approvals in different cancers. PARPi act by inhibiting DNA single‐strand break repair by PARP enzymes, leading to DNA double‐strand breaks. In patients with alterations in DNA repair pathways (HRR deficiency), this leads to DNA damage and cancer cell apoptosis. 1L, first‐line; ARPI, androgen receptor pathway inhibitor; FDA, US Food and Drug Administration; HER2, human epidermal growth factor receptor 2; HRD, homologous recombination deficiency; HRR, homologous recombination repair; mCRPC, metastatic castrate‐resistant prostate cancer; PARP, poly(adenosine diphosphate ribose) polymerase; PARPi, poly(adenosine diphosphate ribose) polymerase inhibitors. Created with BioRender.com.

Several PARPi have been developed and approved for various cancer types and indications. ⁷ In the United States, olaparib, niraparib, rucaparib, and talazoparib have received approval by the US Food and Drug Administration (FDA). The primary difference among these agents lies in their potency to trap PARP1. ⁷ Talazoparib has a PARP‐trapping potency of 100, with rucaparib at 1 and niraparib at 2, all compared with olaparib. Given these differences in their trapping potencies, talazoparib has the lowest half‐maximal inhibitory concentration of 4 nM, whereas niraparib has the highest at 60 nM. ⁷

In this review article, we aim to provide a comprehensive clinical overview of PARPi indications, highlighting their efficacy across various cancers, such as prostate, ovarian, breast, and pancreatic cancers.

INDICATIONS IN PROSTATE CANCER

In 2024, prostate cancer remains the most common noncutaneous malignant neoplasm in men ⁸ ; however, despite recent advancements, the 5‐year survival rate for individuals diagnosed with metastatic prostate cancer remains low at around 32%. ⁹ Among people with metastatic prostate cancer, the prevalence of germline DNA‐repair gene mutations is 11.8%; for people with localized disease, it is estimated to be 4.6%. ¹⁰ Furthermore, germline and/or somatic HRR alterations were identified in 23% of patients with metastatic prostate tumors. ¹¹ These data led to the evaluation of PARPi in prostate cancer.

PARPi monotherapy in patients with metastatic castrate‐resistant prostate cancer

Olaparib

PROfound (ClinicalTrials.gov identifier NCT02987543) was the first randomized, open‐label, phase 3 trial assessing olaparib in patients with metastatic, castrate‐resistant prostate cancer (mCRPC; Table 1). ¹² , ¹³ , ¹⁴ For this trial, patients had to have progressed on an androgen receptor pathway inhibitor (ARPI) with tumor alteration in at least one of 15 prespecified genes with a direct or indirect role in HRR function: BRCA1/2, ATM, BRIP1, BARD1, CDK12, CHEK1/2, FANCL, PALB2, PPP2R2A, RAD51B/C/D, and RAD54L. Two cohorts were tested: cohort A comprised patients with alterations in BRCA1/2 and/or ATM, whereas cohort B included patients with alterations in the remaining 12 genes. Patients were randomized in a 2:1 ratio to receive olaparib (300 mg twice daily) in the experimental arm or the physician's choice (abiraterone or enzalutamide) in the control arm. Crossover to olaparib was allowed. Radiographic progression‐free survival (rPFS) by blinded, independent central review (BICR) in cohort A was the primary end point.

TABLE 1.

Summary of the PROfound and TRITON3 phase 3 studies assessing poly(adenosine diphosphate ribose) polymerase inhibitor monotherapy in patients with metastatic castrate‐resistant prostate cancer.

		PROfound	TRITON3
	ClinicalTrials.gov identifier	NCT02987543	NCT02975934
	References	de Bono 2020, 12 Hussain 2020 13	Fizazi 2023 14
Study design	Inclusion criteria	mCRPC with prior progression on an ARPI	mCRPC with prior progression on an ARPI
		Prior taxane allowed	Taxane allowed in mHSPC
		Alteration in one or more of 15 prespecified HRR genes	Alterations in BRCA1/2 or ATM
	Randomization and design	2:1	2:1
		Olaparib vs. physician's choice of abiraterone or enzalutamide	Rucaparib vs. physician's choice of docetaxel, enzalutamide, or abiraterone
		Cohort A: One or more alteration in BRCA1/2, ATM
		Cohort B: One or more alteration in the remaining 12 genes
	Primary end point	rPFS by BICR in cohort A	rPFS by independent review
	Stratification factors	Previous taxane	ECOG PS 0 or 1
		Measurable disease	Hepatic metastases
			Genetic alteration (BRCA1, BRCA2, or ATM)
	HRR genes tested	BRCA1/2, ATM, BRIP1, BARD1, CDK12, CHEK1/2, FANCL, PALB2, PPP2R2A, RAD51B/C/D, and RAD54L	BRCA1/2 and ATM

Patient population, no. (%)		Olaparib	Enzalutamide/abiraterone	Rucaparib	Enzalutamide/abiraterone/docetaxel
	No. of patients	256	131	270	135
	Age: Median [range], years	69 [47–91]	69 [49–87]	70 [45–90]	71 [47–92]
	Baseline PSA: Median [range], ng/mL	68.2 [IQR, 24.1–294.4]	106.5 [IQR, 37.2–326.6]	26.9 [0.1–1247]	28.8 [0–1039]
	Visceral metastases	68 (27.0)	44 (34.0)	74 (27.0)	46 (34.0)
	Prior taxane	170 (66.0)	84 (64.0)	63 (23.0)	28 (21.0)
	Prior ARPI	256 (100.0)	131 (100.0)	270 (100.0)	135 (100.0)
Outcomes	rPFS in patients with HRRm: Median, months	5.8 vs. 3.5		10.2 vs. 6.4
	HR [95% CI]	0.49 [0.38–0.63]		0.61 [0.47–0.80]
	p	< .001		< .001
	rPFS in patients with BRCAm: Median, months	9.8 vs. 3.0		11.2 vs. 6.4
	HR [95% CI]	0.22 [0.15–0.32]		0.50 [0.36–0.69]
	p	—		< .001
	OS in patients with HRRm: Median, months	17.3 vs. 14.0		23.6 vs. 20.9 a
	HR [95% CI]	0.79 [0.61–1.03]		0.94 [0.72–1.23]
	p	—		—
	OS in patients with BRCAm: Median, months	19.1 vs. 15.1		24.3 vs. 20.8 a
	HR [95% CI]	0.61 [0.37–1.01]		0.81 [0.58–1.12]
	p	—		.21
	ORR, %	21.7 vs. 4.5		45.1 vs. 17.1

		Olaparib	Enzalutamide/abiraterone	Rucaparib	Enzalutamide/abiraterone/docetaxel
Adverse events: Any grade/grade ≥3, %	Anemia	50/23	15/5	47/24	18/1
	Neutropenia	—	—	14/7	8/8
	Thrombocytopenia	—	—	19/6	0/0
	Fatigue	42/3	33/5	61/7	63/9
	Nausea	43/2	21/0	50/3	19/1
Drug approvals	FDA	mCRPC and prior progression on enzalutamide/abiraterone and alterations in one or more of BRCA1/2, ATM, BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, RAD51B/C/D, and RAD54L		mCRPC and prior progression on an ARPI and taxane and BRCA1/2 alterations
	EMA	mCRPC and prior progression on an ARPI and BRCA1/2 alterations		—

Abbreviations: 1L, first‐line; ARPI, androgen receptor pathway inhibitor; BICR, blinded, independent central review; BRCAm, mutations in BRCA1/2; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; EMA, European Medicines Agency; FDA, US Food and Drug Administration; HR, hazard ratio; HRR, homologous recombination repair; HRRm, homologous recombination repair mutations; IQR, interquartile range; mCRPC; metastatic castrate‐resistant prostate cancer; mHSPC, metastatic hormone‐sensitive prostate cancer; ORR, objective response rate; OS, overall survival; PSA, prostate‐specific antigen; R, range; rPFS, radiographic progression‐free survival.

^a Immature OS data.

The trial met this primary end point with a 66% reduction in the risk of rPFS. Compared with placebo, people in cohort A who received olaparib had a significantly longer median rPFS (7.4 vs. 3.6 months, respectively; hazard ratio [HR], 0.34; 95% confidence interval [CI], 0.25–0.47). This was also seen across the study population treated (median rPFS, 5.8 vs. 3.5 months; HR, 0.49; 95% CI, 0.38–0.63). ¹² In an exploratory analysis, the benefit of olaparib was significant in patients with BRCA1/2 alterations (HR, 0.22; 95% CI, 0.15–0.32) but not in those with ATM alterations (HR, 1.04; 95% CI, 0.61–1.87). ¹² Median overall survival (OS) was also significantly prolonged among the patients in cohort A who received olaparib (19.1 vs. 14.7 months; HR, 0.69; 95% CI, 0.50–0.97), even after adjustment for crossover (HR, 0.42; 95% CI, 0.19–0.91). ¹³ OS was not significantly increased in the overall population, although a trend toward improved OS in the experimental arm was noted (median OS, 17.3 vs. 14 months; HR, 0.79; 95% CI, 0.61–1.03). The most common adverse events (AEs) encountered with olaparib were anemia (50%), nausea (43%), and fatigue (42%), with grade ≥3 anemia occurring in 23% of patients. ¹³ Based on these results, olaparib was approved by the FDA in May 2020 in this population, with approval covering germline and/or somatic alterations in any of the following genes: BRCA1/2, ATM, BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, RAD51B/C/D, and RAD54L. ¹⁵

Rucaparib

TRITON3 (ClinicalTrials.gov identifier NCT02975934) was an open‐label, randomized, controlled, phase 3 trial that tested rucaparib in patients with mCRPC who progressed on a prior ARPI and had alterations in BRCA1/2 or ATM ¹⁴ (Table 1). Patients were also randomized in a 2:1 ratio to receive rucaparib (600 mg twice daily) or a physician's choice control (docetaxel, abiraterone, or enzalutamide). The primary end point was rPFS, and crossover to rucaparib was allowed for those randomly assigned to the physician's choice control. Compared with the physician's choice control, rucaparib significantly improved rPFS (median, 10.2 vs. 6.4 months, respectively; HR, 0.61; 95% CI, 0.47–0.80). ¹⁴ At 59% trial maturity, there was no statistically significant impact on OS (median, 23.6 vs. 20.9 months; HR, 0.94; 95% CI, 0.72–1.23). The most common AEs with rucaparib were also fatigue (61%), nausea (50%), and anemia or decreased hemoglobin (47%), with grade ≥3 anemia or decreased hemoglobin encountered in 24% of patients. ¹⁴ These results are particularly important because they demonstrated that rucaparib had superior efficacy over docetaxel or an alternate ARPI in this specific population with these specific genomic alterations. Based on these findings, rucaparib received FDA approval in May 2020 in patients who had mCRPC and deleterious germline and/or somatic BRCA mutations (gBRCAm and sBRCAm, respectively) and previous progression on an ARPI and taxane‐based chemotherapy. ¹⁶

PARPi‐based combinations in mCRPC

The combination of PARPi with ARPIs has been investigated based on prior findings suggesting a synergistic effect between these two agents. ¹⁷ Androgen receptor inhibition using ARPIs upregulates PARP activity ¹⁸ and downregulates the expression of HRR genes, thus priming an HRR‐deficient–like state, also known as BRCAness. ¹⁹ In addition, PARPi inhibit the transcriptional activity of the androgen receptor, thereby enhancing the activity of ARPIs. ²⁰ These findings provided the rationale behind combining ARPIs and PARPi for treating patients with mCRPC (Figure 2, Table 2). ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷

FIGURE 2.

Rationale behind PARPi‐based combinations in patients with prostate and ovarian cancer. (A) ARPIs downregulate the expression of HRR genes, inducing an HRR‐deficient‐like state also known as BRCAness. PARPi inhibit the transcriptional activity of the androgen receptor. (B) Bevacizumab inhibits angiogenesis, leading to hypoxia that downregulates the expression of key HRR factors, priming cancer cells for PARPi‐induced apoptosis. 1L, first‐line; AR, androgen receptor; ARPI, androgen receptor pathway inhibitor; HRD, homologous recombination deficiency; HRR, homologous recombination repair; mCRPC, metastatic castrate‐resistant prostate cancer; PARP, poly(adenosine diphosphate ribose) polymerase; PARPi, poly(adenosine diphosphate ribose) polymerase inhibitors; VEGF, vascular endothelial growth factor. Created with BioRender.com

TABLE 2.

Summary of the PROpel, MAGNITUDE, and TALAPRO‐2 phase 3 trials assessing the combinations of a poly(adenosine diphosphate ribose) polymerase inhibitor and an androgen receptor pathway inhibitor in patients with metastatic castrate‐resistant prostate cancer.

	ClinicalTrials.gov identifier	PROpel	MAGNITUDE	TALAPRO‐2
				Cohort 1	Cohort 2
		NCT03732820	NCT03748641	NCT03395197
	References	Clarke 2022, 21 Saad 2023 22	Chi 2023, 23 , 24 2024 25	Agarwal 2023, 26 Fizazi 2024 27
Study design	Inclusion criteria	1L mCRPC	1L mCRPC	1L mCRPC	1L mCRPC
		ECOG PS 0–1	ECOG PS 0–1	ECOG PS 0–1	ECOG PS 0–1
		Prior docetaxel allowed	Prior systemic therapies for mHSPC or nmCRPC allowed	ARPI and docetaxel allowed in mHSPC	ARPI and docetaxel allowed in mHSPC
		Prior ARPI (except abiraterone) allowed if stopped ≥12 months before randomization	Abiraterone allowed in 1L mCRPC for ≤4 months before randomization	All comers	Patients with HRR mutations
		All comers
	Randomization and design	1:1	1:1	1:1
		Abiraterone + olaparib vs. abiraterone + placebo	Abiraterone + niraparib vs. abiraterone + placebo	Enzalutamide + talazoparib vs. enzalutamide + placebo
			Cohort 1: HRRm cohort
			Cohort 2: HRR‐proficient (closed prematurely because of futility)
	Primary end point	rPFS by investigator assessment	rPFS by BICR	rPFS by BICR
	Stratification factors	Site of metastases	Prior taxane	Previous ARPI or docetaxel for mHSPC
		Previous docetaxel in mHSPC	Prior ARPI	HRR gene alteration status
			Prior abiraterone for 1L mCRPC
			BRCA1/2 vs. non‐BRCA HRR
	HRR genes tested	ATM, BRCA1/2, BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, RAD51B/C/D, and RAD54L	ATM, BRCA1/2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, or PALB2	BRCA1/2, PALB2, ATM, ATR, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A, CDK12
	Molecular testing	Retrospective	Prospective	Prospective
		Tumor tissue or ctDNA	Tumor tissue or ctDNA	Tumor tissue or ctDNA

Patient population, no. (%)		Abiraterone + olaparib	Abiraterone + placebo	Abiraterone + niraparib	Abiraterone + placebo	Enzalutamide + talazoparib	Enzalutamide + placebo	Enzalutamide + talazoparib	Enzalutamide + placebo
	No. of patients	399	397	212	211	402	403	200	199
	Age: Median [range], years	69 [43–91]	70 [46–88]	69 [45–100]	69 [43–88]	71 [IQR, 66–76]	71 [IQR, 65–76]	70 [41–90]	71 [44–90]
	Baseline PSA: Median [range], ng/mL	17.9 [IQR, 6.09–67.0.	16.81 [IQR, 6.26–53.3]	21.4 [0.0–4826.5]	17.4 [0.1–4400.0]	18.2 [IQR, 6.9–59.4]	16.2 [IQR, 6.4–53.4]	19.6 [0.2–3412.0]	18 [0.0–1055.0]
	Visceral metastases	55 (13.8)	60 (15.1)	51 (24.1)	39 (18.5)	57 (14.0)	77 (19.0)	32 (16.0)	32 (16.0)
	HRRm	111 (27.8)	115 (29.0)	212 (100.0)	211 (100.0)	85 (21.0)	84 (21.0)	198 (99.0)	197 (99.0)
	Prior docetaxel in mHSPC	90 (22.6)	89 (22.4)	41 (19.3)	44 (20.9)	86 (21.0)	93 (23.0)	57 (28.0)	60 (30.0)
	Prior ARPI in mHSPC or nmPC	1 (0.3)	0 (0.0)	8 (3.8)	5 (2.4)	23 (6.0)	27 (7.0)	17 (9.0)	17 (9.0)
	Prior ARPI in mCRPC	0 (0.0)	0 (0.0)	50 (23.6)	48 (22.7)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Outcomes	rPFS–All comers: Median, months	25.0 vs. 16.5		—		NR vs. 21.9		—
	HR [95% CI]	0.68 [0.57–0.81]		—		0.63 [0.51–0.78]		—
	p	—		—		< .0001		—
	rPFS in patients with HRRm: Median, months	NR vs. 13.9		16.7 vs. 13.7		27.9 vs. 16.4		NR vs. 13.8
	HR [95% CI]	0.50 [0.34–0.73]		0.76 [0.6–0.97]		0.46 [0.30–0.70]		0.45 [0.33–0.61]
	p	—		.028		.0003		< .0001
	rPFS in patients with proficient or unknown HRR status: Median months	24.1 vs. 19.0		—		NR vs. 22.5		—
	HR [95% CI]	0.76 [0.60–0.97]		—		0.70 [0.54–0.89]		—
	p	—		—		.0039		—
	rPFS in patients with BRCAm: Median, months	NR vs. 8.4		19.5 vs. 10.9		—		NR vs. 11.0
	HR [95% CI]	0.23 [0.12–0.43]		0.55 [0.39–0.78]		0.23 [0.10–0.53] b		0.20 [0.11–0.36]
	p	—		.0007		.0002		< .0001
	OS–All comers: Median, months	42.1 vs. 34.7		—		36.4 vs. NR		—
	HR [95% CI]	0.81 [0.67–1.00]		—		0.89 [0.69–1.14] a		—
	p	.054		—		.35		—
	OS in patients with HRRm: Median, months	NR vs. 28.5		29.3 vs. 32.2		—		NR vs. 33.7
	HR [95% CI]	0.66 [0.45–0.95]		0.70 [0.49–0.99] c		—		0.69 [0.46–1.03] a
	p	—		.0414		—		.07
	OS in patients with proficient or unknown HRR status: Median. months	42.1 vs. 38.9		—		—		—
	HR [95% CI]	0.89 [0.70–1.14]		—		—		—
	p	—		—		—		—
	OS in patients with BRCAm: Median, months	NR vs. 23.0		30.4 vs. 28.6		—		—
	HR [95% CI]	0.29 [0.14–0.56]		Preplanned MVA: 0.66 [0.46–0.95]		—		0.61 [0.31–1.23] a
	p	—		.024		—		.16
	ORR, %	58.4 vs. 48.1		59.7 vs. 28.1		61.7 vs. 43.9		67.1 vs. 40.0

Adverse events: Any grade/grade ≥3, %		Abiraterone + olaparib	Abiraterone + placebo	Abiraterone + niraparib	Abiraterone + placebo	Enzalutamide + talazoparib	Enzalutamide + placebo	Enzalutamide + talazoparib	Enzalutamide + placebo
	Anemia	50/16	18/3	52/31	23/9	66/46	17/4	65/41	16/5
	Neutropenia	10/5	4/2	16/7	7/2	36/18	7/1	32/19	7/1
	Thrombocytopenia	<10	<10	24/9	10/2	25/7	3/1	25/7	3/<1
	Fatigue	39/3	30/2	30/4	19/5	34/4	29/2	33/2	27/1
	Nausea	31/<1	14/<1	25/1	15/1	21/<1	12/<1	21/2	17/<1
Drug approvals	FDA	mCRPC with BRCA1/2 alterations		mCRPC with BRCA1/2 mutations		mCRPC with any HRR mutations
	EMA	mCRPC when chemotherapy is not clinically indicated		mCRPC with BRCA1/2 mutations		mCRPC when chemotherapy is not clinically indicated

Abbreviations: 1L, first‐line; ARPI, androgen receptor pathway inhibitor; BICR, blinded, independent central review; BRCAm, mutations in BRCA1/2; CI, confidence interval; ctDNA, circulating tumor DNA; ECOG PS, Eastern Cooperative Oncology Group performance status; EMA, European Medicines Agency; FDA, US Food and Drug Administration; HR, hazard ratio; HRR, homologous recombination repair; HRRm, homologous recombination repair mutations; IQR, interquartile range; mCRPC; metastatic castrate‐resistant prostate cancer; mHSPC, metastatic hormone‐sensitive prostate cancer; MVA, multivariate analysis; nmCRPC, nonmetastatic castration‐resistant prostate cancer; nmPC, nonmetastatic prostate cancer; NR, not reached; ORR, objective response rate; OS, overall survival; PARPi, poly(adenosine diphosphate ribose) polymerase inhibitor; PSA, prostate‐specific antigen; R, range; rPFS, radiographic progression‐free survival.

^a Immature OS data.

^b Among patients with HRR deficiency.

^c After adjusting for subsequent PARPi and other life‐prolonging therapies in an inverse probability, censoring, weighting analysis.

Meta‐analysis

A recent meta‐analysis pooled the results of three randomized, placebo‐controlled trials assessing the combinations of PARPi with ARPIs in the first‐line mCRPC setting using random‐effect and fixed‐effect models. ²⁸ The combinations of olaparib with abiraterone, niraparib with abiraterone, and talazoparib with enzalutamide were assessed in the PROpel, MAGNITUDE, and TALAPRO‐2 trials, respectively (ClinicalTrials.gov identifiers NCT03732820, NCT03748641, and NCT03395197). This meta‐analysis included a total of 2601 patients. In the intention‐to‐treat (ITT) population, results from PROpel and TALAPRO‐2 demonstrated a 38% reduction in the risk of radiographic progression or death (HR, 0.62; 95% CI, 0.53–0.72) and a 16% reduction in the risk of death (HR, 0.84; 95% CI, 0.72–0.98) in the combination arms. The pooled HR for rPFS from the three trials in patients with HRR‐proficient status was 0.76 (95% CI, 0.65–0.90), and it was 0.57 (95% CI, 0.42–0.78) in patients with HRR mutations (HRRm), favoring the treatment arms. In patients with BRCA mutations, a significant improvement in rPFS was also noted in the combination arms in the PROpel and MAGNITUDE trials (HR, 0.36; 95% CI, 0.16–0.82). ²⁸

Olaparib with abiraterone

PROpel was a randomized, double‐blinded, phase 3 trial assessing the combination of olaparib (300 mg twice daily) and abiraterone in the first‐line mCRPC setting regardless of HRR status. ²¹ HRR status was retrospectively assessed based on tumor tissue or circulating tumor DNA testing. The primary end point was imaging‐based progression‐free survival (PFS), as assessed by the treating investigator. Compared with placebo, the incorporation of olaparib significantly improved PFS (median, 24.8 vs. 16.6 months; HR, 0.66; 95% CI, 0.54–0.81). ²¹ At a median follow‐up of around 36 months, there was no statistically significant impact on OS with olaparib versus placebo in the total treated population, although a trend toward improvement was noted (median OS, 42.1 vs. 34.7 months; HR, 0.81; 95% CI, 0.67–1.00). ²² However, a significant improvement in OS was seen in those with HRRm (median OS, not reached [NR] vs. 28.5 months; HR, 0.66; 95% CI, 0.45–0.95) and those with BRCA mutations (BRCAm; median OS, NR vs. 23 months; HR, 0.29; 95% CI, 0.14–0.56). Patients with non‐HRRm disease had a nonsignificant trend toward an improved OS with the combination of olaparib plus abiraterone (median OS, 42.1 vs. 38.9 months; HR, 0.89; 95% CI, 0.70–1.14). In an exploratory analysis of patients harboring alterations in any of the remaining 12 HRR non‐BRCA genes, those receiving the combination of olaparib plus abiraterone had investigator‐assessed PFS (HR, 0.80; 95% CI, 0.50–1.27) and OS (HR, 1.02; 95% CI, 0.65–1.59) similar to those of patients who received abiraterone, suggesting a limited efficacy of the combination in this subgroup. ²⁹ The most common AEs in the treatment arm were anemia (50%), fatigue (39%), and nausea (31%). Grade ≥ 3 anemia occurred in 16% of patients. ²² Based on the results of the PROpel trial, in May 2023, the FDA approved olaparib with abiraterone in patients with mCRPC and BRCAm. ³⁰

Niraparib with abiraterone

The combination of niraparib with abiraterone was assessed in the MAGNITUDE trial, in which patients who had mCRPC underwent prospective testing for HRRm and were randomized 1:1 in two separate cohorts based on the presence or absence of HRRm to receive abiraterone and prednisone with either niraparib (200 mg once daily) or placebo as a first‐line treatment. ²³ The primary end point was rPFS by BICR.

At the time of the first interim analysis, abiraterone plus niraparib significantly improved rPFS compared with abiraterone plus placebo in patients with HRRm (median rPFS, 16.5 vs. 13.7 months; HR, 0.73; 95% CI, 0.56–0.96) and in the BRCA1/2 subgroup (median rPFS, 16.6 vs. 10.9 months; HR, 0.53; 95% CI, 0.36–0.79). ²³ A preplanned multivariate analysis demonstrated that niraparib resulted in a significant OS benefit in those with BRCAm (median OS, 30.4 vs. 28.6 months; adjusted HR, 0.66; 95% CI, 0.46–0.95). ²⁵ Cytopenias were the most common AEs encountered in patients in the HRRm cohort who received niraparib (anemia, 52.4%; thrombocytopenia, 24.1%; neutropenia, 16%), with grade ≥3 anemia reported in 30.7% of patients. ²⁵ No benefit in the composite end point of time to prostate‐specific antigen progression and/or rPFS was seen among those with HRR‐proficient disease (HR, 1.09; 95% CI, 0.75–1.57). ²³ The results of this trial led to FDA approval of the combination of niraparib and abiraterone in August 2023 for patients with mCRPC with approval restricted to those harboring deleterious or suspected deleterious BRCAm. ³¹

Talazoparib with enzalutamide

The combination of talazoparib with enzalutamide was tested in the TALAPRO‐2 trial, a randomized, double‐blinded, placebo‐controlled, phase 3 trial with two cohorts. ²⁶ Cohort 1 was recruited first (n = 805) and included an all‐comer population of patients with mCRPC regardless of their HRRm status (HRRm‐positive [n = 169] or HRRm‐negative or unknown [n = 636]). All patients were prospectively assessed for HRRm status based on solid tumor testing. After the completion of recruitment in cohort 1, an additional 230 patients with HRRm (prospectively assessed) were enrolled. Cohort 2 comprised all patients with HRRm‐positive status (n = 399) who were enrolled in the study (n = 169 + 230). Patients in the treatment arm in both cohorts received enzalutamide with talazoparib (0.5 mg once daily). The primary end point was rPFS by BICR.

In cohort 1 (n = 805), the combination of talazoparib and enzalutamide significantly improved rPFS (median, NR vs. 21.9 months; HR, 0.63; 95% CI, 0.51–0.78). This improvement was consistent in the subgroup of patients with HRR deficiency (median rPFS, 27.9 vs. 16.4 months; HR, 0.46; 95% CI, 0.30–0.70) and those with nondeficient or unknown HRR status (median rPFS, NR vs. 22.5 months; HR, 0.70; 95% CI, 0.54–0.89). Although the results are not yet mature, no statistically significant improvement in OS was observed (HR, 0.89; 95% CI, 0.69–1.14). Anemia (66%), neutropenia (36%), and fatigue (34%) were the most common AEs in the treatment arm, with grade ≥3 anemia occurring in 46% of patients. ²⁶

In cohort 2 of patients with HRRm (n = 399), the combination of talazoparib with enzalutamide significantly improved rPFS over control (median rPFS, NR vs. 13.8 months; HR, 0.45; 95% CI, 0.33–0.61). ²⁷ No statistically significant improvement in OS was reported, although the trial has not yet sufficiently matured (HR, 0.69; 95% CI, 0.46–1.03). ²⁷ Based on these findings, the combination of talazoparib with enzalutamide was approved by the FDA for the treatment of patients with mCRPC and any HRRm in June 2023. ³²

Patient selection and future directions

With both ARPIs and PARPi single agents approved for treating patients with mCRPC, the question of whether to sequence ARPIs and PARPi or to combine them has emerged. The phase 2 BRCAAway trial (ClinicalTrials.gov identifier NCT03012321) randomized patients with BRCA1/2 and/or ATM alterations to receive olaparib monotherapy, abiraterone monotherapy, or the combination of olaparib and abiraterone in the first‐line mCRPC setting. ³³ Crossover was allowed from olaparib to abiraterone, and vice versa. The median PFS from randomization was 39 months in the combination arm of abiraterone plus olaparib, compared with 16 months for abiraterone followed by olaparib or olaparib followed by abiraterone. These data support the therapeutic strategy of an upfront combination of ARPI plus PARPi over the sequencing of these agents. Another pertinent question in clinical practice is the efficacy of PARPi in patients with HRR alterations other than BRCA1/2. The FDA conducted a pooled analysis to evaluate the efficacy of PARPi in individual HRR gene subsets. Although many of the subgroups of HRRm were not sufficiently powered for this analysis, the study reported a benefit of these agents that was greatest among patients harboring alterations in BRCA1/2, CDK12, and PALB2 and was more limited in those with ATM or CHEK2 alterations. ³⁴

As of this writing, PARPi are being investigated in an earlier hormone‐sensitive setting in combination with an ARPI in patients in different randomized phase 3 clinical trials (i.e., TALAPRO‐3, AMPLITUDE, EvoPAR‐PR01; ClinicalTrials.gov identifiers NCT04821622, NCT04497844, and NCT06120491, respectively; Table 3). Importantly, access to genetic testing is of utmost importance given these results. Between 2015 and 2022, 29.3% of patients with metastatic prostate cancer underwent next‐generation sequencing (27.1% in 2022); and Black patients, Hispanic patients, and those with low socioeconomic status or those covered by Medicaid, Medicare, or other government programs were less likely to be tested. Further efforts are needed to incorporate and increase access to tumor genomic testing as part of the standard‐of‐care management of patients with metastatic prostate cancer. ³⁵

TABLE 3.

Design of ongoing phase 3 studies assessing the combination of a poly(adenosine diphosphate ribose) polymerase inhibitor with an androgen receptor pathway inhibitor in patients with metastatic hormone‐sensitive prostate cancer.

	TALAPRO‐3	AMPLITUDE	EvoPAR‐PR01
ClinicalTrials.gov identifier	NCT04821622	NCT04497844	NCT06120491
Inclusion criteria	Patients with mHSPC harboring HRR alterations and no prior receipt of life‐prolonging systemic therapy for mHSPC, N = 599	Patients with mHSPC harboring HRR alterations, N ∼ 788	Patients with mHSPC, N ∼ 1800
Randomization and design	1:1 Phase 3 double‐blinded randomized study	1:1 Phase 3 double‐blinded randomized study	1:1 Phase 3 double‐blinded randomized study Two cohorts Cohort 1: Patients with HRRm (N ∼ 550) Cohort 2: Patients with non‐HRRm (N ∼ 1250)
Experimental arm	Talazoparib + enzalutamide	Niraparib + abiraterone	Saruparib (AZD5305) + physician's choice of ARPI (abiraterone, enzalutamide, or darolutamide)
Control arm	Placebo + enzalutamide	Placebo + abiraterone	Placebo + physician's choice of ARPI (abiraterone, enzalutamide, or darolutamide)
Primary end point	Investigator‐assessed rPFS	rPFS	Investigator‐assessed rPFS
Stratification factors	De novo status (de novo vs. relapsed mHSPC) Volume of disease (high vs. low) BRCA vs. non‐BRCA mutational status	Type of HRR alteration Prior docetaxel treatment Volume of disease	—
HRR genes tested	ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C	BRCA1, BRCA2, BRIP1, CHEK2, FANCA, PALB2, RAD51B, RAD54L	BRCA1, BRCA2, ATM, CDK12, PALB2, RAD51B, RAD51C, RAD51D, BARD1

Abbreviations: ARPI, androgen receptor pathway inhibitor; HRR, homologous recombination repair; HRRm, homologous recombination repair mutations; mHSPC, metastatic hormone‐sensitive prostate cancer; rPFS, radiographic progression‐free survival.

Key summary: mCRPC

For people with mCRPC and known HRRm, the combination of enzalutamide with talazoparib is a valid option for first‐line treatment. For those with BRCA1/2 mutations, combinations of abiraterone with either niraparib or olaparib are also available. For those who have more advanced disease and a known mutation in any of 14 prespecified HRR genes and who have received prior therapies, olaparib is available; whereas rucaparib is available for those with BRCA1/2 alterations specifically after prior treatment with ARPI and docetaxel.

INDICATIONS IN OVARIAN CANCER

In 2021, ovarian cancer (OC) was the fifth leading cause of cancer death among women of all ages in the United States. ⁸ Among patients with newly diagnosed, advanced disease, relapse occurs in up to 80% after initial cytoreductive surgery with neoadjuvant chemotherapy. ³⁶ Efforts to enhance long‐term first‐line treatment outcomes, such as weekly paclitaxel, intraperitoneal chemotherapy, and the use of bevacizumab, have seen limited success. ³⁷ , ³⁸ , ³⁹ , ⁴⁰ In this context, PARPi have garnered attention as important therapeutic modalities. Approximately 10%–20% of patients with OC carry pathogenic or likely pathogenic germline variants in the BRCA1 or BRCA2 genes, whereas around 50% exhibit somatic defects in the HRR pathway. These genomic characteristics are linked to a higher response rate to both platinum chemotherapy and PARPi. ⁴¹ Currently, three PARPi agents, olaparib, niraparib, and rucaparib, have received approval from the FDA as maintenance therapy in patients with advanced OC (Tables 4 and 5). ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ , ⁴⁶ , ⁴⁷ , ⁴⁸ , ⁴⁹ , ⁵⁰ , ⁵¹ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵

TABLE 4.

Summary of the SOLO1, PAOLA‐1, and PRIMA phase 3 trials assessing the use of poly(adenosine diphosphate ribose) polymerase inhibitor as a first‐line maintenance therapy in patients with ovarian cancer.

		SOLO1	PAOLA‐1	PRIMA
	ClinicalTrials.gov identifier	NCT01844986	NCT02477644	NCT02655016
	References	Moore 2018, 42 Banerjee 2021, 43 DiSilvestro 2023 44	Ray‐Coquard 2019, 45 2023 46 ; Gonzalez‐Martin 2022 47	Gonzalez‐Martin 2019, 48 2023 49
Study design	Inclusion criteria	Stage III/IV high‐grade EOC Prior cytoreductive surgery for stage III or biopsy/surgery for stage IV BRCA1/2m CR or PR on platinum‐based CT without bevacizumab	Stage III/IV high‐grade EOC No evidence of disease or CR or PR on 1L treatment with platinum–taxane CT + bevacizumab	Stage III/IV high‐grade EOC Visible residual tumor after primary debulking surgery or inoperable stage III CR or PR on 1L platinum‐based CT
	Randomization and design	2:1 Olaparib vs. placebo	2:1 Olaparib + bevacizumab vs. placebo + bevacizumab	2:1 Niraparib vs. placebo
	Primary end point	PFS by investigator assessment	PFS by investigator assessment	PFS by BICR
	Stratification factors	Clinical response (CR or PR) on platinum‐based CT	Outcome of 1L treatment BRCA status	Clinical response (CR or PR) on 1L platinum‐based CT Receipt of neoadjuvant CT HRD status

Patient population, no. (%)		Olaparib	Placebo	Olaparib + bevacizumab	Placebo + bevacizumab	Niraparib	Placebo
	No. of patients	260	131	537	269	487	246
	Age: Median [range], years	—	—	61 [32–87]	60 [26–85]	62 [32–85]	62 [33–88]
	CA‐125 level ≤ULN	247 (95.0)	123 (94.0)	463 (86.0)	234 (87.0)	465 (92.4)	226 (91.9)
	BRCA1/2m	260 (100.0)	131 (100.0)	161 (30.0)	80 (30.0)	—	—
	Primary tumor location: Ovary	220 (85.0)	113 (86.0)	456 (85.0)	238 (88.0)	388 (79.7)	201 (81.7)
	Serous histologic type	246 (95.0)	130 (99.0)	519 (97.0)	253 (94.0)	665 (95.5)	230 (93.5)
	FIGO stage III	220 (85.0)	105 (80.0)	378 (70.0)	186 (69.0)	318 (65.3)	158 (64.2)
	CR on platinum‐based CT	213 (82.0)	107 (82.0)	106 (20.0)	53 (20.0)	337 (69.2)	172 (70.0)
Outcomes	PFS: Median, months	56 vs. 13.8		22.9 vs. 16.6		13.8 vs. 8.2
	HR [95% CI]	0.33 [0.25–0.43]		0.63 [0.53–0.74]		0.66 [0.56–0.79]
	PFS in patients with BRCAm: Median, months	BRCA1: 41.4 vs. 13.8; BRCA2: NR vs. 13.8		60.7 vs. 21.7		31.5 vs. 11.5
	HR [95% CI]	BRCA1: 0.42 [0.31–0.57]; BRCA2: 0.25 [0.14–0.45]		0.45 [0.32–0.64]		0.45 [0.32–0.64]
	PFS in patients with HRD: Median, months	—		46.8 vs. 17.6		24.5 vs. 11.2
	HR [95% CI]	—		0.41 [0.32–0.54]		0.52 [0.40–0.68]
	OS: Median, months	NR vs. 75.2		56.5 vs. 51.6		— a
	HR [95% CI]	0.55 [0.40–0.76]		1.92 [0.76–1.12]		—
	p	.0004		.4118		—

Adverse events: Any grade/grade ≥3, %		Olaparib	Placebo	Olaparib + bevacizumab	Placebo + bevacizumab	Niraparib	Placebo
	Anemia	40/22	10/2	41/17	10/<1	65/32	20/2
	Neutropenia	23/9	12/5	18/6	16/3	43/21	8/2
	Thrombocytopenia	11/<1	4/2	8/2	3/<1	67/40	5/<1
	Fatigue	64/4	42/2	53/5	32/1	37/2	31/<1
	Nausea	78/<1	38/0	53/2	22/1	58/1	30/<1
Drug Approvals	FDA	Maintenance treatment of patients with advanced EOC and CR or PR on 1L platinum‐based treatment with germline or somatic BRCAm		Maintenance treatment of patients with advanced EOC and CR or PR on 1L platinum‐based treatment with HRD		Maintenance treatment of patients with advanced EOC and CR or PR on 1L platinum‐based treatment
	EMA	Maintenance treatment of patients with advanced EOC and CR or PR on 1L platinum‐based treatment with germline or somatic BRCAm		Maintenance treatment of patients with advanced EOC and CR or PR on 1L platinum‐based treatment with HRD		Maintenance treatment of patients with advanced EOC and CR or PR on 1L platinum‐based treatment

Abbreviations: 1L, first‐line; 2L, second‐line; BICR, blinded, independent central review; BRCAm, BRCA1/2 mutations; CA 125, cancer antigen 125; CI, confidence interval; CR, complete response; CT, chemotherapy; EMA, European Medicines Agency; EOC, epithelial ovarian cancer; FDA, US Food and Drug Administration; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; HRD, homologous recombination deficiency; NR, not reached; OS, overall survival; PFS, progression‐free survival; PR, partial response; ULN, upper limit of normal.

^a Data remain immature.

TABLE 5.

Summary of the SOLO2, NOVA, and ARIEL3 phase 3 trials assessing the use of poly(adenosine diphosphate ribose) polymerase inhibitor as maintenance therapy in patients with ovarian cancer beyond the first‐line setting.

		SOLO2	NOVA	ARIEL3
	ClinicalTrials.gov identifier	NCT01874353	NCT01847274	NCT01968213
	References	Pujade‐Lauraine 2017, 50 Poveda 2021 51	Mirza 2016, 52 2023 53	Coleman 2017, 2022 54 , 55
Study design	Inclusion criteria	Relapsed, high‐grade EOC ≥2L of platinum‐based CT and platinum‐sensitive disease BRCA1/2 mutations	EOC with high‐grade histologic features ≥2L of platinum‐based CT and platinum‐sensitive disease	High‐grade EOC ≥2L of platinum‐based CT and platinum‐sensitive disease Last platinum‐based regimen administered as a CT doublet for four or more cycles
	Randomization and design	2:1 Olaparib vs. placebo	2:1 Niraparib vs. placebo	2:1 Rucaparib vs. placebo
	Primary end point	PFS by investigator assessment	PFS by BICR	PFS by investigator assessment
	Stratification factors	Response to prior CT Length of platinum‐free interval	Time to progression after completion of the penultimate platinum regimen Best response to last platinum regimen (CR or PR) Prior bevacizumab	Progression‐free interval after penultimate platinum‐based regimen Best response to last platinum‐based regimen HRR gene mutation status

Patient population, no. (%)		Olaparib	Placebo	Niraparib a	Placebo a	Rucaparib	Placebo
	No. of patients	196	99	138	65	375	189
	Age: Median [range], years	56 [IQR, 51–63]	56 [IQR, 49–63]	57 [36–83]	58 [38–73]	61 [IQR, 53–67]	62 [IQR, 53–68]
	Primary tumor location: Ovary	164 (84.0)	86 (87.0)	—	—	312 (83.0)	159 (84.0)
	Serous histologic type	183 (93.0)	86 (87.0)	—	—	357 (95.0)	179 (95.0)
	International FIGO stage III	—	—	95 (68.8)	46 (70.8)	—	—
	CR on platinum‐based CT	91 (46.0)	47 (47.0)	71 (51.4)	33 (50.8)	126 (34.0)	64 (34.0)
	BRCA1/2m	190 (97.0)	96 (97.0)	138 (100.0)	65 (100.0)	130 (35.0)	66 (35.0)
Outcomes	PFS: Median, months	19.1 vs. 5.5		—		10.8 vs. 5.4
	HR [95% CI]	0.30 [0.22–0.41]		—		0.36 [0.30–0.45]
	p	< .0001		—		< .0001
	PFS in patients with BRCAm: Median, months	—		21.0 vs. 5.5		16.6 vs. 5.4
	HR [95% CI]	—		0.27 [0.17–0.41]		0.23 [0.16–0.34]
	p	—		< .001		< .0001
	PFS in patients with HRD: Median, months	—		12.9 vs. 3.8 b		13.6 vs. 5.4
	HR [95% CI]	—		0.38 [0.24–0.59]		0.32 [0.24–0.42]
	p	—		< .001		< .0001
	OS: Median, months	51.7 vs. 38.8		—		36.0 vs. 43.2
	HR [95% CI]	0.74 [0.54–1.00]		—		1.0 [0.81–1.22]
	p	.054		—		.96
	OS in patients with BRCAm: Median, months	52.4 vs. 37.4		40.9 vs. 38.1		45.9 vs. 47.8
	HR [95% CI]	0.71 [0.52–0.97]		0.85 [0.61–1.20]		0.83 [0.59–1.19]
	p	.031		—		.32
	OS in patients with HRD: Median, months	—		35.6 vs. 41.4 b		40.5 vs. 47.8
	HR [95% CI]	—		1.29 [0.85–1.95]		1.01 [0.77–1.32]
	p	—		—		.97

Adverse events: Any grade/grade ≥3, %		Olaparib	Placebo	Niraparib	Placebo	Rucaparib	Placebo
	Anemia	46/21	10/2	50/25	7/0	37/19	6/1
	Neutropenia	24/8	6/4	30/20	6/2	18/7	5/2
	Thrombocytopenia	17/3	4/1	61/34	6/<1	28/5	3/0
	Fatigue	67/6	39/2	59/8	41/<1	69/7	44/3
	Nausea	76/3	35/0	74/3	35/1	75/4	37/1
Drug approvals	FDA	Maintenance treatment of patients with recurrent EOC and CR or PR on 1L platinum‐based treatment with BRCAm		Maintenance treatment of patients with recurrent EOC and platinum‐sensitive disease with gBRCAm		Maintenance treatment of patients with recurrent EOC and platinum‐sensitive disease with BRCAm
	EMA	Maintenance treatment of patients with recurrent EOC and CR or PR on 1L platinum‐based treatment		Maintenance treatment of patients with recurrent EOC and CR or PR on platinum‐based treatment		Maintenance treatment of patients with recurrent EOC and CR or PR on platinum‐based treatment

Abbreviations: 1L, first‐line; 2L, second‐line; BICR, blinded, independent central review; CI, confidence interval; CR, complete response; CT, chemotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; EMA, European Medicines Agency; EOC, epithelial ovarian cancer; FDA, US Food and Drug Administration; FIGO, International Federation of Gynecology and Obstetrics; gBRCA1/2m, germline BRCA1/2 mutations; HR, hazard ratio; HRD, homologous recombination deficiency; HRR, homologous recombination repair; IQR, interquartile range; OC, ovarian cancer; OS, overall survival; PFS, progression‐free survival; PR, partial response.

^a gBRCAm cohort.

^b HRD without a BRCAm.

First‐line maintenance therapy

Meta‐analysis

A recent meta‐analysis extracted individual patient data from three major studies (PRIMA, PAOLA‐1, and VELIA; ClinicalTrials.gov identifiers NCT02655016, NCT02477644, and NCT02470585, respectively) evaluating PARPi as maintenance therapy for advanced OC. ⁴¹ Data from SOLO1 (ClinicalTrials.gov identifier NCT01844986), focusing exclusively on patients with gBRCAm disease, were analyzed separately with BRCAm subgroups from the other studies. Key findings demonstrated a significant PFS advantage for patients who received PARPi compared with placebo. In the combined analysis of the three studies, the median PFS was 20.4 months for the PARPi group versus 14.9 months for the placebo group (HR, 0.67; p < .001). At 1, 2, and 3 years, the proportion of patients remaining progression‐free was significantly higher in the PARPi group. Subgroup analyses demonstrated that PARPi significantly improved PFS in patients with BRCAm and HRD‐positive tumors, whereas no significant benefit was observed in patients with HRD‐negative tumors. Trial‐level analyses confirmed these findings across clinical and molecular subgroups, with PARPi providing significant PFS improvements in BRCAm, HRD‐positive, and clinically relevant populations, including those with different stages and residual disease after surgery.

Olaparib

In 2018, olaparib was granted approval by the FDA as maintenance therapy for patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer harboring deleterious or suspected deleterious gBRCAm or sBRCAm who had a complete response (CR) or a partial response (PR) to initial platinum‐based chemotherapy. ⁵⁶ In 2020, the approval was expanded to include the combination of olaparib and bevacizumab (an antivascular endothelial growth factor monoclonal antibody) as first‐line maintenance therapy in those with HRD‐positive status that includes either a deleterious or suspected deleterious BRCAm and/or genomic instability (Figure 2). ⁵⁷

In SOLO1, a randomized, double‐blinded, phase 3 trial, 391 patients with International Federation of Gynecology and Obstetrics (FIGO) stage III or IV, high‐grade, serous or endometrioid OC, primary peritoneal cancer, or fallopian tube cancer harboring gBRCAm or sBRCAm who had a PR or CR to frontline, platinum‐based chemotherapy received either olaparib (300 mg twice daily) or placebo for up to 2 years (off‐protocol olaparib was available beyond 2 years for patients who had a PR). ⁴² At a median follow‐up of 41 months, patients who received olaparib had a significant improvement in the median PFS (primary end point; investigator‐assessed) compared with the placebo arm (NR vs. 13.8 months; HR, 0.30; 95% CI, 0.23–0.41), with a 3‐year PFS rate of 60% vs. 27%. This benefit was consistent across both low‐risk and high‐risk groups. ⁵⁸ The PFS benefit remained consistent at a median follow‐up of 5 years, with a median PFS of 56.0 versus 13.8 months (HR, 0.33; 95% CI, 0.25–0.43). ⁴³ A prespecified long‐term analysis demonstrated a clinically meaningful improvement in the median OS with olaparib versus placebo (NR vs. 75.2 months, respectively; HR, 0.55; 95% CI, 0.40–0.76) after a median follow‐up of 7 years. ⁴⁴ The median time to first subsequent therapy was 64 versus 15.1 months, and the 84‐month time to first subsequent therapy rates were 45.3% versus 20.6% in the olaparib and placebo arms, respectively (HR, 0.37; 95% CI, 0.28–0.48). These data suggest a potentially higher fraction of patients who are cured with olaparib. The most common grade ≥3 AEs encountered with olaparib were anemia (21.9%) and neutropenia (8.5%). Health‐related quality of life (HRQoL) changes from baseline were similar between the two arms. ⁵⁹

Olaparib with bevacizumab

Similarly, PAOLA‐1 was a phase 3, double‐blinded trial in which 806 patients who had stage III or IV high‐grade serous or endometrioid OC, primary peritoneal cancer, or fallopian tube cancer and who had no evidence of disease or clinical CR or PR after first‐line platinum‐taxane chemotherapy and bevacizumab were randomized to receive maintenance therapy with bevacizumab combined with either olaparib (300 mg twice daily) or placebo. ⁴⁵ Patients were enrolled regardless of clinical risk, the presence of postsurgical residual disease, or the presence of HRD alteration (stratified by the presence of BRCAm). ⁴⁵ At a median follow‐up of 22.9 months, the median PFS (primary end point; investigator‐assessed) was significantly improved in the olaparib plus bevacizumab arm compared with the placebo plus bevacizumab arm at 22.1 versus 16.6 months, respectively (HR, 0.59; 95% CI, 0.49–0.72). This benefit was particularly pronounced in patients harboring BRCAm (HR, 0.31; 95% CI, 0.20–0.47) or who tested positive for HRD (HR, 0.33; 95% CI, 0.25–0.45) and was absent in those who tested negative for HRD (HR, 1.00; 95% CI, 0.75–1.35). Improvement in the median PFS was consistent across risk groups. ⁶⁰ The most common grade 3‐4 AEs that occurred more commonly in the olaparib plus bevacizumab arm were anemia (17%), lymphopenia (7%), and fatigue (5%). ⁴⁵ The 5‐year analysis of the trial demonstrated a clinically meaningful improvement in OS in the BRCAm (HR, 0.60; 95% CI, 0.39–0.93) and HRD‐positive (HR, 0.62; 95% CI, 0.45–0.85) subgroups (including BRCA and non‐BRCAm), but not in the HRD‐negative subgroup (HR, 1.19; 95% CI, 0.88–1.63). ⁴⁶ The global health status quality of life score was not different between the two treatment arms, with gains in time without significant symptoms of toxicity in the olaparib plus bevacizumab arm compared with the placebo plus bevacizumab arm. ⁴⁵ , ⁶¹

Niraparib

In 2020, the FDA granted approval for niraparib for the maintenance treatment of patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who have responded partially or completely to initial platinum‐based chemotherapy, regardless of HRD status. ⁶²

In the phase 3 PRIMA trial, 733 patients with advanced OC were randomized to receive either niraparib (200/300 mg twice daily based on body weight and platelet count) or placebo if they had a CR or PR after first‐line platinum‐based chemotherapy, irrespective of known or unknown HRD status (patients were stratified by HRD status). ⁴⁸ At a median follow‐up of 13.8 months, patients treated with niraparib had a significantly improved BICR‐assessed PFS in the HRD positive (defined as a BRCA alteration and/or a score ≥42 on the myChoice test [Myriad Genetics]) subgroup (primary end point; median PFS, 21.9 vs. 10.4 months; HR, 0.43; 95% CI, 0.31–0.59) as well as the overall population (co‐primary end point; median PFS, 13.8 vs. 8.2 months; HR, 0.62; 95% CI, 0.50–0.76). A long‐term analysis update revealed that the PFS benefit persisted even after a median follow‐up of 3.5 years. ⁴⁹ The HR for investigator‐assessed PFS comparing niraparib to placebo was 0.66 (95% CI, 0.56–0.79) in the ITT population (co‐primary end point), 0.52 (95% CI, 0.40–0.68) in patients who had tumors that tested positive for HRD (co‐primary end point), and 0.65 (95% CI, 0.49–0.87) in patients who had tumors that tested negative for HRD (subset analysis). The most common grade 3–4 AEs were thrombocytopenia (39.7%), anemia (31.6%), and neutropenia (21.3%). ⁴⁹ HRQoL was not different between the two arms. ⁶³ Similarly, PRIME (ClinicalTrials.gov identifier NCT03709316) was a trial with the same objectives in which 384 patients with advanced OC were randomized to niraparib or placebo in the same setting as the PRIMA trial. ⁶⁴ Eligibility was irrespective of HRD status or the presence of postsurgical residual disease. In the ITT population, the median PFS was improved with niraparib compared with placebo (HR, 0.45; 95% CI, 0.34–0.60). This benefit was consistent across HRD status and postsurgical residual disease subgroups.

Although niraparib‐based combinations are not approved as maintenance therapy to date, the single‐arm phase 2 OVARIO trial (ClinicalTrials.gov identifier NCT03326193) evaluated the safety and efficacy of niraparib plus bevacizumab in this setting. ⁶⁵ The trial included 105 patients with FIGO stage IIIB–IV ovarian, fallopian tube, or primary peritoneal cancer who had attempted debulking surgery and had a CR, PR, or no evidence of disease after first‐line platinum‐based chemotherapy and a minimum of three cycles of bevacizumab. The PFS rate at 18 months was the primary end point and was 62% (95% CI, 52%–71%) in the ITT population, 76% (95% CI, 61%–87%) in the HRD‐positive subgroup, and 47% (95% CI, 31%–64%) in the HRD‐negative subgroup. At a median follow‐up of 28.7 months, the median PFS was 19.6 months (95% CI, 16.5–25.1 months) in the ITT population and 28.3 months (95% CI, 19.9 months to not evaluated) in the HRD‐positive subgroup.

Rucaparib

ATHENA‐MONO (ClinicalTrials.gov identifier NCT03522246) was a randomized phase 3 trial that assessed the effectiveness of rucaparib monotherapy (600 mg twice daily) versus placebo in 538 patients with advanced OC who underwent cytoreductive surgery and responded to a platinum/taxane doublet. ⁶⁶ Patients were stratified by HRD status. The primary end point was PFS (investigator‐assessed according to Response Evaluation Criteria in Solid Tumors) in the HRD‐positive subgroup and the overall population. At a median follow‐up of 26.1 months, the median PFS was improved with rucaparib versus placebo in the HRD‐positive subgroup (28.7 vs. 11.3 months; HR, 0.47; 95% CI, 0.31–0.72) and in the overall ITT population (20.2 vs. 9.2 months; HR, 0.52; 95% CI, 0.40–0.68). This benefit was particularly pronounced in patients who had a deleterious BRCAm (HR, 0.40; 95% CI, 0.21–0.75) and was consistent in patients who had non‐BRCAm/HRD‐positive disease (high and low loss of heterozygosity scores) and those who had HRD‐negative disease. The most frequently encountered grade 3–4 AEs in the rucaparib arm were anemia (28.7%) and neutropenia (14.6%). Changes in patient‐reported outcomes (Functional Assessment of Cancer Therapy‐Ovarian Trial Outcome Index scores) were comparable between both arms.

Maintenance therapy in platinum‐sensitive recurrent disease

In patients with recurrent, platinum‐sensitive (defined as an objective response for >6 months), advanced OC, the FDA granted regulatory approval to olaparib (2017; later restricted to patients with BRCAm only), niraparib (2017; later restricted to patients with gBRCAm only), and rucaparib (2018; later restricted to patients with BRCAm only). ⁶⁷ , ⁶⁸ , ⁶⁹ , ⁷⁰ , ⁷¹

Meta‐analysis

In 2021, Lee et al. pooled the results of four randomized controlled trials (SOLO2, ARIEL3, NOVA, and Study 19; ClinicalTrials.gov identifiers NCT01874353, NCT01968213, NCT01847274, and NCT00753545, respectively) evaluating the efficacy of maintenance PARPi versus placebo in patients with high‐grade, recurrent, platinum‐sensitive OC. ⁷² In total, 1677 patients were included, focusing on subgroups based on HRR deficiency status, including the presence or absence of BRCAm. The analysis indicated that PARPi significantly improved PFS across all subgroups, with the greatest benefit observed in patients with BRCAm (gBRCAm and sBRCAm). Specifically, the pooled PFS HR for patients who had gBRCAm and sBRCAm was 0.27 (95% CI, 0.23–0.34), and there was no significant difference between germline and somatic mutations. In patients with HRR‐deficient tumors who did not harbor a BRCAm, the PFS HR was 0.41 (95% CI, 0.31–0.56), and, in those with HRR‐proficient tumors, it was 0.64 (95% CI, 0.49–0.83). Subgroup analyses demonstrated that the benefit of PARPi was consistent regardless of clinicopathologic characteristics, such as age, the number of prior platinum chemotherapy lines, and prior bevacizumab use. The platinum‐free interval also did not substantially alter the benefit of PARPi, although patients with a longer platinum‐free interval (>12 months) generally had better outcomes, particularly those with BRCAm or HRD tumors.

Olaparib

Study 19 was a phase 2 trial that involved the randomization of 265 patients who had recurrent, platinum‐sensitive OC to receive either maintenance olaparib (400 mg twice daily) or placebo until disease progression. ⁷³ The study met its primary end point, and there was an improvement in PFS among the ITT population with maintenance olaparib versus placebo (median PFS, 8.4 vs. 4.8 months; HR, 0.35; 95% CI, 0.25–0.49). A secondary analysis of this trial revealed a consistent PFS advantage with maintenance olaparib over placebo both in patients with BRCAm (HR, 0.18; 95% CI, 0.10–0.31) and those without BRCAm (HR, 0.54; 95% CI, 0.34–0.85). ⁷⁴ The most commonly reported AEs in the olaparib arm were nausea (68.4%), fatigue (48.5%), vomiting (31.6%), and anemia (16.9%). ⁷³ The results of the final analysis with 79% data maturity suggested an OS benefit observed with olaparib versus placebo in the ITT population (HR, 0.73; 95% CI, 0.55–0.95; p = .02138; the predetermined threshold for statistical significance was p < .0095), in the subgroup of patients with a BRCAm (HR 0.62, 95% CI 0.42–0.93, p = .0214) and in those without a BRCAm (HR, 0.84; 95% CI, 0.57–1.25; p = .397). ⁷⁵ It is worth mentioning that 23% of patients harboring a BRCAm subsequently received a PARPi upon progression. ⁷⁴

In the phase 3 SOLO2 trial, a cohort of 295 patients who had recurrent, platinum‐sensitive OC and harbored a gBRCAm underwent randomization to receive either maintenance olaparib (300 mg twice daily) or placebo until disease progression (patients with sBRCAm were eligible, but all randomized patients ended up harboring a gBRCAm). ⁵⁰ Patients were required to have received at least two platinum‐based regimens. At a median follow‐up of around 22 months, the primary end point of investigator‐assessed PFS was improved in the olaparib group compared with the placebo group (median PFS, 19.1 vs. 5.5 months; HR, 0.30; 95% CI, 0.22–0.41). Notably, the 24‐month PFS rate was 43% for the olaparib group and 15% for the placebo group. After a median follow‐up of around 65 months, the median OS was 51.7 months in the olaparib group compared with 38.8 months in the placebo group (HR, 0.74; 95% CI, 0.54–1.00), without adjustment for the 38% of patients in the placebo group who subsequently received PARPi therapy. ⁵¹ In a secondary analysis of the trial that accounted for subsequent PARPi therapy, the adjusted HR for OS was 0.56 (95% CI, 0.35–0.97). ⁵¹ Changes in the Functional Assessment of Cancer Therapy‐Ovarian Trial Outcome Index score were not different between the two arms. ⁷⁶ The most common grade 3–4 AEs in the olaparib group were anemia (19%), neutropenia (5%), and fatigue (4%). ⁵⁰

Based on the outcome data related to other PARPi as maintenance therapy in patients with recurrent, platinum‐sensitive OC (described below), the FDA restricted the use of olaparib to patients who harbor BRCAm. ⁷¹

Niraparib

In NOVA, a double‐blinded, phase 3 trial, in total, 553 patients with platinum‐sensitive, recurrent OC were enrolled, consisting of 203 individuals with a gBRCAm and 350 without. ⁵² Patients were eligible if they had previously received at least two platinum‐based regimens. They were randomly assigned to receive maintenance niraparib (300 mg once daily) or placebo. At a median follow‐up of 16.9 months, the primary end point of PFS displayed a significant improvement with maintenance niraparib across all three subgroups: patients with a gBRCAm (median PFS, 21.0 vs. 5.5 months; HR, 0.27; 95% CI, 0.17–0.41), patients without a gBRCAm (median PFS, 9.3 vs. 3.9 months; HR, 0.45; 95% CI, 0.34–0.61), and patients with HRD‐positive tumors without a gBRCAm (median PFS, 12.9 vs. 3.8 months; HR, 0.38; 95% CI, 0.24–0.59). This benefit was consistent among patients harboring a sBRCAm (HR, 0.27; 95% CI, 0.08–0.90), those testing positive for HRD but negative for a BRCAm (HR, 0.38; 95% CI, 0.23–0.63), and those testing negative for HRD (HR, 0.58; 95% CI, 0.36–0.92). The most common grade 3–4 AEs reported in the niraparib arm were thrombocytopenia (33.8%), anemia (25.3%), and neutropenia (19.6%). ⁵² Patient‐reported HRQoL outcomes were similar between the two arms. ⁷⁷ In the final analysis of the trial, accounting for missing survival data, the comparison of median OS with maintenance niraparib versus placebo resulted in an OS of 40.9 versus 38.1 months in the gBRCAm cohort (HR, 0.85; 95% CI, 0.61–1.20), 31.0 versus 34.8 months in the non‐gBRCAm cohort (HR, 1.06; 95% CI, 0.81–1.37), and 35.6 versus 41.4 months in the non‐gBRCAm, HRD‐positive cohort (HR, 1.29; 95% CI, 0.85–1.95). ⁵³ Although the NOVA trial was not designed to compare OS between the two groups, these findings raise concerns about a potential OS disadvantage for patients in the non‐gBRCAm and non‐gBRCAm, HRD‐positive subgroups. Consequently, maintenance therapy with niraparib beyond first‐line treatment has been limited to patients with platinum‐sensitive, recurrent OC who are positive for a gBRCAm. ⁶⁹

Rucaparib

ARIEL3 is a randomized, double‐blinded, placebo‐controlled, phase 3 trial that evaluated the efficacy of rucaparib (600 mg twice daily) versus placebo as maintenance therapy in patients with high‐grade, recurrent, platinum‐sensitive OC who had responded to second‐line or later platinum‐based chemotherapy. ⁵⁴ Rucaparib significantly prolonged median PFS compared with placebo across all primary analysis groups: in patients with a BRCAm (whether gBRCAm or sBRCAm; median PFS, 16.6 vs. 5.4 months; HR, 0.23; 95% CI, 0.16–0.34), patients who tested positive for HRD (high loss of heterozygosity regardless of BRCA mutation status; median PFS, 13.6 vs. 5.4 months; HR, 0.32; 95% CI, 0.24–0.42), and the overall ITT population (median PFS, 10.8 vs. 5.4 months; HR, 0.36; 95% CI, 0.30–0.45). The grade 3–4 AEs most commonly reported in the rucaparib group were anemia (19%) and increased liver enzymes (10%). ⁵⁴ In the final analysis, at a median follow‐up of 77 months, patients who received rucaparib did not achieve a significant OS benefit compared with those who received placebo in any of the groups (the trial was not powered to detect differences in OS): in patients with a BRCAm (median OS, 45.9 vs. 47.8 months; HR, 0.83; 95% CI, 0.58–1.19), patients who tested positive for HRD (median OS, 40.5 vs. 47.8 months; HR, 1.005; 95% CI, 0.77–1.32), and the ITT population (median OS, 36.0 vs. 43.2 months; HR, 0.995; 95% CI, 0.81–1.22). ⁷⁸ Of note, approximately 45% of patients in the placebo group received a PARPi upon progression. In light of those results, the FDA took action to restrict the use of maintenance rucaparib in the platinum‐sensitive setting for patients harboring a deleterious BRCAm only. ⁷⁹

Former indication for second‐line therapy onward

The FDA previously approved three PARPi—olaparib, niraparib, and rucaparib—for patients who have advanced OC with BRCAm or HRD‐positive tumors. ⁸⁰ , ⁸¹ , ⁸² , ⁸³ , ⁸⁴ , ⁸⁵ , ⁸⁶ , ⁸⁷ However, these approvals have been withdrawn. ⁸⁰ , ⁸¹ , ⁸² , ⁸³ , ⁸⁴ , ⁸⁵ , ⁸⁶ , ⁸⁷ Rucaparib was withdrawn after the phase 3 ARIEL4 trial (ClinicalTrials.gov identifier NCT02855944) demonstrated a potential detriment in OS compared with chemotherapy, and many patients did not receive subsequent treatments after progression. ⁸⁰ , ⁸¹ , ⁸² Similarly, approval of olaparib, originally based on the phase 2 Study 42 trial (ClinicalTrials.gov identifier NCT01078662), was retracted after the phase 3 SOLO3 trial (ClinicalTrials.gov identifier NCT00628251) demonstrated no significant OS or PFS benefit, with a post‐hoc analysis suggesting possible detriment in heavily pretreated patients. ⁸³ , ⁸⁴ , ⁸⁵ Approval of niraparib was withdrawn after the results of the phase 2 QUADRA study (ClinicalTrials.gov identifier NCT02354586), which demonstrated limited efficacy in later line treatments for HRD‐positive OC. ⁸⁶ , ⁸⁷ Consequently, none of these PARPi are now recommended for recurrent, platinum‐resistant OC in the United States.

Take‐home messages

Olaparib monotherapy is recommended as maintenance therapy after the completion of first‐line chemotherapy in patients who have advanced OC harboring a BRCAm and who have responded to front‐line, platinum‐based therapy. Olaparib plus bevacizumab is a reasonable alternative recommendation as a maintenance therapy after first‐line chemotherapy containing bevacizumab in patients with advanced OC characterized as HRD (inclusive of BRCA). Because they have not been directly compared together, currently, it is not clear which is the more appropriate strategy.

Niraparib monotherapy is indicated as maintenance therapy after the completion of first‐line chemotherapy in patients with advanced OC in response to platinum‐based chemotherapy regardless of HRD status, although the absolute benefit of treatment requires individual discussion regarding the risks and benefits. Whereas rucaparib as front‐line maintenance is not approved in the United States as of this writing, it is authorized by the European Medicines Agency's Committee for Medicinal Products for Human Use as of October 2023 for use as maintenance irrespective of HRD status. ⁸⁸ Olaparib, niraparib, and rucaparib are all reasonable to use as maintenance therapy for patients with recurrent OC harboring a BRCAm who have responded to platinum‐based chemotherapy. PARPi should not be used as a later line treatment for recurrent OC at this time.

INDICATIONS IN BREAST CANCER

In 2024, breast cancer remains the most frequent cancer and the second leading cause of cancer‐related deaths in women. ⁸ Alterations in BRCA1 and BRCA2 are associated with 35 and 25% of cases of hereditary breast cancer, respectively, and with 5%–10% of overall breast tumors. ⁸⁹ Hence, in recent years, investigators have assessed PARPi as a potential new therapeutic option in patients with breast cancer, either as adjuvant therapy or for patients with advanced disease (Table 6). ⁹⁰ , ⁹¹ , ⁹² , ⁹³ , ⁹⁴ , ⁹⁵ , ⁹⁶ , ⁹⁷

TABLE 6.

Summary of the OlympiA, OlympiAD, EMBRACA, and BROCADE3 phase 3 trials assessing the use of poly(adenosine diphosphate ribose) polymerase inhibitors in patients with breast cancer.

		OlympiA	OlympiAD	EMBRACA	BROCADE3
	ClinicalTrials.gov identifier	NCT02032823	NCT02000622	NCT01945775	NCT02163694
	References	Tutt 2021, 90 Geyer 2022 91	Robson 2017, 92 2019 93	Litton 2018, 94 2020 95	Diéras 2020, 96 2024 97
Study design	Inclusion criteria	High‐risk, HER2‐negative, early BC gBRCA mutations Prior definitive local treatment	HER2‐negative BC gBRCA mutation Prior progression on two or less CT regimens	HER2‐negative, locally advanced or metastatic BC gBRCA mutations Prior progression on three or less CT regimens	HER2‐negative, metastatic BC gBRCA mutations Prior progression on two or less CT regimens
	Randomization and design	1:1 Olaparib vs. placebo	2:1 Olaparib vs. physician's choice of CT (capecitabine, eribulin, or vinorelbine)	2:1 Talazoparib vs. physician's choice of CT (capecitabine, eribulin, gemcitabine, or vinorelbine)	2:1 Veliparib with carboplatin and paclitaxel vs. placebo with carboplatin and paclitaxel
	Primary end point	Invasive disease‐free survival by BICR	PFS by BICR	PFS by BICR	PFS by investigator assessment
	Stratification factors	CT type (neoadjuvant or adjuvant) Prior platinum‐based therapy Hormone receptor status	Prior CT for metastatic disease Prior platinum‐based therapy Hormone receptor status	Prior CT regimens Hormone receptor status Presence of CNS metastases	Prior platinum‐based therapy Hormone receptor status Presence of CNS metastases

Patient population		Olaparib	Placebo	Olaparib	Physician's choice of CT	Talazoparib	Physician's choice of CT	Veliparib + CT	Placebo + CT
	No. of patients	921	915	205	97	287	144	337	172
	Median age [range], years	42 [IQR, 36–49]	43 [IQR, 36–50]	44 [22–76]	45 [24–68]	45 [27–84]	50 [24–88]	47 [39–54]	45 [39–54]
	Hormone receptor‐positive, no. (%)	168 (18.2)	157 (17.2)	103 (50.2)	49 (50.5)	157 (54.7)	84 (58.3)	174 (52.0)	92 (53.0)
	Triple‐negative BC, no. (%)	751 (81.5)	758 (82.8)	102 (49.8)	48 (49.5)	130 (45.3)	60 (41.7)	163 (48.0)	80 (47.0)
	BRCA1 alteration, no. (%)	657 (71.3)	670 (73.2)	121 (59)	51 (52.6)	133 (46.3)	63 (43.8)	177 (53.0)	89 (52.0)
	BRCA2 alteration, no. (%)	261 (28.3)	239 (26.1)	88 (43)	46 (47.4)	154 (53.7)	81 (56.2)	167 (50.0)	86 (50.0)
	Prior platinum therapy, no. (%)	247 (26.8)	239 (26.1)	60 (29.3)	26 (26.8)	46 (16.0)	30 (20.8)	27 (8.0)	16 (9.0)
Outcomes	PFS: Median, months	85.9 vs. 77.1 a		7.0 vs. 4.2		8.6 vs. 5.6		14.5 vs. 12.6
	HR [95% CI]	0.58 [99.5% CI, 0.41–0.82]		0.58 [0.43–0.80]		0.54 [0.41–0.71]		0.71 [0.57–0.88]
	p	< .001		< .001		< .001		.0016
	OS: Median, months	89.8 vs. 86.4 b		19.3 vs. 17.1		19.3 vs. 19.5		32.4 vs. 28.2
	HR [95% CI]	0.68 [98.5% CI, 0.47–0.97]		0.90 [0.66–1.23]		0.85 [0.67–1.07]		0.92 [0.74–1.14]
	p	.009		.513		.17		.434

Adverse events: Any grade/grade ≥3, %		Olaparib	Placebo	Olaparib	Physician's choice of CT	Talazoparib	Physician's choice of CT	Veliparib + CT	Placebo + CT
	Anemia	24/9	4/<1	40/16	26/4	55/40	19/5	82/42	70/40
	Neutropenia	16/5	7/<1	27/9	50/26	36/22	43/35	89/81	92/84
	Thrombocytopenia	—	—	—	—	28/15	8/2	81/40	71/28
	Nausea	57/<1	23/0	58/0	35/1	50/<1	48/2	73/6	64/4
	Fatigue	40/2	27/<1	30/3	23/1	51/2	43/3	50/7	50/4
Drug approvals	FDA	Adjuvant treatment of high‐risk, HER2‐negative, early BC and gBRCA mutations		HER2‐negative, metastatic BC with gBRCA mutations		HER2‐negative, locally advanced or metastatic BC with gBRCA mutations		—
	EMA	Adjuvant treatment as monotherapy or in combination with endocrine therapy for high‐risk, HER2‐negative, early BC and gBRCA mutations		HER2‐negative, locally advanced or metastatic BC with gBRCA mutations		HER2‐negative, locally advanced or metastatic BC with gBRCA		—

Abbreviations: BICR, blinded, independent central review; BC, breast cancer; gBRCA, germline BRCA1/2 mutations; CI, confidence interval; CNS, central nervous system; CT, chemotherapy; EMA, European Medicines Agency; FDA, US Food and Drug Administration; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; IQR, interquartile range; OS, overall survival; PFS, progression‐free survival.

^a Three‐year invasive disease‐free survival (%).

^b Four‐year overall survival (%).

Adjuvant setting

Olaparib

The OlympiA trial (ClinicalTrials.gov identifier NCT02032823) was a randomized, double‐blinded phase 3 trial that investigated the efficacy of olaparib as an adjuvant therapy in patients with HER2‐negative early breast cancer displaying germline BRCA1/2 alterations and high‐risk clinicopathologic features. ⁹⁰ These patients previously underwent definitive local treatment and received neoadjuvant or adjuvant chemotherapy. They were randomized in a 1:1 ratio to receive one year of oral olaparib (300 mg twice daily) or placebo. The primary end point was invasive disease‐free survival, and secondary end points were OS, distant disease‐free survival, and safety.

The prespecified interim analysis indicated that patients who received olaparib had a 42% reduction in the risk of subsequent invasive disease or death compared with those who received placebo (HR 0.58, 99.5% CI 0.41–0.82). ⁹⁰ The 3‐year invasive disease‐free survival was 85.9% in the olaparib arm compared with 77.1% in the placebo arm (difference 8.8%, 95% CI 4.5–13). At a median follow‐up of 3.5 years, patients in the olaparib group had a significantly improved OS compared with those in the placebo group (HR 0.68; 98.5% CI 0.47–0.97). ⁹¹ Furthermore, the 4‐year distant disease‐free survival rate was significantly higher in the experimental group compared with the placebo group (86.5 vs. 79.1%, difference 7.4%, 95% CI 3.6–11.3%). ⁹¹ The most frequent AEs with olaparib were nausea (56.9%), fatigue (40.1%), and anemia (23.5%). ⁹⁰ Anemia was the most frequent grade ≥ 3 AE, occurring in 8.7% of patients receiving olaparib.

Based on the results of the OlympiA trial, olaparib was granted FDA approval in 2022 as adjuvant therapy in patients with high‐risk HER2‐negative early breast cancer harboring deleterious or suspected deleterious germline BRCA alterations and prior receipt of neoadjuvant or adjuvant chemotherapy. ⁹⁸

Metastatic setting

A recent meta‐analysis pooled the results of four trials evaluating the efficacy of PARPi, either alone or in combination with chemotherapy, against the physician's choice of treatment or placebo in patients with locally advanced or metastatic breast cancer harboring BRCAm. ⁹⁹ The efficacy of olaparib and talazoparib as single agents was assessed in the OlympiAD and EMBRACA trials, respectively (ClinicalTrials.gov identifiers NCT02000622 and NCT01945775, respectively), whereas the combination of veliparib with carboplatin and paclitaxel was tested in the BROCADE2 and BROCADE3 trials (ClinicalTrials.gov identifiers NCT01506609 and NCT02163694, respectively). This meta‐analysis included a total of 1540 patients with BRCA‐altered, advanced breast cancer and demonstrated that patients who received a PARPi had a 36% reduction in the risk of progression or death (pooled HR, 0.64; 95% CI, 0.56–0.74) compared with patients in the control arms. This superiority of PARPi was maintained across both combinatorial regimens (HR, 0.73; 95% CI, 0.60–0.88) and monotherapy arms (HR, 0.56; 95% CI, 0.46–0.68). Furthermore, OS was significantly improved in patients who received PARPi across the different trials (HR, 0.86; 95% CI, 0.74–0.99). In addition, based on the available data, PARPi showed comparable or superior quality‐of‐life outcomes compared with control groups in patients with BRCAm, advanced breast cancer.

Olaparib

In the setting of metastatic disease, OlympiAD was a randomized, double‐blinded, phase 3 trial that assessed olaparib in patients with metastatic, HER2‐negative breast cancer harboring germline BRCA1/2 alterations who had previously progressed on no more than two chemotherapeutic regimens. ⁹² Patients were randomized in a 2:1 ratio to receive either olaparib monotherapy (300 mg twice daily) or the physician's choice of chemotherapy (capecitabine, eribulin, or vinorelbine). The primary end point was PFS by BICR, and OS was a secondary end point.

Patients receiving olaparib had a 42% decrease in the risk of progression or death compared with those in the control arm (median, 7.0 vs. 4.2 months; HR, 0.58; 95% CI, 0.43–0.80). ⁹² At 76.8% maturity, there was a trend toward improved OS with olaparib; however, it did not reach statistical significance (median OS, 19.3 vs. 17.1 months; HR, 0.89; 95% CI, 0.67–1.18). ¹⁰⁰ In an exploratory analysis of patients who received olaparib as a first‐line treatment in the metastatic setting, the median OS was significantly longer compared with that in those who received the standard therapy (22.6 vs. 14.7 months; HR, 0.55; 95% CI, 0.33–0.95). ¹⁰⁰

The most frequent AEs with olaparib were nausea (58%), anemia (40%), and vomiting (32.2%). Grade ≥3 anemia occurred in 16.1% of patients. ⁹³

Based on the results of the OlympiAD trial, olaparib was approved in 2018 by the FDA for the treatment of patients who have HER2‐negative, metastatic breast cancer with deleterious or suspected deleterious gBRCA1/2m and prior exposure to chemotherapy either in the neoadjuvant, adjuvant, or metastatic setting. ¹⁰¹

Talazoparib

Another randomized phase 3 study was the EMBRACA trial, which investigated the efficacy of talazoparib in patients with HER2‐negative, locally advanced disease who were not candidates for curative treatment or those with metastatic breast cancer and gBRCA1/2m. ⁹⁴ Eligible patients had previously been treated with no more than three chemotherapeutic regimens in the metastatic setting. They were randomized in a 2:1 ratio to receive either talazoparib (1 mg once daily) or the physician's choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). The primary end point was PFS by BICR.

At the time of the primary analysis, patients receiving talazoparib had a 46% reduction in the risk of progression or death (median PFS, 8.6 vs. 5.6 months; HR, 0.54; 95% CI, 0.41–0.71). ⁹⁴ At a median follow‐up of 44.9 and 36.8 months in the talazoparib and control groups, respectively, the final OS analysis showed no significant improvement in the talazoparib arm (median OS, 19.3 vs. 19.5 months; HR, 0.85; 95% CI, 0.67–1.07). ⁹⁵ The cause of this, in part, may be that 32.6% of patients in the control group were subsequently treated with a PARPi because olaparib was approved in 2018, when the EMBRACA trial was still ongoing. ⁹⁵

The most frequently encountered AEs in the talazoparib group were anemia (54.9%), fatigue (51.4%), and nausea (49.7%). Grade ≥3 anemia occurred in 40.2% of patients. ⁹⁵

Based on the results of the EMBRACA trial, talazoparib was approved by the FDA in 2018 for the treatment of patients who have HER2‐negative, locally advanced or metastatic breast cancer with deleterious or suspected deleterious gBRCAm. ¹⁰²

Preclinical studies suggested a potentiation of platinum chemotherapy activity by concomitant use of PARPi; however, the implementation of this observation in clinical settings was limited by myelosuppression. ¹⁰³ , ¹⁰⁴ , ¹⁰⁵ Among PARPi, veliparib was the least likely to cause PARP trapping; thus it leads to less bone marrow cytotoxicity, ¹⁰⁶ , ¹⁰⁷ providing the rationale behind the BROCADE3 trial. This was a randomized, double‐blinded, phase 3 study that assessed the efficacy of veliparib in combination with carboplatin and paclitaxel in patients with HER2‐negative, locally advanced, unresectable or metastatic breast cancer and gBRCA1/2m previously treated with no more than two chemotherapy regimens. ⁹⁶ These patients were randomized in a 2:1 ratio to receive carboplatin and paclitaxel with either veliparib (120 mg twice daily) or placebo. Patients who progressed on the control treatment could crossover to receive veliparib monotherapy. Interestingly, patients could also stop chemotherapy and continue with either veliparib at the higher dose of 300–400 mg twice daily (40.4% of patients) or single‐agent placebo (33.7%). ¹⁰⁸ The primary end point was PFS.

The trial reported a significantly improved PFS in the veliparib group compared with the control group (median PFS, 14.5 vs. 12.6 months; HR, 0.71; 95% CI, 0.57–0.88). There was no statistical difference in OS between the two groups (median OS, 33.5 vs. 28.2 months; HR, 0.95; 95% CI, 0.73–1.23). ⁹⁶

The most frequent AEs in the veliparib arm were neutropenia (89%), thrombocytopenia (81%), and anemia (80%). Grade ≥3 neutropenia and anemia occurred in 81% and 42% of patients in the veliparib group, respectively. ⁹⁶

The lack of outcome results of the triplet versus chemotherapy alone without the subsequent veliparib monotherapy versus placebo monotherapy portion of the trial makes the true benefit of the combination of taxane, carboplatin, and veliparib challenging to estimate.

Future directions

PARPi have enlarged the therapeutic landscape for patients with localized or advanced breast cancer. Additional studies have further investigated these agents in an earlier setting. NeoTALA (ClinicalTrials.gov identifier NCT03499353) was a single‐arm, phase 2 trial that assessed the efficacy and safety of neoadjuvant talazoparib in patients with early stage, triple‐negative breast cancer harboring germline BRCA1/2 alterations. ¹⁰⁹ The pathologic CR rate was 49.2% by BICR and 47.5% by investigator assessment in the ITT cohort (n = 61). This did not meet the prespecified criteria for statistical significance. ¹⁰⁹ In more recent work, the addition of olaparib to carboplatin‐paclitaxel was also evaluated as a neoadjuvant treatment in patients with wild‐type germline BRCA1/2, triple‐negative breast cancer (n = 559) in the randomized phase 2/3 PARTNER trial (ClinicalTrials.gov identifier NCT03150576). ¹¹⁰ The pathologic CR rate was 51% in the olaparib arm and 52% in the control arm (p = .753), suggesting a limited benefit of adding olaparib in this setting. ¹¹⁰

In the metastatic setting, beyond patients who harbored germline BRCA1/2 alterations, PARPi were evaluated in multiple trials that included patients with HRR, non‐BRCA mutations. In the phase 2 Talazoparib Beyond BRCA trial (ClinicalTrials.gov identifier NCT02401347), the efficacy of talazoparib was investigated in patients with pretreated, advanced, HER2‐negative breast cancer or other solid tumors harboring HRR, non‐BRCA alterations. ¹¹¹ Interestingly, treatment‐associated tumor regression was observed in all patients with germline PALB2 mutations. TBCRC 048 (ClinicalTrials.gov identifier NCT03344965) was another phase 2 study that assessed olaparib in patients with metastatic breast cancer harboring germline non‐BRCA, homologous recombination‐related gene mutations (cohort 1) or somatic BRCA1/2 or homologous recombination, non‐BRCA mutations (cohort 2). ¹¹² The objective response rate (ORR) was 33% in cohort 1 and 31% in cohort 2. Specifically, patients with germline PALB2 alterations or somatic BRCA1/2 alterations had higher ORRs (82% and 50%, respectively), but no responses were observed in patients with ATM or CHEK2 alterations. These studies demonstrate that the efficacy of PARPi in patients with breast cancer could extend beyond those with germline BRCA1/2 alterations.

Although PARPi have demonstrated efficacy for the treatment of patients with germline BRCA alterations, resistance frequently develops. To overcome this, investigators sought to combine these agents with molecules that have nonoverlapping mechanisms of action. A previous report demonstrated that PARPi enhanced programmed cell death‐ligand 1 (PD‐L1) upregulation in breast cancer cells and led to an increased antitumor activity when combined with anti–PD‐L1 agents. ¹¹³ In this context, the MEDIOLA (ClinicalTrials.gov identifier NCT02734004) was a phase 1/2 trial that assessed the efficacy and safety of the combination of olaparib and durvalumab (anti–PD‐L1) in patients with HER2‐negative, metastatic breast cancer and germline BRCA1/2 alterations. ¹¹⁴ The ORR was 63.3%, and the median PFS was 8.2 months. The activity of olaparib with or without atezolizumab is currently undergoing investigation in a phase 2 trial in patients with advanced breast cancer harboring BRCAm (ClinicalTrials.gov identifier NCT02849496). In the primary analysis, the addition of atezolizumab to olaparib did not significantly improve PFS compared with single‐agent olaparib (median PFS, 7.7 vs. 7.0 months; p = .92). ¹¹⁵

In different combinations, multiple phase 1/2 studies are investigating the efficacy of the addition of PARPi to cyclin‐dependent kinase 4/6 inhibitors in different settings (ClinicalTrials.gov identifiers NCT04481113 and NCT05759546). In patients with metastatic, HER2‐positive breast cancer, a phase 1/2 study is also assessing the combination of niraparib with trastuzumab (anti‐HER2 monoclonal antibody) (ClinicalTrials.gov identifier NCT03368729).

Key summary

In breast cancer, patients with high‐risk, HER2‐negative early tumor and germline BRCA1/2 alterations can receive olaparib in the adjuvant setting after prior receipt of neoadjuvant or adjuvant chemotherapy. Furthermore, patients with HER2‐negative tumors harboring gBRCA1/2m can receive talazoparib in the locally advanced or metastatic setting or olaparib in the metastatic setting after prior exposure to chemotherapy in earlier settings or lines.

INDICATIONS IN PANCREATIC CANCER

Metastatic pancreatic cancer remains a lethal disease, with a median OS <1 year. ¹¹⁶ gBRCA1/2m are present in up to 7% of patients with metastatic pancreatic cancer. ¹¹⁷ In these patients, olaparib is the only PARPi approved.

Olaparib

POLO (ClinicalTrials.gov identifier NCT02184195) was the first randomized, double‐blinded, phase 3 trial that investigated maintenance therapy with olaparib in patients with metastatic pancreatic adenocarcinoma harboring germline BRCA1/2 alterations. ¹¹⁸ Eligible patients had to present with no evidence of disease progression after at least 16 weeks of platinum‐based chemotherapy administered in the first‐line setting. In this trial, 154 patients were randomly assigned 3:2 to receive either olaparib monotherapy (n = 92; 300 mg twice daily) or placebo (n = 62). The primary end point was PFS by BICR. At the time of the prespecified analysis, patients receiving olaparib had a 47% reduction in the risk of progression or death (median PFS, 7.4 vs. 3.8 months; HR, 0.53; 95% CI, 0.35–0.82). ¹¹⁸ At a median follow‐up of 31.3 months in the olaparib arm and 23.9 months in the placebo arm, no statistically significant difference in OS between the two arms was noted (median OS, 19.0 vs. 19.2 months; HR, 0.83; 95% CI, 0.56–1.22). ¹¹⁹ Among patients who survived for >2 years, those in the olaparib arm continued on study treatment for over three times longer than those in the placebo arm (25.9 vs. 7.3 months), potentially reflecting a distinct biologic subgroup of patients to be further investigated. ¹¹⁹ The most frequently encountered AEs with olaparib were nausea (48.9%), fatigue (46.7%), and diarrhea (37.8%). Anemia occurred in 32.2% of patients receiving olaparib, with grade ≥3 AEs encountered in 12.2% of patients. ¹¹⁹ Based on these results, the FDA approved olaparib in December 2019 as a maintenance therapy for patients with metastatic pancreatic adenocarcinoma harboring germline BRCA1/2 alterations whose disease has not progressed after at least 16 weeks of platinum‐based chemotherapy. ¹²⁰

Future directions

In the metastatic setting, another randomized phase 3 trial (ClinicalTrials.gov identifier NCT04300114) is investigating maintenance fluzoparib in patients with metastatic pancreatic ductal adenocarcinoma harboring germline BRCA1/2 or PALB2 alterations and no evidence of disease progression on platinum‐based chemotherapy. Furthermore, ongoing efforts aim to assess these agents in an earlier adjuvant setting and improve survival outcomes through PARPi‐based combinations. In the adjuvant setting, the APOLLO trial (ClinicalTrials.gov identifier NCT04858334) is a randomized, phase 2 study assessing olaparib versus placebo in patients who have germline or somatic BRCA1/2 or PALB2 mutations with prior receipt of neoadjuvant and/or adjuvant chemotherapy. Another nonrandomized phase 2 study (ClinicalTrials.gov identifier NCT02498613) is investigating the combination of cediranib, a vascular endothelial growth factor inhibitor, with olaparib in patients with solid tumors, including metastatic pancreatic ductal adenocarcinoma. These ongoing efforts aim to transition these agents into a more upfront setting and enhance therapeutic outcomes through combination regimens.

Key summary

In pancreatic cancer, patients who harbor gBRCA1/2m and have platinum‐sensitive, metastatic disease (i.e., absence of disease progression after ≥16 weeks of platinum‐based chemotherapy) can receive maintenance olaparib.

CONCLUSIONS

PARPi are important options in the therapeutic landscape of patients with prostate, ovarian, breast, and pancreatic cancers. Other clinical trials are also assessing these agents in different settings and cancers, including small cell lung cancer and metastatic colorectal cancer. ¹²¹ , ¹²² Despite their proven efficacy, PARPi have been associated with several AEs, including hematologic toxicities, such as a higher risk of developing myelodysplastic syndrome and acute myeloid leukemia. ¹²³ , ¹²⁴ Thus investigators are actively seeking new‐generation PARPi that could display a better safety profile.

Previous reports have indicated that the hematologic side effects of PARPi appear to arise from the inhibition of PARP2. ¹²⁵ An investigational PARPi, saruparib (AZD5305), has been designed to selectively inhibit PARP1. ¹²⁶ Preclinical studies have demonstrated that saruparib effectively inhibits cancer cell proliferation with minimal effects on hematologic functions. ¹²⁷ EvoPAR‐PR01 is a phase 3 trial assessing the efficacy of this PARPi in combination with an ARPI in patients with metastatic, hormone‐sensitive prostate cancer. Furthermore, PETRA (ClinicalTrials.gov identifier NCT04644068) is an ongoing phase 1/2 trial investigating saruparib as a single agent and in combination with other antineoplastic drugs in patients with advanced solid tumors. Meanwhile, PARPi, either as single agents or in different combinations, are likely to shape the treatment landscape of various solid malignancies for the foreseeable future.

CONFLICT OF INTEREST STATEMENT

Tony Crispino reports personal/consulting fees from EMMES Consulting and support for attending meetings and/or travel from Pfizer Inc. outside the submitted work. Talia Golan reports grants/contracts from AstraZeneca and MSD Merck; personal/consulting fees from AbbVie, AstraZeneca, and MSD Merck; support for other professional activities from AbbVie; and owns stock in CURESPONSE outside the submitted work. Jennifer K. Litton reports grants/contracts from AstraZeneca, EMD‐Serono, Genentech, GlaxoSmithKline, Merck, Novartis, Pfizer/Medivation, and Zenith outside the submitted work. Umang Swami reports grants from Janssen, Exelixis, and Astellas Pharma/Seattle Genetics, Exelixis, and Janssen; and honoraria from Adaptimmune, Astellas Pharma, AstraZeneca; Exelixis, Imvax, Pfizer Inc., Sanofi, and Seattle Genetics outside the submitted work. Kathleen N. Moore reports grants/contracts from Eli Lilly and Company, GlaxoSmithKline LLC, Merck, and PTC Therapeutics; and personal/consulting fees from Aadi, Adaptimmune, Alkermes Inc., Aravive, Artios, AstraZeneca, BioNTech, Blueprint Medicines Corporation, Boehringer Ingelheim, Caris, Celsion, Clovis Oncology Inc., Corcept Therapeutics, Daiichi Sankyo Inc., Duality Biologics, EISAI INC., Eli Lilly and Company, EMD Serono Inc., Elevar, Exelixis Inc., Genentech USA Inc., Genentech/Roche, GlaxoSmithKline, Hengrui, I‐MAB, Immunogen, InterVen Biosciences, InxMed, Jansen MacroGenics, Merck, Mereo BioPharma, Mersana, Novartis, Novocure Inc., Oasmia, OncoC4, Onconova, OncXerna Therapeutics, Regeneron Pharmaceuticals Inc., Schrodinger, Seagen Inc., Toray Industries, Trillium Therapeutics Inc., VBL Therapeutics, Verastem Inc., and Zentalis Pharmaceuticals outside the submitted work. Neeraj Agarwal reports institutional research funding from Arnivas, Astellas, AstraZeneca, Bavarian Nordic, Bayer, Bristol Meyers Squibb, Calithera, Celldex, Clovis Oncology, CRISPR Therapeutics, Eisai, Eli Lilly & Company, EMD Serono, Exelixis, Genentech, Gilead, GlaxoSmithKline, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon; and personal/consulting fees or honoraria from Astellas, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis Oncology, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics outside the submitted work. The remaining authors disclosed no conflicts of interest.

Hage Chehade C, Gebrael G, Sayegh N, et al. A pan‐tumor review of the role of poly(adenosine diphosphate ribose) polymerase inhibitors. CA Cancer J Clin. 2025;75(2):141‐167. doi: 10.3322/caac.21870