Sustained benefit of adjuvant olaparib in women with germline BRCA1- and BRCA2- -associated high-risk HER2-negative early breast cancer: Updated results from the OlympiA phase III trial

Abstract

Background:

The randomised phase III OlympiA trial (NCT02032823) compared 1 year of adjuvant olaparib (oral poly-(ADP-ribose) polymerase [PARP] inhibitor) to placebo in 1,836 patients with pathogenic/likely pathogenic BRCA1 or BRCA2 (gBRCApv) germline variants and high-risk human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (BC). Previous interim analyses (IA) demonstrated statistically significant improvements in invasive disease-free survival (IDFS), distant disease-free survival (DDFS) and overall survival (OS), irrespective of hormone receptor status, prior platinum, timing of prior chemotherapy or type of gBRCApv. Herein are the results of the third pre-specified IA with a median follow-up (MFU) of 6.1 years.

Patients and methods:

Descriptive analyses are presented for the primary endpoint IDFS, and key secondary endpoints of DDFS and OS. Estimates of the hazard ratio (HR) based on the stratified Cox’s Proportional Hazards Model and 95% confidence intervals (CI) are presented with yearly event rates up to 6.1 years MFU. Safety analyses included AESIs.

Results:

Olaparib benefits were maintained in IDFS [HR=0.65 (95% CI: 0.53, 0.78)], DDFS [HR=0.65 (95% CI: 0.53, 0.81)] and OS [HR=0.72 (95% CI: 0.56, 0.93)]. The 6-year OS for olaparib vs. placebo was 87.5% vs. 83.2% [Difference 4.4% 95% CI: 0.9%, 6.7%]. Olaparib benefit was consistent across all key subgroups, including patients with high-risk hormone receptor-positive disease. There were fewer BRCA-associated new breast and ovarian/fallopian tube cancers and no increase in AESI risks (6.3% versus 9.3%), including myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) (0.4% versus 0.7%), with olaparib versus placebo.

Conclusions:

At 6.1 years MFU, 1 year of adjuvant olaparib after (neo)adjuvant chemotherapy demonstrates ongoing clinically meaningful improvements in IDFS, DDFS and OS in patients with gBRCApv and high-risk, HER2-negative early BC, with acceptable toxicity and without increased risk of MDS/AML. These data continue to provide support for adjuvant olaparib in the treatment of gBRCApv-associated high-risk, HER2-negative early BC.

INTRODUCTION

BRCA1 and BRCA2 (BRCA1/2 ) play critical roles in the homologous recombination repair pathway, which is essential for the accurate repair of double-strand DNA breaks.^1–3 The homologous recombination pathway is impaired in the tumours of individuals with germline BRCA pathogenic variants (gBRCApv), making these cells unable to efficiently repair lesions created by the inhibition and trapping of oral poly-(ADP-ribose) polymerase (PARP).^4,5–7 This causes replication fork collapse and double-strand breaks, which are repaired through error-prone pathways in BRCA-deficient tumour cells causing genomic instability and cell death.⁷

The clinical activity of olaparib and talazoparib, which inhibit and trap PARP, for the treatment of BRCA-associated metastatic breast cancer (BC) in the OlympiAD and EMBRACA trials led to their approval for this indication.^{8, 9} Ongoing research in advanced BC is focusing on understanding and tackling resistance mechanisms,¹⁰ and the design of potential combination therapy strategies to improve efficacy.

OlympiA is a phase III, randomised, double-blinded, placebo-controlled clinical trial that examines the efficacy of 1 year of adjuvant olaparib in patients with high-risk gBRCA1/2pv-associated early BC. The trial enrolled 1,836 eligible individuals from 2014 to 2019. The first pre-specified interim analysis (IA1) of the primary endpoint, invasive disease-free survival (IDFS), was reported with median follow-up (MFU) of 2.5 years, demonstrating statistically significant improvement in IDFS in the olaparib group compared to the placebo group (hazard ratio [HR] 0.58; 99.5% confidence intervals [CI] 0.41 to 0.82; p<0.001) and distant disease-free survival (DDFS) (HR 0.57; 99.5% CI 0.39 to 0.83; p<0.001) with absolute improvements at 3 years in IDFS of 8.8% and DDFS of 7.1%.¹¹ Although the absolute number of deaths was lower in the olaparib group versus placebo (59 versus 86), the reduction in the risk of death in the olaparib arm compared with the placebo arm (HR 0.68; 99% CI 0.44 to 1.05; p=0.02) did not then meet the pre-specified boundary for statistical significance for OS (p<0.01). Subgroup analyses were consistent with overall results, and the safety analysis identified no evidence of increased risk of acute myeloid leukaemia or myelodysplastic syndrome (AML/MDS).

The second pre-specified interim analysis (IA2) took place at 3.5 years MFU, demonstrating statistically significant improvement in OS (HR 0.68; 98.5% CI 0.47 to 0.97; p=0.009) with 4-year OS of 89.8% in the olaparib group compared to 86.4% in the placebo group (difference 3.4%; 95% CI −0.1% to 6.8%).¹² The benefit was maintained for olaparib compared to the placebo group for both 4-year IDFS (82.7% versus 75.4%; difference 7.3%; 95% CI 3.0% to 11.5%) and 4-year DDFS (86.5% versus 79.1%; difference 7.4%; 95% CI 3.6% to 11.3%). While gBRCA1pv-associated tumours are most often triple negative BC (TNBC), and gBRCA2pv-associated tumours are most often hormone receptor-positive, HER2-negative, with molecularly high-risk features in prognostic assays,^{13, 14} the initial OlympiA findings demonstrated consistent outcomes across subgroups, irrespective of hormone receptor status, prior platinum administration, timing of prior chemotherapy (neoadjuvant or adjuvant) or type of germline pathogenic variant.

The current report includes descriptive analyses at the third pre-specified IA (IA3) at 10 years after first patient enrolment, now with 6.1 years MFU. It evaluates the stability of efficacy endpoints and longer-term toxicities and examines exploratory data on second malignancies in the olaparib and placebo groups occurring during follow-up.

PATIENTS AND METHODS

Study design and patient population

The details of the study design and populations for the primary and secondary efficacy endpoints, as well as safety, are described in the report of the first interim analysis.¹¹ The protocol was approved by the institutional review board of each participating centre. The study met the requirements of the Declaration of Helsinki.¹⁵ Written informed consent was provided by all participants. AstraZeneca provided all doses of olaparib and placebo.

In brief, eligible participants with high-risk HER2-negative primary BC and gBRCA1/2pv were identified by germline testing locally or centrally (see Table 1). Consented participants were randomised to receive 1 year of study medication either as oral olaparib 300 mg BID or matching placebo. Stratification was based on tumour hormone receptor status, prior neoadjuvant chemotherapy (NACT) versus adjuvant chemotherapy (ACT), and platinum therapy for current BC (yes versus no). Eligible participants received at least six cycles of ACT or NACT containing a taxane, an anthracycline or both, and had completed surgery and adjuvant radiation if indicated as per local standards at least 2 weeks before randomisation. Patients receiving NACT were ineligible to receive ACT.

Table 1.

Demographic and baseline disease characteristics of the patients^a

Characteristic	Olaparib (n=921)	Placebo (n = 915)
Age, years — median (interquartile range)	42 (36–49)	43 (36–50)
gBRCA P/LP variant — n (%)b
BRCA1	656 (71.2)	669 (73.1)
BRCA2	260 (28.2)	238 (26.0)
BRCA1 and BRCA2	2 (0.2)	5 (0.5)
No gBRCA P/LP variant	2 (0.2)	3 (0.3)
Missing	1 (0.1)	0 (0.0)
Prior adjuvant/neoadjuvant chemotherapy — n (%)
Adjuvant	461 (50.1)	455 (49.7)
Neoadjuvant	460 (49.9)	460 (50.3)
Anthracycline and taxane regimen	871 (94.6)	849 (92.8)
Anthracycline regimen (without taxane)	7 (0.8)	13 (1.4)
Taxane regimen (without anthracycline)	43 (4.7)	52 (5.7)
Regimen not reported	0 (0.0)	1 (0.1)
<6 cycles of (neo)adjuvant chemotherapy	7 (0.8)	13 (1.4)
Platinum-based (neo)adjuvant therapy — n (%)
No	674 (73.2)	677 (74.0)
Yes	247 (26.8)	238 (26.0)
Concurrent hormone therapy (hormone receptor-positive only) — n (%)	146/168 (86.9)	146/157 (93.0)
Hormone receptor status — n (%)c
Hormone receptor-positive/HER2-negatived	168 (18.2)	157 (17.2)
Triple-negative breast cancere	751 (81.5)	758 (82.8)
Menopausal status (females only) — n (%)
Premenopausal	572/919 (62.2)	552/911 (60.6)
Postmenopausal	347/919 (37.8)	359/911 (39.4)
Primary breast cancer surgery — n (%)
Mastectomy	699 (75.9)	673 (73.6)
Conservative surgery only	222 (24.1)	240 (26.2)
Missing	0 (0.0)	2 (0.2)

P/LP, pathogenic or likely pathogenic; IHC, immunohistochemistry; HER2, human epidermal growth factor receptor 2.

^aFurther information on baseline characteristics is provided in Supplementary Appendix (SA) Table S2. Percentages may not total 100 because of rounding.

^bFor a detailed description of local and central Myriad BRCA testing in patients enrolled in the trial, see SA Figure S2. Variant interpretation by Myriad Genetics (BRCAnalysis) (1649 patients) and BGI Genomics (247 patients) was performed with the use of multiple established databases (e.g., ClinVar, ClinGen and ENIGMA) and published and internal functional and clinical data, compliant with American College of Medical Genetics published guidelines. 85 patients randomised in China had variant interpretation by both BGI Genomics and Myriad Genetics. The 24 pathogenic or likely pathogenic variants from local laboratories without central Myriad confirmation were confirmed by the OlympiA genetics advisory committee with the use of published databases as above. Discordant data are referred to SA Figure S2. Listing of pathogenic or likely pathogenic BRCA1 and BRCA2 variants that occurred in more than 1 patient have previously been reported.¹¹

^cHormone-receptor status was defined by local test results.

^dThe original protocol that was activated in 2014 was developed for HER2-negative patients but included only patients with triple-negative breast cancer. When the safety rationale with respect to recurrence risk relative to combination therapy with olaparib and endocrine therapy was accepted, the protocol was amended in 2015 to include patients with high-risk, hormone receptor-positive disease and to increase the sample size to the current number of 1,800 patients (see the protocol). The first patient with hormone receptor-positive disease was enrolled in December 2015.

^eTriple-negative breast cancer was defined in the eligibility criteria as oestrogen receptor-negative and progesterone receptor-negative, as indicated by IHC nuclear staining of <1%, and HER2-negative (not eligible for anti-HER2 therapy), as indicated by one of the following: an IHC score of 0 or 1+; an IHC score of 2+ and HER2-nonamplified disease on in situ hybridisation with a ratio of <2.0 and, if reported, an average HER2 copy number of <4 signals per cell; or HER2-nonamplified disease on in situ hybridisation with a ratio <2.0 and, if reported, an average HER2 copy number <4 signals per cell (without IHC). Two patients (both in the olaparib group) were excluded from the summary of the subgroup with triple-negative breast cancer because they did not have confirmed HER2-negative status.

Eligible patients with TNBC included patients who had residual invasive cancer in the breast or axillary nodes after NACT, and those who had received ACT for node-positive disease or for node-negative disease with a primary tumour >2 cm at surgery. Given concerns regarding the potential risks associated with olaparib, patients with hormone receptor-positive (cutoff point for positivity, >1%), HER2-negative tumours were required to have a recurrence risk comparable to that of patients with TNBC based on globally applicable criteria. The selected criteria were clinical and pathological stage, plus an oestrogen receptor and nuclear grade (CPS+EG) score of ≥3 following NACT or ≥4 positive nodes at initial surgery. Adjuvant endocrine therapy as indicated locally was planned for at least 5 years, initially concurrent with study medication. Adjuvant denosumab and bisphosphonates were permitted as per the investigator’s discretion and local practice.

Endpoints and assessments

The primary endpoint of IDFS was defined in accordance with the Standardised Definitions for Efficacy End Points (STEEP) system,¹⁶ as the time from randomisation until the date of first occurrence of one of the following events: ipsilateral invasive breast tumour, regional invasive BC recurrence, distant recurrence, contralateral invasive BC (CIBC), second primary non-breast invasive cancer or death from any cause. Patients with no documented IDFS event were censored at the date they were last known to be disease-free. Secondary endpoints include DDFS (time from randomisation until documented evidence of first distant recurrence of BC or death) and OS (defined as time from the date of randomisation until time of death from any cause).

Efficacy analyses were based on the intention-to-treat (ITT) population. Survival functions were estimated by the Kaplan–Meier method. The stratified Cox proportional hazards model was used to estimate HRs and CIs. Safety was assessed in the population who received at least one dose of study medication.

A total of 1,800 patients were to be randomised into the study to achieve 330 IDFS events. If the true HR for the comparison of olaparib versus placebo in terms of IDFS was 0.7, then with 330 events, the analysis would have 90% power to demonstrate a statistically significant difference in IDFS, assuming a 2-sided 5% significance level. Four analysis time points were pre-planned, with a hierarchical multiple testing procedure to strongly control type 1 error across analysis timepoints and endpoints (Supplementary Appendix [SA] Table S1). As previously reported, IA1 was triggered when 165 IDFS events were observed in the first 900 patients randomised. Superiority boundaries were p<0.005 for IDFS, followed by p<0.005 for DDFS, and p<0.01 for OS (SA Table S1). Superiority boundaries for both IDFS and DDFS were crossed, but not for OS. The second pre-specified interim analysis (IA2) of OS was triggered by 330 IDFS events in the ITT population. This third pre-specified analysis (IA3) was scheduled to occur 10 years after the first patient was randomised. As the pre-specified significance boundaries were crossed at IA1 for IDFS and DDFS, and at IA2 for OS, no further significance testing was performed for the analysis of IDFS, DDFS and OS at the time of IA3; all treatment estimates (HRs and 95% CIs) are presented descriptively.

RESULTS

Patients

A total of 1,836 patients were enrolled and randomly assigned to receive either placebo or olaparib 300 mg twice daily. The data cut-off for IA3 occurred on 5 June 2024, 10 years after the first patient was randomised. MFU at this point was 6.1 years (interquartile range [IQR] 5.1–7.4 years) in the ITT population with maximum follow-up of 9.6 years, 6.3 years (IQR 5.1–7.5 years) in the TNBC cohort and 5.7 years (IQR 5.1–6.6 years) in the hormone receptor-positive cohort. This IA provides an additional 2.6 years of follow-up since the previous analysis.¹²

Following randomisation, the assigned therapy was not received by 10 patients in the olaparib group and 11 in the placebo group (SA Figure S1). The two groups were balanced for the characteristics presented in Table 1 and SA Table S2, which include patient baseline characteristics, other tumour features, radiation treatment and additional pathology details. Eligibility requirements for patients with hormone receptor-positive BC included high pathologic stage, which contributed to the predominance of patients with TNBC and, therefore, of patients with gBRCA1pv.

gBRCApv were distributed evenly between the treatment groups. Seven patients had both a gBRCA1pv and a gBRCA2pv. The cohort was nearly evenly divided between those receiving ACT and NACT; most (93.7%) received both anthracycline and taxane chemotherapy. A platinum agent was also received by 26.4% of patients, most often as NACT. OlympiA fully enrolled before pembrolizumab was licensed as neoadjuvant therapy in breast cancer so no patients received this drug.

Efficacy

With an additional 2.6 years of follow-up since IA2, the olaparib benefit on the primary endpoint IDFS is maintained. The 6-year IDFS was 79.6% in the olaparib group and 70.3% in the placebo group (difference 9.4%; 95% CI 5.1% to 12.7%) with an HR of 0.65 (95% CI 0.53 to 0.78) (Figure 1A). All first IDFS event frequencies, including local, regional and distant recurrences, as well as central nervous system recurrences, remain lower in the olaparib group (SA Table S3).

Figure 1. Kaplan-Meier estimates of survival.

In accordance with the standardized definitions for efficacy end points (STEEP) system, the primary end point of invasive disease–free survival (FIG 1A) was defined as the time from randomisation until the date of one of the following events: ipsilateral invasive breast tumour, locoregional invasive disease, distant recurrence, contralateral invasive breast cancer, second primary invasive cancer, or death from any cause. Data for patients without a documented event of invasive disease or death were censored at the date they were last known to be disease-free.

Distant disease–free survival (FIG 1B) was defined as the time from randomisation until documented evidence of first distant recurrence of breast cancer or death. Distant recurrence includes the following events: distant recurrence (metastatic breast cancer that has either been biopsy confirmed or radiologically diagnosed as recurrent invasive breast cancer); death attributable to any cause, including breast cancer, non-breast cancer, or unknown cause; and second primary non-breast invasive cancer. Evidence of distant recurrence requires either radiologic examination or histopathological confirmation by biopsy.

Overall survival (FIG 1C) was defined as the time from the date of randomisation until death due to any cause (see SA Table S4 for primary cause of death).

For invasive disease–free survival, distant disease–free survival and Overall survival, 95% confidence intervals only are shown for the hazard ratios as these results are descriptive.

Based on the pooling strategy for stratification factors described in Section 2 in the Supplementary Appendix, the primary stratified Cox proportional hazards model of IDFS, DDFS and OS were based on the stratification factor of hormone-receptor status and chemotherapy timing only. The event-free rates at 12, 24, 36, 48, 60 and 72 months in each group are displayed above and below the curves.

Similarly, sustained benefit from olaparib was observed for DDFS. There were 142 (15.4%) distant recurrences in the olaparib group and 207 (22.6%) in the placebo group with HR 0.65 (95% CI 0.53 to 0.81). DDFS at 6 years was 83.5% in the olaparib group and 75.7% in the placebo group (difference 7.8%; 95% CI 3.8% to 11.5%) (Figure 1B).

With additional follow-up, OS remains superior for the olaparib group at 6 years, with 87.5% versus 83.2% for the placebo group (difference 4.4%; 95% CI 0.9% to 6.7%) and a HR of 0.72 (95% CI 0.56 to 0.93) (Figure 1C). The cause of death was mainly due to BC recurrence and is presented in SA Table S4.

Subgroup analyses of IDFS across the stratification groups (NACT versus ACT, prior platinum administration and hormone receptor status), and gBRCA1pv or gBRCA2pv groups are generally consistent with the olaparib benefit observed in the overall results without evidence of heterogeneity (Figure 2A¹⁷, SA Figure S3, SA Table S5). Subgroup analyses were similarly consistent for olaparib versus placebo in DDFS (Figure 2B, SA Table S6) and OS (Figure 2C, SA Table S7) for prior chemotherapy (NACT versus ACT), prior platinum, hormone receptor status and gBRCA1pv compared to gBRCA2pv.

Figure 2. Subgroup analyses.

Forest plots for invasive disease–free survival, distant disease–free survival, and overall survival are shown in Figures 2A, 2B and 2C respectively.

The solid vertical line indicates the overall hazard-ratio estimate, and the dashed vertical line indicates a hazard ratio of 1.00, as recommended by Cuzick.¹⁷ The size of the blue squares corresponds to the number of events contributing to the estimate of the treatment effect.

BRCA mutation data reflect central Myriad testing results only.

Secondary objectives also include assessment of the effect of olaparib on the incidence of CIBC (SA Figure S4), contralateral non-invasive BC (CNBC), ovarian cancer (SA Figure S5), and fallopian tube cancer (SA Figure S6). No primary peritoneal cancers were reported in either group. The number of bilateral mastectomies and risk-reducing fallopian tube and ovarian surgeries performed before randomisation is similar between the two groups. Fewer BRCA-associated new invasive BC (34 versus 42) were reported after randomisation to olaparib versus placebo. Among the 1,176 patients without bilateral mastectomies prior to randomisation, the incidence of CIBC, accounting for competing risks of post-randomisation bilateral mastectomies or death, is illustrated in SA Figure S4. The HR accounting for competing risks for the incidence of CIBC is 0.83 (95% CI: 0.52 to 1.32). At 6.1 years MFU, there were too few CNBC, ovarian and fallopian tube cancers to generate the HR and associated CI (as per the statistical analysis plan, >=5 events per arm were required). In supplemental Figures S5 and S6, the cumulative incidence of salpingo-oophorectomies and salpingectomies is plotted, as is the cumulative incidence of ovarian and fallopian tube malignancies.

Safety

By the time of IA2, all 1,815 patients had completed their protocol-specified course of olaparib or placebo (911 in the olaparib group and 904 in the placebo group). Therefore, summaries of exposure data and on-treatment adverse events remain unchanged since previously reported.¹²

Adverse events of special interest (AESIs) included pneumonitis, AML/MDS and new primary malignancies other than AML/MDS. No AESIs were reported to occur more frequently in the olaparib group than in the placebo group. From the start of the study to IA3, there were four cases (0.4%) of AML/MDS in the olaparib group and six (0.7%) in the placebo group, an increase from two cases on olaparib and three on placebo at IA2. There were nine (1.0%) cases of pneumonitis in the olaparib group and 13 (1.4%) in the placebo group, all of which had occurred by IA2 except one new case in the placebo group (Table 2 and SA Table S8).

Table 2.

Fatal adverse events and adverse events of special interest

	Olaparib (n=911)	Placebo (n = 904)
AE leading to death — n (%)a	5 (0.5)	10 (1.1)
AESI at any time — n (%)	57 (6.3)	84 (9.3)
On treatment AESIsb	14 (1.5)	28 (3.1)
AESI >30 days after last dose	44 (4.8)	57 (6.3)
MDS/AML	4 (0.4)	6 (0.7)
Pneumonitis	9 (1.0)	13 (1.4)
New primary malignancy	45 (4.9)	68 (7.5)

AE, adverse event; AESI, adverse event of special interest; AML, acute myeloid leukaemia; MDS myelodysplastic syndrome.

^aSee Table S9 in the supplementary appendix (S9: Summary of fatal AEs).

^bNo patients were still on treatment at the second pre-specified interim analysis.

New primary malignancies collected as AESIs after randomisation were reported for 45 patients (4.9%) in the olaparib group and 68 patients (7.5%) in the placebo group (SA Table S8).

DISCUSSION

The third pre-specified interim analysis of the OlympiA trial demonstrates sustained and clinically meaningful improvement in multiple outcomes from 1 year of adjuvant olaparib relative to placebo, including the primary endpoint, IDFS (HR 0.65; 95% CI 0.53 to 0.78) as well as DDFS (HR 0.65; 95% CI 0.53 to 0.81), and OS (HR 0.72; 95% CI 0.56 to 0.93) in patients with gBRCApv-associated high-risk HER2-negative early BC following standard of care chemotherapy (NACT or ACT), appropriate local therapy and with concurrent hormonal therapy when indicated.

Established data demonstrate that 70% of gBRCA1pv-associated BCs are TNBC, while 70% of gBRCA2pv-associated BCs are hormone receptor-positive and HER2-negative.^{13, 18} OlympiA was planned to enrol gBRCApv carriers irrespective of hormone receptor status. Initial enrolment was opened for the TNBC cohort, and a subsequent amendment added the high-risk, hormone-receptor-positive cohort following regulatory review and approval of eligibility criteria and safety of olaparib in combination with endocrine therapy. High-risk was defined as those with a CPS+EG score of ≥3 following NACT or ≥4 involved lymph nodes at primary surgery, criteria estimated to confer risk of recurrence comparable to the TNBC group. The results of the present analysis indicate that this objective was achieved. As the main mechanisms of action of PARP inhibitors in BRCA-mutant BC cells, inhibiting and trapping PARP on DNA¹⁹ and exploiting defective homologous recombination repair (synthetic lethality), are equally applicable to those with a gBRCA1pv or gBRCA2pv and either hormone receptor-positive HER2-negative or TNBC, it was considered important to have representation of all groups and their associated BC hormone receptor subtypes in the trial. Patients with HER2-positive disease were excluded from the trial because of the relative infrequency of this cancer subtype in patients with gBRCA1/2pv and lack of data on the safety of anti-HER2-directed established postsurgical treatments in combination with olaparib.

Distant recurrences for gBRCApv-associated TNBC occur in the first 5 years, as they do in sporadic TNBC.^20,21 In contrast, high-risk, hormone receptor-positive gBRCApv-associated tumours appear to be more aggressive than their sporadic counterparts, with higher rates of distant recurrence events occurring earlier in follow-up.^{22, 23} Recent data on the rapidity of acquisition of resistance to PARP inhibitors in the metastatic setting by multiple mechanisms warrants continued surveillance of the OlympiA cohorts beyond the 6.1-year MFU reported herein to confirm that early benefits persist.¹⁰

While global approval of olaparib based on the earlier results of OlympiA - significant improvements in DFS, IDFS and, most important, OS - has resulted in its frequent incorporation into treatment plans for patients with gBRCA1/2pv and high-risk HER2 negative early BC, changes in other standard-of-care treatments for high-risk early TNBC and hormone receptor-positive BCs outside the gBRCA1/2pv context have influenced the use of olaparib.²⁴ The CREATE-X data have made capecitabine an important post-adjuvant therapy in much of the world for patients with TNBC.²⁵ The superior efficacy of the PARP inhibitors olaparib (OlympiAD)⁸ and talazoparib (EMBRACA)⁹, in comparison with capecitabine as a physician’s choice control in early-line treatment of patients with gBRCA1/2pv-associated advanced BC has been considered in recommendations for olaparib’s use as the preferred first-line, post-neoadjuvant therapy for non-pathologic complete response (non-pCR) status after NACT in the gBRCApv TNBC population.^{12, 26, 27} Practice-changing data supporting platinum- and taxane-based NACT with pembrolizumab immunotherapy in TNBC have led to their rapid adoption as standard of care.²⁸ Trial data have demonstrated the feasibility and tolerability of olaparib in combination with pembrolizumab in metastatic BC.^{29, 30} Although there are currently no data for the combination in early BC, these trials have led to the use of adjuvant olaparib in combination with continuation of pembrolizumab in patients with gBRCA1/2pv TNBC without pCR, as per the St. Gallen Consensus Statement 2025.³¹ It is noted, however, that the efficacy of the combination of olaparib with pembrolizumab in this setting is not established and does not have regulatory approval.

The benefit of olaparib in patients with more moderate risk hormone receptor-positive early BC than those who participated in OlympiA is unknown and specific trials in these patients are unlikely to be feasible. Patients with high-risk genomic scores with Grade 2, T2 primary tumours and 0–3 nodes have a similar magnitude of risk for distant recurrence,^{32, 33} although data on the effect of olaparib in these specific groups were not collected in OlympiA.¹² The European Society for Medical Oncology (ESMO) 2024 Early Breast Cancer Guidelines³⁴ recommend that high recurrence risk patients with estrogen receptor-positive, HER2-negative breast cancer that would typically warrant chemotherapy, such as multiple positive lymph nodes and/or residual disease after NACT, be considered for gBRCA1/2 testing. The potential role of olaparib in patients with hormone receptor-positive disease where recurrence risk is determined by combination of genomic assay and clinical stage remains the subject of discussion in guideline development panels. Those testing positive should receive 1 year of olaparib with basic endocrine therapy, with the addition of olaparib preceding CDK4/6 inhibitor therapy (and not combined due to lack of safety data given potential overlapping toxicities).

OlympiA used a CPS+EG post-NACT staging system and required scores of ≥3 for hormone receptor-positive disease. Patients with hormone receptor-positive tumours and residual cancer burden scores of 2 or 3, as defined by the commonly used Residual Cancer Burden system, also have a substantial risk of recurrence after NACT and may also be suitable for treatment with PARP inhibitors.³⁵ Questions about the optimal use of olaparib in combination with newer anti-hormonal agents in the adjuvant setting for these patients remain unanswered, pending further trials. The EVOPAR-BR01 trial (NCT06380751) is directly comparing the efficacy of the selective oral oestrogen receptor degrader camizestrant plus the oral selective PARP1 inhibitor saruparib to camizestrant plus physician choice CDK4/6 inhibitor to CDK4/6 inhibitor plus physician choice endocrine therapy in germline and somatic BRCApv-associated advanced hormone receptor-positive BC. Although not an adjuvant trial, its results in the control arm may indirectly provide additional information.

Concerns exist about the potential contribution of PARP inhibitors to the development of MDS/AML. Bone marrow dyscrasias have been reported at concerning frequencies following PARP inhibitor use, with higher rates in trials with longer duration PARP inhibitor therapy as well as higher doses and durations of prior cytotoxic chemotherapy, generally in ovarian and other advanced malignancies.^36–40 Rates of MDS/AML in BC trials comparing a PARP inhibitor to placebo have generally been lower than those in ovarian cancer trials. It is important to note that DNA-interacting chemotherapies used in breast and ovarian cancer treatment also raise risks of MDS/AML⁴¹ and that, in ovarian cancer adjuvant trials, both the platinum agents and PARP inhibitors are given for considerably longer periods than in BC trials. In OlympiA, 1 patient in the olaparib arm and 1 patient in the placebo arm who received prior platinum-based (neo)adjuvant chemotherapy developed AML/MDS. Whether because of the shorter duration of olaparib exposure or the more limited prior chemotherapy exposure, the rates of MDS/AML in OlympiA remain low with extended follow-up at 0.4% in the olaparib group and 0.7% in the placebo group with only a small number of additional cases reported in both groups between IA2 (rates were 0.2% and 0.3% at 3.5 years MFU) and IA3. Risk of MDS/AML remains an important consideration in the adjuvant treatment of early BC, especially where chemotherapy has been used. The association between pathogenic variants in BRCA1 or BRCA2 and risk of haematologic malignancy remains an important research question^{42, 43}. We find no evidence of olaparib effect in this chemotherapy pre-treated population but given the long latency of therapy-induced haematologic malignancy continued follow-up remains essential for all PARP inhibitor trials, and is planned in OlympiA until 2029, 10 years after the enrolment of the last patient.

The fact that gBRCA1/2pv increase the risk of development of homologous recombination-deficient second malignancies in carriers, including invasive and non-invasive BC in residual breast tissue, ovarian cancer (in women), pancreas cancer and prostate cancer (in men) raises the possibility that exposure to a PARP inhibitor could reduce the risk of the development of these specific tumours, even if this effect were transient. In OlympiA, absolute numbers are small, but there are fewer breast and ovarian/fallopian tube cancers in the olaparib arm in follow-up (SA Table S8); pancreatic cancers were not lower (3 in olaparib, 1 in placebo). The denominators for breast and ovarian tissue at risk in OlympiA change as patients undergo risk-reducing mastectomies and salpingo-oophorectomies (RRSO), the latter by guidelines.^{44, 45} Premenopausal women with hormone receptor-positive BCs may undergo RRSO for additional therapeutic benefit.⁴⁶ Recent data from a large international cohort of young women with gBRCA1/2pv-associated early BCs suggest improved outcomes with both RRSO and with bilateral mastectomies.⁴⁷ In OlympiA to date, similar rates of risk-reducing surgeries in the olaparib and placebo arms were observed, HR for CIBC (accounting for competing risks) was 0.83 (95% CI 0.52 to 1.32). In the final planned analysis of OlympiA at study completion in 2029, further events may enable additional competing risk analyses.

In summary, at 6.1 years MFU, 1 year of adjuvant olaparib after completion of NACT/ACT continues to demonstrate clinically meaningful improvements in IDFS, DDFS and OS in all subgroups of patients with gBRCApv-associated high-risk HER2-negative primary BC. AESIs remain numerically lower in the olaparib versus placebo groups. More mature data on second cancers and pregnancy outcomes will be forthcoming. Additional blinded follow-up remains essential, and planned translational exploratory analyses will add important insights into potential resistance mechanisms. These studies may identify subgroups with varying benefits and further inform therapeutic strategies that address resistance. The IA3 findings further solidify the important role for olaparib as an active targeted agent in the adjuvant treatment of high-risk HER2-negative primary BC diagnosed in carriers of gBRCApv, and the need to identify all such patients through widespread access to germline genetic testing so that they can benefit from olaparib treatment.

DATA SHARING

Individual participant data that underlie the results reported in this article, after deidentification, will be made available to investigators whose proposed use of the data has been approved by the OlympiA Steering Committee. The data provided will be limited to that required to answer the objectives of the proposal and in line with the informed consent form and country-level legislation. Proposals can be submitted once an end point defined in the protocol has been reached, the corresponding analysis performed, and the data related to the end point released through the first public presentation (retention period will be mentioned in the data transfer agreement [DTA]). Proposals should be directed to olympiaproposals@frontier-science.co.uk. To gain access, data requestors will need to sign a DTA.