This nonrandomized controlled trial aims to determine the activity of olaparib monotherapy among patients with high-risk biochemically recurrent prostate cancer after radical prostatectomy.
Key Points
Question
Is olaparib monotherapy effective for patients with high-risk biochemically recurrent prostate cancer in the absence of androgen deprivation therapy?
Findings
In this phase 2, single-arm nonrandomized controlled trial of 51 patients, 13 patients (26%) had a confirmed 50% or higher decline in prostate-specific antigen from baseline. This varied by the presence of homologous recombination repair alterations, with the greatest benefit being in those with BRCA2 alterations, and the adverse effect profile was consistent with prior studies of olaparib.
Meaning
Olaparib without androgen deprivation has activity in certain patients with biochemically recurrent prostate cancer.
Abstract
Importance
Olaparib is a poly(adenosine diphosphate–ribose) polymerase inhibitor that provides benefit in combination with hormonal therapies in patients with metastatic prostate cancer who harbor homologous recombination repair (HRR) alterations. Its efficacy in the absence of androgen deprivation therapy has not been tested.
Objective
To determine the activity of olaparib monotherapy among patients with high-risk biochemically recurrent (BCR) prostate cancer after radical prostatectomy.
Design, Setting, and Participants
This phase 2, single-arm nonrandomized controlled trial enrolled genetically unselected patients across 4 sites in the US from May 2017 to November 2022. Eligible patients had BCR disease following radical prostatectomy, a prostate-specific antigen (PSA) doubling time of 6 months or shorter, an absolute PSA value of 1.0 ng/mL or higher, and a testosterone level of 150 ng/dL or higher.
Intervention
Treatment was with olaparib, 300 mg, by mouth twice daily until doubling of the baseline PSA, clinical or radiographic progression, or unacceptable toxic effects.
Main Outcome and Measure
The primary end point was a confirmed 50% or higher decline in PSA from baseline (PSA50). Key secondary end points were outcomes by HRR alteration status, as well as safety and tolerability.
Results
Of the 51 male patients enrolled (mean [SD] age, 63.8 [6.8] years), 13 participants (26%) had a PSA50 response, all within the HRR-positive group (13 of 27 participants [48%]). All 11 participants with BRCA2 alterations experienced a PSA50 response. Common adverse events were fatigue in 32 participants (63%), nausea in 28 (55%), and leukopenia in 22 (43%), and were consistent with known adverse effects of olaparib.
Conclusions and Relevance
In this nonrandomized controlled trial, olaparib monotherapy led to high and durable PSA50 response rates in patients with BRCA2 alterations. Olaparib warrants further study as a treatment strategy for some patients with BCR prostate cancer but does not have sufficient activity in those without HRR alterations and should not be considered for those patients.
Trial Registration
ClinicalTrials.gov Identifier: NCT03047135
Introduction
While most patients with localized prostate cancer are cured with surgery or radiotherapy, up to 40% will develop a recurrence, evidenced by a rising prostate-specific antigen (PSA) level in the absence of metastases, a state known as biochemically recurrent (BCR) prostate cancer.1,2 The natural history of BCR disease is variable, with some patients having prolonged survival while others develop rapid metastases. Patients classified as having high-risk BCR prostate cancer are those with short PSA doubling times, high Gleason grades (sum of 8-10), and a short time from surgery to PSA recurrence.3,4 Current treatment approaches for BCR prostate cancer include observation, salvage radiotherapy, androgen deprivation therapy (ADT), or enzalutamide (with or without ADT), although many patients prefer to defer such therapy given the negative effects on quality of life and cardiometabolic health.5,6
Olaparib is a poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor that has shown benefit in patients with metastatic castration-resistant prostate cancer who harbor homologous recombination repair (HRR) alterations.7,8,9 It is unknown if PARP inhibitor treatment has efficacy in the absence of hormonal therapy in prostate cancer. We hypothesized that PARP inhibition would be an alternative treatment strategy to ADT among patients with BCR prostate cancer.10 We designed a phase 2 clinical trial to investigate the efficacy and safety of olaparib monotherapy in patients with high-risk BCR prostate cancer, irrespective of underlying HRR status.
Methods
Trial Design and Oversight
This was a phase 2, multicenter, single-arm nonrandomized controlled trial initiated by an investigator/sponsor (E.S.A.), who holds the Investigational New Drug application. AstraZeneca provided an investigational supply of the study drug, olaparib. The study used a 2-stage design in a molecularly unselected population, with 2 interim stopping rules.11
The study was approved by the institutional review boards at each of the participating sites, and all participants provided written informed consent. This study followed the Transparent Reporting of Evaluations With Nonrandomized Designs (TREND) reporting guidelines.
Patients and Treatment
Patients were enrolled from May 2017 to November 2022 across 4 sites in the US (Johns Hopkins University, Thomas Jefferson University, Allegheny Health Network Cancer Institute, and University of Nebraska). Eligible patients had a histologic diagnosis of prostate adenocarcinoma, with prior curative-intent radical prostatectomy and prostate tissue available for correlative studies. Participants were eligible if they had a PSA doubling time of 6 months or shorter, an absolute PSA value of 1.0 ng/mL or higher (to convert to μg/L, multiply by 1), and a testosterone level of 150 ng/dL or higher (to convert to nmol/L, multiply by 0.0347). Those with radiographic evidence of metastatic disease based on conventional computed tomography or bone scan, ADT within 6 months, or prior ADT longer than 24 months were excluded.
Participants were treated with olaparib, 300 mg, by mouth twice daily until a doubling of their baseline PSA level, clinical or radiographic progression, or unacceptable toxic effects. Additional rationale and design of the trial are described in the protocol (Supplement 1).
Outcomes
The primary end point was the PSA50 response, defined as a decline in PSA of 50% or higher from baseline, confirmed by a second measurement 4 or more weeks later. Key secondary end points included safety and tolerability of olaparib, time to PSA doubling from baseline, and PSA progression-free survival (PFS; defined as time until a PSA increase of ≥25% above baseline or nadir and a minimum increase of 2.0 ng/mL). Key exploratory end points included analysis of these outcomes according to biomarker (HRR alteration) status. Patients with positive biomarker results were those with germline or somatic alterations in ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FANCE, PALB2, RAD51B, RAD51C, or RAD51D. Additional exploratory end points included (1) association of PSA response rate with biallelic HRR alteration status and genomic loss of heterozygosity (gLOH), (2) association of RNA expression signatures with PSA response, and (3) association of PSA response with ATM protein loss. Key clinical exploratory end points included metastasis-free survival (MFS; time to first metastasis on conventional imaging or death) and time to next anticancer therapy.
DNA Analysis
Radical prostatectomy tissue was subjected to somatic tumor testing using a hybrid capture-based next-generation sequencing analysis using the FoundationOne assay (Foundation Medicine) in a Clinical Laboratory Improvement Amendments (CLIA)–certified and College of American Pathologists–accredited laboratory, according to methods previously described.12 gLOH was defined as the percentage of the genome demonstrating LOH, excluding whole-arm and whole-chromosome events, using validated pipelines as previously described.13 Germline genetic testing was completed using clinically available platforms at the discretion of each treating physician.
RNA Analysis
Transcriptome profiling was performed with tumor region of interest selection, RNA extraction, and microarray hybridization in a CLIA-certified laboratory (Veracyte). The radical prostatectomy tissue block with the highest grade and largest volume of tumor was selected for macrodissection (4 unstained slides), with the region of interest marked by an experienced pathologist. All samples were required to pass prespecified criteria for tumor sampling, RNA extraction, complementary DNA amplification, and microarray quality-control metrics as described previously.14
Immunohistochemistry
Immunohistochemistry for ATM was performed at the Johns Hopkins University CLIA-accredited laboratory using a previously described validated protocol15 on the Ventana Benchmark immunostaining system (Roche) with a rabbit monoclonal antibody (32420 [Abcam]). A representative whole slide section from the primary tumor from each patient was visually dichotomously scored for the presence or absence of nuclear ATM signal by 2 urologic pathologists (T.L.L. and L.O.). Both pathologists were blinded to DNA sequencing results when reading immunohistochemistry slides. Samples were considered to show ATM protein loss if any tumor cells exhibited loss of nuclear ATM, with intact staining in admixed surrounding stromal cells, endothelial cells, lymphocytes, or benign prostate glands. Tumor areas without internal control staining in the vicinity were considered ambiguous and excluded from final scoring. Some cases exhibited focal loss of ATM nuclear staining and were scored as having heterogeneous (subclonal) ATM loss.
Statistical Analysis
This trial was designed to enroll 50 patients with 2 preplanned interim statistical analyses. The first stage was designed to enroll 20 biomarker-unselected patients, and because more than 2 participants had a PSA50 response, the study proceeded to its second phase, allowing enrollment of 10 additional biomarker-unselected participants. If the study did not meet criteria for futility (<6 of the first 30 patients achieving a PSA50 response), then the study would proceed to complete accrual of an additional 20 biomarker-unselected patients to obtain a better estimate of the PSA50 response rate. With this design, a total sample size of 50 patients would provide 90% power to detect a PSA50 response rate of 30% against the null hypothesis of 10% in a biomarker-unselected population, with an overall type I error of 0.10, assuming the biomarker prevalence to be 10% to 15%, based on 10 000 simulations of possible outcomes. The statistical section of the protocol (Supplement 1) contains full details.
The primary end point, PSA50 response, was assessed as the proportion of patients with a 50% or higher PSA reduction before the end of treatment, and 95% CIs were calculated using Clopper-Pearson method. The best PSA response was reported as the largest decline or the smallest increase (in the absence of decline) from baseline. Safety was analyzed as the incidence of toxic effects, which were graded according to the Common Terminology Criteria for Adverse Events, version 4.0, standardized grading scales.
PSA PFS and MFS16 were estimated using the Kaplan-Meier method. The comparison of survival curves between the HRR-positive and HRR-negative groups were performed using log-rank test, and the Cox proportional hazards regression model was used to estimate hazard ratios (HRs) and 95% CIs. As a sensitivity analysis, a restricted mean survival time (RMST) up to 36 months for PSA PFS and MFS was also estimated using the Kaplan-Meier method. The correlation between gLOH score and best PSA response was assessed using the Spearman test. Statistical significance of differences in continuous genomic markers across alteration groups was determined by Kruskal-Wallis tests. All tests were 2-sided, and P < .05 was considered statistically significant. Statistical analysis was performed with R, version 4.3.0 (R Foundation for Statistical Computing).
Results
Patients
A total of 51 male patients were enrolled (Figure 1). Demographic and baseline disease characteristics are summarized overall and by biomarker status in Table 1. Of the 51 enrolled patients, 27 (53%) were considered to have positive biomarker results. The mean (SD) age of the participants was 63.8 (6.8) years, the median (range) baseline PSA was 2.8 (1.0-37.6) ng/mL, and the mean (SD) PSA doubling time was 2.9 (1.5) months. Gleason grade group 5 disease was present in 11 of the 27 patients (41%) in the biomarker-positive group and 5 of the 24 patients (21%) in the biomarker-negative group. The median (IQR) time from surgery to study entry was 4.8 (3.1-7.9) years.
Figure 1. Flowchart of Recruitment, Treatment, and Follow-Up.
BCR indicates biochemically recurrent.
Table 1. Baseline Characteristics of Participants.
| Characteristic | No. (%) | ||
|---|---|---|---|
| Overall (N = 51) | Biomarker negative (n = 24) | Biomarker positive (n = 27) | |
| Age, mean (SD), y | 63.8 (6.8) | 63.5 (7.2) | 64.2 (6.6) |
| Self-reported race | |||
| African American or Black | 3 (6) | 2 (8) | 1 (4) |
| White | 47 (92) | 21 (88) | 26 (96) |
| Unknown | 1 (2) | 1 (4) | 0 |
| PSA, median (range), ng/mL | 2.8 (1.0-37.6) | 2.5 (1.2-23.8) | 2.9 (1.0-37.6) |
| PSA doubling time, mean (SD), mo | 2.92 (1.5) | 3.25 (1.4) | 2.62 (1.4) |
| Time from surgery to study start, median (IQR), y | 4.75 (4.8) | 4.56 (4.1) | 5.00 (5.4) |
| Gleason grade group | |||
| 1 | 1 (2) | 0 | 1 (4) |
| 2 | 8 (16) | 5 (21) | 3 (11) |
| 3 | 19 (37) | 12 (50) | 7 (26) |
| 4 | 7 (14) | 2 (8) | 5 (19) |
| 5 | 16 (31) | 5 (21) | 11 (41) |
| Tumor stage at diagnosis | |||
| T2 | 16 (31) | 6 (25) | 10 (37) |
| T3 | 34 (67) | 18 (75) | 16 (59) |
| T4 | 1 (2) | 0 | 1 (4) |
| Nodal stage at diagnosis | |||
| N0 | 44 (86) | 20 (83) | 24 (89) |
| N1 | 7 (14) | 4 (17) | 3 (11) |
| Prior salvage/adjuvant radiotherapy | 44 (86) | 22 (92) | 22 (82) |
| HRR alteration present | |||
| BRCA2 | 11 (22) | NA | 11 (41) |
| ATM | 6 (12) | 6 (22) | |
| CHEK2 | 6 (12) | 6 (22) | |
| FANCA | 2 (4) | 2 (7) | |
| CDK12 | 1 (2) | 1 (4) | |
| FANCE | 1 (2) | 1 (4) | |
| BRCA1 | 0 | 0 | |
| Unknown | 4 (8) | 4 (17) | NA |
| Negative | 20 (39) | 20 (8) | |
| ATM status | |||
| ATM protein loss only | 3 (6) | 1 (4) | 2 (7) |
| ATM genomic alteration only | 1 (2) | 0 | 1 (4) |
| Both ATM protein loss and ATM genomic alteration | 5 (10) | 0 | 5 (19) |
| Neither ATM protein loss nor ATM genomic alteration | 42 (82) | 23 (96) | 19 (70) |
| Biallelic HRR alteration | 12 (23.5) | NA | 12 (44) |
| gLOH score | |||
| Mean (SD) | 7.57 (3.1) | 6.34 (4.1) | 8.08 (2.6) |
| Missing | 34 (67) | 19 (79) | 15 (56) |
Abbreviations: gLOH, genomic loss of heterozygosity; HRR, homologous recombination repair; NA, not applicable; PSA, prostate-specific antigen.
SI conversion factor: To convert PSA to micrograms per liter, multiply by 1.
Of the 27 participants in the biomarker-positive group, BRCA2 alterations were the most common within 11, followed by ATM and CHEK2 alterations in 6 for both, then FANCA alterations among 2. Four of 51 patients (8%) had unknown alteration status due to tumor-sequencing failure after insufficient nucleic acid isolation, and 20 patients (39%) had negative results for HRR alterations. eFigure 1 in Supplement 2 includes the most commonly altered genes. The eTable in Supplement 2 summarizes the specific alterations.
Primary End Point
Overall, 13 of 51 patients (26%; 95% CI, 14%-40%) achieved a PSA50 response. There were no PSA50 responses seen among the 24 participants in the biomarker-negative group. Of the 27 patients in the biomarker-positive group, 13 (48%; 95% CI, 29%-68%) had a PSA50 response (Figure 2A). All 11 patients with BRCA2 alterations experienced a PSA50 response, with a median response duration of 25.1 (95% CI, 15.0-31.4) months (Figure 2B). The other 2 confirmed PSA50 responses were seen in a patient with a CHEK2 alteration and a patient with an ATM alteration (Figure 2).
Figure 2. Best Prostate-Specific Antigen (PSA) Response Relative to Baseline and Over Time by Homologous Recombination Repair (HRR) Alteration Status.
The other category includes alterations in BARD1, BRCA1, BRIP1, CDK12, CHEK1, FANCA, FANCE, PALB2, RAD51B, RAD51C, or RAD51D.
Secondary End Points
The median overall PSA PFS in the cohort was 19.3 months (95% CI, 6.4 months-not reached [NR]). The median time to PSA progression in the biomarker-positive group was 22.1 months (95% CI, 6.4 months-NR) and in the biomarker-negative group was 12.8 months (95% CI, 4.5 months-NR) (HR for difference, 0.80; 95% CI, 0.33-1.97; Figure 3A). In the sensitivity analysis using RMST over 36 months, PSA PFS in the biomarker-positive group vs the biomarker-negative group was 19.3 months vs 8.5 months (P = .001).
Figure 3. Kaplan-Meier Curves of Prostate-Specific Antigen (PSA) Progression-Free Survival, Metastasis-Free Survival, and Time To Next Cancer Therapy by Homologous Recombination Repair (HRR) Alteration Status.
The median MFS was 32.9 (95% CI, 24.6-56.7) months overall. In the biomarker-positive group, median MFS was 41.9 months (95% CI, 32.9 months-NR) compared to 16.9 months (95% CI, 10.9 months-NR) in the biomarker-negative group (HR, 0.53; 95% CI, 0.23-1.18; Figure 3B). In the sensitivity analysis, RMST for MFS over 3 years was 28.9 months in the biomarker-positive group and 19.6 months in the biomarker-negative group (P = .02). The median time to next anticancer therapy was 15.4 (95% CI, 11.1-24.6) months overall. There was a statistically significant longer time period in the biomarker-positive group (22.7 months; 95% CI, 9.5 months-NR) compared to the biomarker-negative group (12.4 months; 95% CI, 8.7-24.6 months) (HR, 0.43; 95% CI, 0.21-0.90; P = .02) (Figure 3C).
Exploratory End Points
PSA50 responses were more frequent in participants with biallelic (12 of the 27 participants in the HRR-positive group) vs monoallelic HRR alterations (eFigure 2 in Supplement 2). Two of 11 participants with BRCA2 alterations and PSA50 responses did not have detectable biallelic alterations. The single participant with an ATM alteration and the single participant with a CHEK2 alteration who had PSA50 responses had monoallelic alterations with intact ATM protein expression.
The gLOH score was evaluable in 17 participants. The median (IQR) gLOH score was 8.1% (5.9%-8.8%). There was no statistically significant difference in PSA50 response rate among those with gLOH scores below the median compared to those above the median, and there was no correlation between PSA response and gLOH score (R2 = 0.04; P = .43; Spearman correlation coefficient, −0.21; eFigure 3 in Supplement 2). There was also no difference in PSA PFS by gLOH score above or below the median (HR, 0.58; 95% CI, 0.13-2.61; P = .48) or MFS (HR, 0.28; 95% CI, 0.05-1.45; P = .13).
Five participants (10%) had both ATM protein loss and genomic alterations in ATM, 1 participant (2%) had an ATM genomic alteration only (with preservation of ATM protein by immunohistochemistry), and 3 participants (6%) had ATM protein loss in the absence of detectable ATM genomic alterations (1 of these patients also had a BRCA2 alteration). ATM protein loss was not associated with PSA50 response (eFigure 4 in Supplement 2).
Thirty-nine of 51 participants (77%) had samples that were evaluable for RNA-based transcriptome analysis. Twenty participants (51%) had high-risk Decipher scores (>0.60-1.00), 5 (13%) had intermediate-risk Decipher scores (0.45-0.60), and 14 (36%) had low-risk Decipher scores (<0.45). There were statistically significant differences with respect to multiple RNA-based signatures between the 10 participants with BRCA2 alterations relative to the 13 participants with other HRR alterations or the 16 participants with no HRR alterations. Those with BRCA2 alterations had very high14,17 (median [IQR], 0.93 [0.65-0.98]) Decipher scores, higher DNA-repair hallmark scores,18 higher luminal proliferating scores,19 higher homologous recombination deficiency scores,20 more chromosomal instability,21 higher neuroendocrine signature scores,22 higher cell-cycle progression scores,23 and higher proliferation (E2F target) scores18 (eFigure 5 in Supplement 2). The BRCA2-altered samples also showed signatures consistent with lower immune infiltration and CD8+ T cells,24,25 higher immune-suppressor cells,26 and lower interferon γ response scores18 (eFigure 5 in Supplement 2).
Adverse Events
The most common adverse events were fatigue in 32 participants (63%), nausea in 28 (55%), and leukopenia in 22 (43%) (Table 2). There were no deaths during the trial. There were 2 serious adverse events: anemia (related to the study drug) and a cerebrovascular accident (unrelated to the study drug). Three participants stopped therapy due to treatment-related toxic effects (2 for anemia, and 1 for leukopenia). One participant developed venous thromboembolism, possibly related to study treatment. Patient-reported outcomes were not collected. There were no new safety signals with olaparib in this population.
Table 2. Adverse Events Occurring in at Least 3 Participants (N = 51).
| Adverse event | No. (%) | |||
|---|---|---|---|---|
| All grade | Grade 1 | Grade 2 | Grade 3 | |
| Fatigue | 32 (63) | 29 (57) | 3 (6) | 0 |
| Nausea | 28 (55) | 24 (47) | 4 (8) | 0 |
| Leukopenia | 22 (43) | 6 (12) | 11 (22) | 5 (10) |
| Anemia | 18 (35) | 14 (27) | 3 (6) | 1 (2) |
| Dysgeusia | 15 (29) | 14 (27) | 1 (2) | 0 |
| Anorexia | 11 (22) | 9 (18) | 2 (4) | 0 |
| Thrombocytopenia | 9 (18) | 9 (18) | 0 | 0 |
| Vomiting | 8 (16) | 8 (16) | 0 | 0 |
| Headache | 7 (14) | 6 (12) | 1 (2) | 0 |
| Creatinine increased | 7 (14) | 7 (14) | 0 | 0 |
| Diarrhea | 6 (12) | 6 (12) | 0 | 0 |
| Weight loss | 5 (10) | 3 (6) | 2 (4) | 0 |
| Dyspepsia | 5 (10) | 4 (8) | 1 (2) | 0 |
| Edema | 4 (8) | 2 (4) | 2 (4) | 0 |
| Dyspnea on exertion | 4 (8) | 4 (8) | 0 | 0 |
| Cough | 4 (8) | 4 (8) | 0 | 0 |
| Alanine transaminase increased | 4 (8) | 3 (6) | 0 | 1 (2) |
| Aspartate aminotransferase increased | 3 (6) | 2 (4) | 0 | 1 (2) |
| Constipation | 3 (6) | 3 (6) | 0 | 0 |
| Dry mouth | 3 (6) | 3 (6) | 0 | 0 |
| Stomach pain | 3 (6) | 2 (4) | 1 (2) | 0 |
Discussion
In this phase 2 single-arm trial of olaparib monotherapy in patients with high-risk BCR prostate cancer, there were clinically significant benefits with the use of olaparib; however, these benefits were limited to a subset of patients defined by HRR alterations. Participants with BRCA2 alterations all had PSA50 responses, while the response rates among those with ATM or other HRR alterations were not consistent, and there were no responses seen among those without HRR alterations. There was also generally a greater likelihood of achieving a PSA response if the HRR alteration involved both alleles, an observation associated primarily with the population with BRCA2 alterations. The higher PSA response rates seen in patients with BRCA2-altered prostate cancer compared to other HRR alterations is consistent with other studies of PARP inhibitors when given with ADT.27,28,29,30 The PSA response rate of 100% in those with BRCA2 alterations is higher than what was seen in other studies in metastatic castration-resistant prostate cancer where responses were about 50% to 60%.30,31 Treating patients with BRCA2-altered prostate cancer earlier in the disease course, prior to the development of greater tumor heterogeneity induced by ADT and other systemic therapies, may be contributing to these higher response rates. Additionally, it is not well established what role concomitant androgen deprivation may be playing in the difference in olaparib sensitivity, but the very high response rate observed here in the absence of ADT is notable. Other therapies for this population now would include enzalutamide alone or in combination with ADT as demonstrated in the EMBARK trial,6 although the trial population included in the present study would be considered higher risk with shorter median PSA doubling time at enrollment. The adverse effect profile of the 2 treatments also differs considerably, and the appeal for the approach taken in this trial is to avoid hormonal therapies.
Other potential predictors of response to PARP inhibitors include ATM genetic alterations or protein loss. However, this was not observed here, consistent with prior studies.27,32 The small sample size evaluable for gLOH scores limits the ability to make conclusions regarding the utility of this biomarker. Interestingly, those with BRCA2 alterations did exhibit statistically significant transcriptomic differences in prognostic risk scores, homologous recombination deficiency scores, cell-cycle markers, immune infiltrates, and metabolism signatures. If validated, these findings may be used to inform future, potential combination therapy approaches for patients with advanced prostate cancer without BRCA2-altered disease or with other non-BRCA2 HRR alterations. Finally, there were no meaningful PSA responses among those without HRR alterations; therefore, olaparib should not be considered as a potential treatment option for those patients based on the results of this trial.
Limitations
This study has several limitations, including a small sample size and lack of a control group. We were not able to molecularly characterize all patients because insufficient nucleic acids were isolated from their prostatectomy specimens for downstream analysis in 4 patients. There was an attempt to use circulating tumor DNA at the time of study entry; however, after the first 25 samples were completed, the yield on this was very low due to the low volume of disease at the time of study entry and therefore stopped. Furthermore, the high prevalence of HRR alterations observed herein is artificial and does not reflect the true prevalence of HRR alterations in BCR prostate cancer,10 since patients with known HRR alterations specifically came to the study sites to participate in this trial. Nevertheless, this is, to our knowledge, the first study to use PARP inhibition in the absence of ADT for treatment of hormone-sensitive prostate cancer, and it demonstrates that complete and durable responses may be observed with olaparib monotherapy. We are not aware of other nonhormonal systemic treatments capable of inducing complete PSA responses in this clinical setting.33 This study will hopefully motivate investigators to design definitive randomized trials incorporating PARP inhibitors for patients with high-risk BCR prostate cancer, either with or without the use of concurrent hormonal agents. Additionally, alternative dosing levels and schedules could be explored in future studies of selected patients with or without the use of metastasis-directed radiation, which has also emerged as a potential treatment option for some patients with BCR prostate cancer. Formal comparisons of patient-reported outcomes are also needed to compare toxic effects in this setting with other therapeutic options. Finally, the patient population historically defined as having BCR disease is changing with the adoption of novel prostate-specific membrane antigen–directed positron emission tomography imaging. It is likely that many of these participants would have had positive prostate-specific membrane antigen positron emission tomography imaging results,34 but we were not able to assess outcomes in this population given that this testing was not routinely available during the conduct of the trial.
Conclusions
In this nonrandomized controlled trial of patients with high-risk BCR prostate cancer following prostatectomy, treatment with olaparib monotherapy led to high and durable PSA response rates in those with BRCA2 alterations, even in the absence of androgen deprivation, with acceptable safety. The response rates in patients with other HRR alterations was variable, and there was no activity observed in those without HRR alterations. Molecularly targeted therapies in select patient populations may be a reasonable treatment strategy for some patients with recurrent prostate cancer, even in the absence of ADT.
Trial Protocol
eTable 1. List of specific gene alterations and germline/somatic status
eFigure 1. Oncoprint figure illustrating the most common genetic alterations found in our participants
eFigure 2. Waterfall plot with best PSA response according to biallelic mutation status
eFigure 3. Best PSA response by gLOH score
eFigure 4. Spider plot of best PSA response according to ATM gene and ATM protein alterations
eFigure 5. RNA signatures according to presence or absence of BRCA2 alteration, other homologous recombination alteration, or no/unknown alteration
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
eTable 1. List of specific gene alterations and germline/somatic status
eFigure 1. Oncoprint figure illustrating the most common genetic alterations found in our participants
eFigure 2. Waterfall plot with best PSA response according to biallelic mutation status
eFigure 3. Best PSA response by gLOH score
eFigure 4. Spider plot of best PSA response according to ATM gene and ATM protein alterations
eFigure 5. RNA signatures according to presence or absence of BRCA2 alteration, other homologous recombination alteration, or no/unknown alteration
Data Sharing Statement
