Response to Rucaparib in BRCA-Mutant Metastatic Castration-Resistant Prostate Cancer Identified by Genomic Testing in the TRITON2 Study

This article is featured in Highlights of This Issue, p. 6617

The PARP inhibitor rucaparib is approved in the United States for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and a deleterious BRCA1 or BRCA2 (BRCA) alteration, based on results from the phase II TRITON2 study (1).

Germline or somatic alterations in BRCA are observed in approximately 12% of men with advanced prostate cancer (2, 3). Protein truncating alterations, such as homozygous deletions, large rearrangements, as well as frameshift, nonsense, and pathogenic missense mutations, have been identified as drivers of the disease (3, 4), highlighting the need for robust approaches to select patients for treatment.

Sequencing of tumor tissue is the standard for genomic subtyping of solid cancers but has limitations in prostate cancer. While tissue samples from the prostate tumor are taken from almost all patients at diagnosis, the time to progression to mCRPC can span many years (5, 6), which can impact sample quality and subsequent success of molecular profiling (7). Furthermore, tumor genomics may evolve with disease progression or development of treatment resistance (7, 8), and diagnostic biopsy or radical prostatectomy samples may not reflect the genomics of advanced disease. Although DNA repair status can be accurately assessed from primary tumors in most cases (9, 10), more recent and metastatic biopsies are preferred for higher next-generation sequencing (NGS) success rate (3); however, mCRPC largely involves skeletal spread, and many patients lack accessible soft tissue lesions (11). Biopsies from bone metastases frequently have insufficient tissue content for NGS, and have high failure rates (3, 12–16).

Blood-based assays have become a viable option for guiding treatment in tumors where tissue biopsies are difficult to obtain, such as non–small cell lung cancer (17–19). As cancer and normal cells undergo apoptosis or necrosis, they shed cell-free DNA (cfDNA) into the bloodstream which can be isolated from peripheral blood (20–22). Patients with mCRPC are frequently found to have sufficiently high fractions of tumor-derived cfDNA (23, 24), containing the DNA from primary and metastatic lesions (21) for tumor profiling through NGS. High fractions of circulating tumor DNA (ctDNA) have been reported to be associated with poor prognosis in mCRPC (25, 26). Sequencing of cfDNA has shown high concordance with tissue sequencing of metastatic biopsies in several tumor types, including mCRPC (27), and is suitable to help guide patient treatment. In contrast to tissue biopsies, the collection of plasma is minimally invasive for patients, ubiquitously accessible, and easily repeatable over the course of the disease.

Studies have demonstrated high concordance between BRCA alterations in the plasma and tissue of patients with mCRPC (3, 28), but no comparative analyses of clinical efficacy in patients who are BRCA⁺ prospectively identified through plasma or tissue testing have been reported, and skepticism towards the clinical applicability of targeted treatment in patients selected through plasma testing remains (2). Of concern are potential false positive results from the cfDNA assay due to technical (2) or biological factors, such as low variant allele frequency (AF) and clonal hematopoiesis of indeterminate potential (CHIP; ref. 29). Although very rarely seen in BRCA, recent analyses found CHIP mutations in non-BRCA DNA damage repair (DDR) genes frequently reported as tumor originating alterations during plasma testing of patients with advanced prostate cancer when sequencing of a matched normal sample is not performed (30). In patients with low tumor burden or less aggressive disease, somatic mutations may be missed due to insufficient amounts of ctDNA, calling into question the suitability of plasma assays to select patients for PARP inhibitor therapy (31, 32). Here, we compare clinical responses to rucaparib in patients with a deleterious BRCA alteration identified by plasma, tissue, or local testing and evaluate the concordance between the selection methodologies.

TRITON2 (NCT02952534) is an ongoing, international, open-label, phase II study evaluating rucaparib in patients with mCRPC associated with DDR deficiency. Men aged ≥18 years with histologically or cytologically confirmed mCRPC, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function were enrolled. Eligible patients had a deleterious germline or somatic alteration in BRCA1, BRCA2, or one of 13 other DDR genes (ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD54L) and disease progression following one to two lines of next-generation androgen receptor (AR)–directed therapy for prostate cancer and one prior taxane-based chemotherapy for castration-resistant disease. Patients treated with a PARP inhibitor, mitoxantrone, cyclophosphamide, or platinum-based chemotherapy, or with an active secondary malignancy were excluded. Patients were enrolled irrespective of measurable disease status.

Patients received a starting dose of 600 mg oral rucaparib twice daily. Dose reductions, in decrements of 100 mg, were permitted in case of grade ≥3 or persistent grade 2 treatment-emergent adverse events.

The study was approved by national or local institutional review boards and performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Patients provided written informed consent before participation.

The primary endpoint was objective response rate (ORR) by blinded independent radiology review (IRR) per modified Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST) and Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria in patients with measurable disease by IRR. Confirmed locally assessed prostate-specific antigen (PSA) response (≥50% decrease from baseline confirmed by a second measurement ≥3 weeks later) in all patients was a secondary endpoint. Duration of response (DOR) was defined as the time from the date of the first confirmed response to the date progression was first documented plus one day, and summarized using Kaplan–Meier methodology.

Efficacy analyses included patients who were BRCA⁺ enrolled by the cut-off date of May 8, 2019. The visit cut-off date was December 23, 2019; therefore, patients had a minimum of 16 weeks of follow up, allowing for at least two radiographic tumor assessments and confirmation of response.

Patients were enrolled by 3 assay groups used to detect deleterious BRCA alterations: central tissue or central plasma testing or by documented evidence of a deleterious alteration from an existing test result performed locally. Patients were encouraged to submit both plasma and tissue samples for central testing. An additional blood sample for central germline testing was collected.

The central tissue assay was the FoundationOne laboratory developed test (F1 LDT) for NGS of 395 cancer-related genes (including BRCA) from formalin-fixed paraffin-embedded tissue (33). The central plasma assay was the FoundationOneLiquid laboratory developed test (F1 L LDT) using circulating cfDNA isolated from plasma to sequence 70 cancer-related genes (including BRCA; ref. 20). Both central NGS assays detected germline and somatic alterations but did not distinguish between them. The Color Hereditary Cancer Test (34) was used to determine the germline status of BRCA alterations.

All assays were executed in Clinical Laboratory Improvement Amendments (CLIA)–certified and College of American Pathologists (CAP)–accredited laboratories.

By the cut-off date, the TRITON2 study had enrolled 115 patients with a BRCA alteration. Clinical analyses of safety and efficacy in patients who were BRCA⁺ have been published (1). Patients who were BRCA⁺ were enrolled based on deleterious alterations in BRCA identified by central plasma (n = 34) or central tissue (n = 37) testing or by documented evidence of a deleterious alteration from local testing (n = 44; Fig. 1). Patients were encouraged to submit plasma and tissue (contemporaneous or archival) samples for central testing. Several patients were BRCA⁺ by both sample types. In those cases, the test result used for enrollment was the result that became available first. Due to this approach, most patients had 2 or more test results: 61 patients had a BRCA⁺ plasma result, 59 a BRCA⁺ tissue result, and 38 had both. Results from central germline testing were available for all patients. An overview of patients who were BRCA⁺ and test data is shown in Fig. 1.

BRCA alterations identified by central tissue or local test results included all alteration types (Fig. 2). The plasma assay was not validated to detect homozygous BRCA deletions, and no patients with this alteration type were identified by the plasma assay.

Central plasma testing was used to enroll 34 of 115 (30%) patients who were BRCA⁺, of whom 35% (12/34) had a germline and 65% (22/34) had a somatic alteration. The most common alteration types were frameshift (62%, 21/34) and nonsense (15%, 5/34) mutations. A subset of 21 patients enrolled by the plasma assay did not have a tissue sample available and was tested solely with the central plasma test.

Central tissue testing was used to enroll 37 of 115 (32%) patients who were BRCA⁺, among them 43% (16/37) with a germline and 57% (21/37) with a somatic alteration. Homozygous BRCA deletions were detected in 41% (15/37) of patients' tissues and frameshift mutations in 30% (11/37).

A variety of local tests were used to enroll 44 (38%) patients who were BRCA⁺, most commonly by NGS-based gene panels (80%, 35/44 patients) or germline tests (20%, 9/44 patients). Of the local assays, 70% (31/44) were based on tissue profiling. Most prevalent were the FoundationOne (ref. 33; 18%, 8/44 patients) and MSK-IMPACT (ref. 35; 16%, 7/44 patients) tests. Plasma-based cfDNA assays were utilized for 9% (4/44) of patients enrolled by local testing; FoundationOne Liquid (20) was used most frequently (5%, 2/44 patients). Blood-based germline tests were used for 20% (9/44) of the patients enrolled by local testing, with tests from Myriad Genetics (ref. 36; 5%, 2/44) and Ambry Genetics (ref. 37; 5%, 2/44) being the most common. Local testing identified a wide range of BRCA alterations: 43% (19/44) were germline and 57% (25/44) were somatic. Patients most commonly had frameshift alterations (55%, 24/44) or homozygous BRCA loss (14%, 6/44).

Overall, of 115 patients who were BRCA⁺ in TRITON2, 13 (11%) had a BRCA1 and 102 (89%) had a BRCA2 alteration. BRCA alterations were germline in 41% (47/115) of patients and somatic in 59% (68/115).

No confounding differences were observed in baseline demographics or prognostic factors in patients across the 3 enrollment assay groups.

Both plasma and tissue data were available for 38 patients who were BRCA⁺ and used to evaluate concordance of BRCA status between the assays. Tissue samples were mostly archival prostate tumor samples (84%; 32/38) with a median age of 3.5 years (range, 25 days–19.1 years). Six (16%) patients submitted metastatic samples, of which 5 were taken within 1 year of NGS testing (range, 2.2–9.6 months). Plasma samples were collected prior to dosing on the first day of treatment.

In the analysis of concordance between the two assay types, the BRCA alterations used for enrollment were found in both tissue and plasma samples among 74% (28/38) of patients.

BRCA alterations in these patients were 50% (19/38) of germline and 50% (19/38) of somatic origin. All 19 germline alterations were detected in both tissue and plasma.

Concordant BRCA status was observed in 47% (9/19) of patients with somatic BRCA alterations. Only 1 patient in this subset had a homozygous deletion, suggesting that the discordance was predominantly due to other biological and technical challenges. For example, in 4 patients a BRCA alteration was detected in the archival tissue but not the plasma. The maximum somatic AF observed in these plasma samples was below 3%. One plasma sample was void of any alterations entirely, indicating no or very low levels of tumor DNA. One of the 4 patients in this group [25%; 95% confidence interval (CI), 0.6–80.6] had a PSA response. Another patient had measurable disease but neither a PSA nor a radiographic response.

In the reverse analysis, 6 patients were BRCA⁺ by plasma but BRCA⁻ by tissue testing. All 6 tissue samples were archival prostate samples with a median age of 2.6 years (range, 11 months–11.5 years), and half (3/6) had low tumor purity (<25%). The majority (67%, 4/6) of BRCA alterations in the matched plasma samples were of very low (<1%) AF, suggesting subclonality. None of these 6 patients had a PSA response, and neither of the 2 patients with measurable disease had a radiographic response.

Patient level genomics and responses from 113 PSA response-evaluable patients were grouped by enrollment assay and detailed in Fig. 3. Two patients did not meet the follow-up criteria required to be response evaluable and were excluded from the analyses.

Patients enrolled by the central tissue assay had a confirmed PSA response rate of 62.2% (95% CI, 44.8–77.5; 23/37; Fig. 4), where 15 patients with homozygous BRCA loss identified by tissue testing had higher PSA response rates (80.0%; 95% CI, 51.9–95.7; 12/15), compared with patients with other BRCA alteration types (50.0%; 95% CI, 28.2–71.8; 11/22). The median duration of PSA response was 9.0 months (range, 1.0–25.8+) in all patients enrolled by tissue, compared with 2.2 months (range, 1.0–9.0) in patients without homozygous BRCA loss and not yet reached (range, 2.7–25.8+ months) in those with homozygous BRCA loss.

Patients enrolled by the central plasma assay had a PSA response rate of 41.2% (95% CI, 24.6–59.3; 14/34), and a median duration of PSA response of 6.3 months (range, 3.7–11.7+). The PSA response rate in patients enrolled by local assays was 59.1% (95% CI, 43.2–73.7; 26/44) with a median duration of PSA response of 4.6 months (range, 1.4–29.4+). The 95% CIs overlapped in response rates across all 3 groups. PSA response rates in all patients with germline BRCA alterations were 61.7% (95% CI, 46.4–75.5; 29/47) and 50.0% in patients with somatic alterations (95% CI, 37.6–62.4; 34/68).

Confirmed ORR by enrollment assay was evaluated in 62 patients with measurable disease: patients enrolled by central tissue testing had an ORR of 55.0% (95% CI, 31.5–76.9; 11/20), compared with 31.3% (95% CI, 11.0–58.7; 5/16) in patients enrolled by central plasma test and 42.3% (95% CI, 23.4–63.1; 11/26) in patients enrolled by local test, while the 95% CIs overlapped across all 3 groups (Fig. 4). Patients enrolled by the tissue test and with homozygous BRCA loss had an ORR of 70.0% (95% CI, 34.8–93.3; 7/10), compared with 40.0% (95% CI, 12.2–73.8; 4/10) in those without homozygous loss. Duration of response was not yet reached (range, 2.3–23.0+ months) in patients enrolled by tissue testing, including patients with homozygous BRCA loss (median not yet reached; range, 4.0–23.0+ months) and without (6.8 months; range, 2.3–12.0+), compared with 6.6 months (range, 4.0–7.7+) in patients enrolled by plasma testing and not yet reached (range, 1.7–24.0+ months) in patients enrolled based on an existing local test result.

Reduction in sum of target lesions is shown in Supplementary Fig. S1. The ORR was 45.8% in patients with a germline BRCA alteration (95% CI, 25.6–67.2; 11/24) and 42.1% in patients with a somatic alteration (95% CI, 26.3–59.2; 16/38).

Assessment of efficacy by plasma and tissue assays was performed in the subgroups of all patients BRCA⁺ by plasma (n = 61) and/or tissue test (n = 59), regardless of their enrollment assay. Consistent with the results above, PSA reductions in the 2 groups were not different (Fig. 5). Patients with homozygous BRCA deletions in tissue frequently showed significant PSA reductions and responses. PSA response rate in patients BRCA⁺ by the plasma assay was 47.5% (95% CI, 34.6–60.7; 29/61) compared with 57.6% in patients BRCA⁺ by tissue testing (95% CI, 44.1–70.4; 34/59; Fig. 4). Radiographic response rates were also not different in the subsets of patients with measurable disease and BRCA⁺ by plasma or tissue testing.

Twenty-one patients who were BRCA⁺ were unable to provide a tissue sample and enrolled by plasma testing (Fig. 1). These patients showed a PSA response rate of 52.4% (95% CI, 29.8–74.3; 11/21) and radiographic responses in 4 of 10 patients with measurable disease (40.0%; 95% CI, 12.2–73.8; Fig. 4), with rates not different to those in patients BRCA⁺ by tissue testing. Patients in this group most commonly had frameshift mutations (42%; 11/21), nonsense mutations (19%; 4/21), or rearrangements (19%; 4/21; Supplementary Fig S2). BRCA alterations were germline in 29% (6/21) and somatic in 71% (15/21) of patients.

The PARP inhibitor rucaparib was approved for patients with BRCA⁺ mCRPC based on results from the TRITON2 study (1). Selection of patients who were BRCA⁺ occurred through central genomic testing of plasma or tissue and by local test result. Radiographic and PSA responses were observed independent of the assay type used to identify patients.

Both tissue and plasma assays face biological, technical, and practical challenges in the identification of patients who were BRCA⁺. Tumor tissue testing has long been a reliable method to assess genomics in patients with mCRPC, but lack of accessible lesions or archival tissue of adequate quality is often prohibitive to assessing tumor BRCA. In addition, a single-site tissue biopsy may not adequately reflect the landscape of somatic tumor heterogeneity that can develop. In contrast, patients' plasma contains DNA from primary and metastatic lesions and can be readily collected from a minimally invasive blood draw. The data presented here provide evidence that plasma testing can detect germline and somatic driver mutations of mCRPC and identify alterations that arise through tumor heterogeneity, which in some cases may be subclonal. A technical challenge for plasma-based assays has been the detection of copy-number loss, and the plasma assay used for TRITON2 enrollment did not identify patients with homozygous BRCA deletions. Patients with this alteration type have been reported to respond particularly well to rucaparib (38), and their identification has been a priority in the technical advancement of plasma-based assays. Consequentially, the plasma assay used for TRITON2 enrollment has since been updated to the FDA-approved FoundationOneLiquid CDx (39), which detects and reports homozygous BRCA deletions.

Data from 115 patients who were BRCA⁺ enrolled in TRITON2 have shown that plasma and tissue samples from central or local testing can be used to identify patients with mCRPC as BRCA⁺. Across these assay groups, patients' genomic characteristics with respect to germline status and alteration type were comparable with those reported in the literature (4, 7). The concordance between patients' somatic BRCA status determined from plasma or tissue testing was 47% in 38 patients with paired samples.

In the 4 cases where the plasma test did not detect BRCA alterations found in tissue, there was evidence of minimal to no tumor DNA shedding in blood (estimated tumor fraction 0% to 3.7%) and lower disease burden (no visceral metastases, 2/4 with <10 bone metastases). Conversely, in 6 patients, the plasma assay detected a BRCA alteration which was not observed in the patient's tissue. While there were no outstanding trends in patient characteristics or clinical factors in this discordant group, the BRCA⁻ tissue samples were mainly archival and frequently had low tumor purity. Simultaneously, the majority of BRCA alterations detected only in plasma were of low AF and likely subclonal. These results suggest that discordance may arise from tumor heterogeneity or lack of sample purity, and larger datasets will be required to assess the impact of these factors on response to therapy.

Radiographic and PSA responses were observed in patients with mCRPC with a BRCA alteration identified by central plasma, central tissue, or local testing. Although patients who were BRCA⁺ by plasma test were found to have numerically lower ORR and PSA response rates compared with patients who were BRCA⁺ by central tissue or local testing, these differences were not statistically significant, and the study was underpowered to draw definitive conclusions about differences in outcomes based on enrollment assay. A factor in this imbalance was the lack of well performing patients with homozygous BRCA deletions combined with an enrichment of patients with subclonal BRCA alterations within the plasma selected group. A subset of patients was unable to provide tissue samples and were assessed solely with the plasma assay. Some patients who were BRCA⁺ in this subgroup experienced objective and PSA responses, suggesting that plasma testing can be a valuable tool to identify patients who may benefit from PARP inhibitor therapy. While patients who were BRCA⁺ may be identified by a variety of assays, determining the best option for any given patient may depend on many clinical and circumstantial factors and relies on clinicians' discretion.

The potential for CHIP has raised concerns about the origin of somatic DDR gene alterations detected by plasma assays (31, 32), and the dataset presented here does not include sequencing of matched whole-blood controls. While we cannot ascertain the tumoral origin of the somatic BRCA alterations, we reason that they are unlikely to be CHIP mutations. In contrast to other DDR genes, BRCA is not frequently associated with CHIP: no case of CHIP in BRCA1 and only 1 case in BRCA2 has been reported in advanced prostate cancer (30). Nevertheless, in cases that were identified as BRCA⁺ in plasma at low AF but not in tissue, CHIP cannot be ruled out.

A strength of our analysis is the large amount of central genomic testing data in association with clinical outcome data. The analysis is limited because the collection of plasma and tissue samples was not concomitant, and metastatic tissue samples were rarely available. Given the expected intratumoral heterogeneity, we are unable to use the tissue NGS data as a ground truth reference for patients' genomics to determine the positive predictive value of the plasma assay. Although TRITON2 did enroll patients with alterations in other DDR genes, the analyses presented here only include patients who were BRCA⁺ and do not allow for the calculation of the negative predictive value of the plasma assay.

In summary, the analyses of concordance and efficacy among genomic testing data from the TRITON2 study demonstrated that plasma, tissue, or local testing of patients with mCRPC can be used to identify patients with BRCA⁺ mCRPC who can benefit from treatment with the PARP inhibitor rucaparib.

A. Loehr reports other support from Clovis Oncology, Inc., during the conduct of the study. A. Patnaik reports other support from Clovis Oncology, Inc., during the conduct of the study as well as grants from Bristol-Myers Squibb and other support from Progenics, Laekna Inc, Exelixis, Prime, Jounce Therapeutics, Janssen, and Merck outside the submitted work. J. Shapiro has served in a consulting or advisory role for Amgen, Astellas, Ipsen, Merck, and Roche and received financial support for travel from Amgen and Merck. A.H. Bryce reports personal fees from Merck, Astellas, Bayer, and Pfizer outside the submitted work. R. McDermott reports personal fees from Clovis Oncology, Inc., during the conduct of the study as well as personal fees from Bayer, MSD, Sanofi, Janssen, Astellas, BMS, Pfizer, and Novartis outside the submitted work. B. Sautois reports other support from Clovis Oncology, Inc., during the conduct of the study as well as personal fees from Janssen, Astellas, and Sanofi outside the submitted work. N.J. Vogelzang reports personal fees from Clovis Oncology, Inc., AstraZeneca, and Pfizer during the conduct of the study. R.M. Bambury reports educational grant support and honoraria from Pfizer, Roche, Janssen, Astellas, and BMS; in addition, R.M. Bambury is the co-founder of Portable Medical Technology Ltd. J. Zhang reports personal fees from Clovis Oncology, Inc., during the conduct of the study as well as grants and personal fees from Astellas, Bayer, and AstraZeneca and personal fees from Merck outside the submitted work. J.M. Piulats reports grants and personal fees from MSD, Pfizer, and Janssen; grants from BeiGene; and nonfinancial support from Clovis Oncology, Inc., during the conduct of the study as well as personal fees from Astellas, Bayer, and Roche and grants, personal fees, and nonfinancial support from BMS outside the submitted work. A. Hussain reports other support from Clovis Oncology, Inc., during the conduct of the study as well as personal fees from Bayer, Merck, and Aveo Pharmaceuticals outside the submitted work; in addition, A. Hussain serves as institutional principal investigator (PI) on several sponsored clinical trials in prostate cancer, renal cancer, and bladder cancer where the respective sponsors provide funding directly to the institution (University of Maryland Greenebaum Comprehensive Cancer Center) to help defray costs of running the clinical trials. C.J. Ryan has received research support from Clovis Oncology, Inc., and has served as a consultant for AstraZeneca and Bayer. A.S. Merseburger reports personal fees, nonfinancial support, and other support from Clovis Oncology, Inc., during the conduct of the study as well as personal fees and nonfinancial support from AstraZeneca, Astellas, Janssen, Pfizer, and Ipsen outside the submitted work. G. Daugaard has served in a consulting or advisory role for Clovis Oncology, Inc., Astellas, AstraZeneca, Janssen, Merck, and Sanofi. A. Heidenreich reports personal fees from Clovis Oncology, Inc., during the conduct of the study as well as personal fees from Astellas, Bayer, Ipsen, Janssen, Pfizer, Takeda and MSD and grants and personal fees from Amgen and BMS outside the submitted work. K. Fizazi reports personal fees from Bayer, CureVac, and Orion and nonfinancial support from Astellas, Sanofi, Janssen, AstraZeneca, Clovis Oncology, Inc., and Novartis outside the submitted work. C.S. Higano reports grants and personal fees from Clovis Oncology, Inc., during the conduct of the study as well as personal fees and other support from Advanced Accelerator Applications, Blue Earth, Janssen, and Merck; grants from Aptevo, Emergent, Hoffman-LaRoche, and Medivation; grants, personal fees, and other support from Astellas, AstraZeneca, and Ferring; grants and personal fees from Bayer, Dendreon, Genetech, and Pfizer; and other support from Exelixis outside the submitted work. L.E. Krieger reports personal fees from Clovis Pharmaceuticals outside the submitted work. C.N. Sternberg reports personal fees from Clovis Oncology, Inc., during the conduct of the study as well as personal fees from Pfizer, BMS, Sanofi-Genzyme, MSD, Merck, Roche-Genentech, Incyte, Foundation Medicine, Immunomedics, Medscape, UroToday, Janssen, CCO Clinical, and NCI outside the submitted work. S.P. Watkins reports other support from Clovis Oncology, Inc., during the conduct of the study as well as other support from Clovis Oncology, Inc., outside the submitted work. D. Despain reports other support from Clovis Oncology, Inc., outside the submitted work; in addition, D. Despain is an employee of Clovis Oncology, Inc., the sponsor of rucaparib and the TRITON2 study. A.D. Simmons reports other support from Clovis Oncology, Inc., during the conduct of the study. M. Dowson reports personal fees from Clovis Oncology, Inc., outside the submitted work. T. Golsorkhi reports other support from Clovis Oncology, Inc., during the conduct of the study. S. Chowdhury reports grants and personal fees from Clovis Oncology, Inc., and personal fees from AstraZeneca, Novartis, Janssen, Bayer, Telix, Astellas, Huma, and Remedy Bio during the conduct of the study. W. Abida reports personal fees from Clovis Oncology, Inc., Roche, Medscape, Onclive, Clinical Education Alliance, Aptitude Health, Janssen, ORIC Pharmaceuticals, and Daiichi and other support from Clovis Oncology, Inc., during the conduct of the study as well as other support from AstraZeneca, Zenith Epigenetics, ORIC Pharmaceuticals, and Epizyme outside the submitted work. No disclosures were reported by the other authors.

A. Loehr: Conception and design, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. A. Patnaik: Provision of study materials or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. D. Campbell: Provision of study materials or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. J. Shapiro: Provision of study materials or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. A.H. Bryce: Provision of study materials or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. R. McDermott: Provision of study materials or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. B. Sautois: Provision of study materials or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. N.J. Vogelzang: Provision of study materials or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. R.M. Bambury: Provision of study materials or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. E. Voog: Provision of study materials or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. J. Zhang: Provision of study materials or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. J.M. Piulats: Provision of study materials or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. A. Hussain: Provision of study materials or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. C.J. Ryan: Provision of study materials or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. A.S. Merseburger: Provision of study materials or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. G. Daugaard: Provision of study materials or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. A. Heidenreich: Provision of study materials or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. K. Fizazi: Provision of study materials or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. C.S. Higano: Provision of study materials or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. L.E. Krieger: Provision of study materials or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. C.N. Sternberg: Provision of study materials or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. S.P. Watkins: Conception and design, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. D. Despain: Data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. A.D. Simmons: Conception and design, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. M. Dowson: Data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. T. Golsorkhi: Conception and design, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. S. Chowdhury: Conception and design, provision of study materials or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work. W. Abida: Conception and design, provision of study materials or patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript, accountability for all aspects of the work.

This work was funded by Clovis Oncology, Inc., and supported in part by the NCI Cancer Center Support Grant No. P30-CA008748, NCI Prostate Specialized Program of Research Excellence (SPORE) Grant No. P50-CA092629-16, Department of Defense Prostate Cancer Research Program Grant No. W81XWH-17-1-0124, and a Prostate Cancer Foundation Young Investigator Award (to W. Abida), and supported in part by a Prostate Cancer Foundation Challenge Award and NCI Prostate SPORE Grant No. P50-CA180995 (to A. Patnaik). Editorial support funded by Clovis Oncology, Inc., was provided by Shelly Lim and Stephen Bublitz of Ashfield MedComms, an Ashfield Health company.

Research support for the study: This study was funded by Clovis Oncology, Inc.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.