Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration

Abstract

Purpose: BRCA1 or BRCA2 (BRCA) alterations are common in men with metastatic castration-resistant prostate cancer (mCRPC) and may confer sensitivity to poly(ADP-ribose) polymerase inhibitors. We present results from patients with mCRPC associated with a BRCA alteration treated with rucaparib 600 mg twice daily in the phase II TRITON2 study.

Methods: We enrolled patients who progressed after one to two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy for mCRPC. Efficacy and safety populations included patients with a deleterious BRCA alteration who received ≥ 1 dose of rucaparib. Key efficacy end points were objective response rate (ORR; per RECIST/Prostate Cancer Clinical Trials Working Group 3 in patients with measurable disease as assessed by blinded, independent radiology review and by investigators) and locally assessed prostate-specific antigen (PSA) response (≥ 50% decrease from baseline) rate.

Results: Efficacy and safety populations included 115 patients with a BRCA alteration with or without measurable disease. Confirmed ORRs per independent radiology review and investigator assessment were 43.5% (95% CI, 31.0% to 56.7%; 27 of 62 patients) and 50.8% (95% CI, 38.1% to 63.4%; 33 of 65 patients), respectively. The confirmed PSA response rate was 54.8% (95% CI, 45.2% to 64.1%; 63 of 115 patients). ORRs were similar for patients with a germline or somatic BRCA alteration and for patients with a BRCA1 or BRCA2 alteration, while a higher PSA response rate was observed in patients with a BRCA2 alteration. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (25.2%; 29 of 115 patients).

Conclusion: Rucaparib has antitumor activity in patients with mCRPC and a deleterious BRCA alteration, but with a manageable safety profile consistent with that reported in other solid tumor types.

FIG 1.

Best change from baseline in (A) sum of target lesion(s) in the independent radiology review–evaluable population and in (B) prostate-specific antigen (PSA) in the overall efficacy population. Visit cutoff date: December 23, 2019. In (A), the upper dotted line indicates the threshold for progressive disease, a 20% increase in the sum of the longest diameter of the target lesions, whereas the lower dotted line indicates the threshold for partial response, a 30% decrease in the sum of the longest diameter of the target lesions. In (B), the upper dotted line indicates the threshold for PSA progression, a 25% increase from baseline (accompanied by an absolute increase of ≥ 2 ng/mL above the nadir), whereas the lower dotted line indicates the threshold for PSA response, a 50% decrease from baseline. Bars were capped at 100% for visual clarity. PSA increases for the 4 leftmost patients were 689%, 231%, 183%, and 133%. In both panels, patients with 0% change from baseline are shown as 0.5% for visual clarity.

FIG 2.

Subgroup analysis of objective response rate (ORR) in independent radiology review (IRR)–evaluable population and prostate-specific antigen (PSA) response rate in overall efficacy population by baseline characteristics. Visit cutoff date: December 23, 2019. The vertical dotted line corresponds to the overall ORR or PSA response. (*)One patient received taxane in the hormone-sensitive setting only, which per protocol was not counted as a line of therapy for eligibility; not receiving taxane for castration-resistant prostate cancer was considered a protocol deviation. NA, not applicable.

FIG 3.

Radiographic progression-free survival by blinded independent radiology review assessment. Visit cutoff date: December 23, 2019. Progression was assessed per modified RECIST/PWCG3 criteria. Details on reasons for censoring are provided in the Data Supplement. IRR, independent radiology review; PCWG3, Prostate Cancer Clinical Trials Working Group 3; RECIST, Response Evaluation Criteria In Solid Tumors version 1.1.