Rucaparib for the Treatment of Metastatic Castration-resistant Prostate Cancer Associated with a DNA Damage Repair Gene Alteration: Final Results from the Phase 2 TRITON2 Study

Abstract

Background: Initial TRITON2 (NCT02952534) results demonstrated the efficacy of rucaparib 600 mg BID in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with a BRCA1 or BRCA2 (BRCA) or other DNA damage repair (DDR) gene alteration.

Objective: To present the final data from TRITON2.

Design, setting, and participants: TRITON2 enrolled patients with mCRPC who had progressed on one or two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy.

Outcome measurements and statistical analysis: The primary endpoint was objective response rate (ORR; as per the modified Response Evaluation Criteria in Solid Tumor Version 1.1/Prostate Cancer Clinical Trials Working Group 3 criteria in patients with measurable disease by independent radiology review [IRR]); prostate-specific antigen (PSA) response rate (≥50% decrease from baseline [PSA50]) was a key secondary endpoint.

Results and limitations: As of July 27, 2021 (study closure), TRITON2 had enrolled 277 patients, grouped by mutated gene: BRCA (n = 172), ATM (n = 59), CDK12 (n = 15), CHEK2 (n = 7), PALB2 (n = 11), or other DDR gene (Other; n = 13). ORR by IRR was 46% (37/81) in the BRCA subgroup (95% confidence interval [CI], 35-57%), 100% (4/4) in the PALB2 subgroup (95% CI, 40-100%), and 25% (3/12) in the Other subgroup (95% CI, 5.5-57%). No patients within the ATM, CDK12, or CHEK2 subgroups had an objective response by IRR. PSA50 response rates (95% CI) in the BRCA, PALB2, ATM, CDK12, CHEK2, and Other subgroups were 53% (46-61%), 55% (23-83%), 3.4% (0.4-12), 6.7% (0.2-32%), 14% (0.4-58%), and 23% (5.0-54%), respectively.

Conclusions: The final TRITON2 results confirm the clinical benefit and manageable safety profile of rucaparib in patients with mCRPC, including those with an alteration in BRCA or select non-BRCA DDR gene.

Patient summary: Almost half of TRITON2 patients with BRCA-mutated metastatic castration-resistant prostate cancer had a complete or partial tumor size reduction with rucaparib; clinical benefits were also observed with other DNA damage repair gene alterations.

Keywords: DNA damage repair gene alteration; Metastatic castration-resistant prostate cancer; Poly(ADP-ribose) polymerase inhibitor.

FIG. 1

PATIENT FLOW DIAGRAM. DDR = DNA damage repair; IRR = independent radiology review. ^a A total of 187 patients were enrolled based on eligible alterations detected from central screening of tissue and/or plasma samples; 90 patients were enrolled based on the results from local genomic testing. The study closed on July 27, 2021; 23 patients continued to receive rucaparib outside of the study after study closure (BRCA [n = 19], CHEK2 [n = 1], and other DDR gene [n = 3]).

FIG. 2

FOREST PLOTS OF ORR AND PSA50 RESPONSE RATE BY SUBGROUP. The vertical dotted line corresponds to the ORR or PSA50 response in the BRCA-mutated group. CI = confidence interval; IRR = independent radiology review; ORR = objective response rate; PSA50 = prostate-specific antigen ≥50% decrease from baseline.

FIG. 3.

Best change from baseline in (A) sum of target lesion(s) in the IRR-evaluable population and (B) PSA in the overall efficacy population. In Figure 3A, the upper dotted line indicates the threshold for progressive disease, a 20% increase in the sum of the longest diameter of the target lesions; 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 Figure 3B), 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); 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 15 leftmost patients were 689%, 373%, 319%, 231%, 220%, 183%, 146%, 142%, 133%, 132%, 126%, 125%, 109%, 106%, and 101%. In both panels, patients with 0% change from baseline are shown as 0.5% for visual clarity. IRR = independent radiology review; PSA50 = prostate-specific antigen ≥50% decrease from baseline.

Fig. 4

Kaplan-Meier curves for (A) IRR-assessed rPFS and (B) OS. CI = confidence interval; IRR = independent radiology review; NR = not reached; OS = overall survival; rPFS = radiographic progression-free survival.