Rucaparib or Physician's Choice in Metastatic Prostate Cancer

Abstract

Background: In a phase 2 study, rucaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), showed a high level of activity in patients who had metastatic, castration-resistant prostate cancer associated with a deleterious BRCA alteration. Data are needed to confirm and expand on the findings of the phase 2 study.

Methods: In this randomized, controlled, phase 3 trial, we enrolled patients who had metastatic, castration-resistant prostate cancer with a BRCA1, BRCA2, or ATM alteration and who had disease progression after treatment with a second-generation androgen-receptor pathway inhibitor (ARPI). We randomly assigned the patients in a 2:1 ratio to receive oral rucaparib (600 mg twice daily) or a physician's choice control (docetaxel or a second-generation ARPI [abiraterone acetate or enzalutamide]). The primary outcome was the median duration of imaging-based progression-free survival according to independent review.

Results: Of the 4855 patients who had undergone prescreening or screening, 270 were assigned to receive rucaparib and 135 to receive a control medication (intention-to-treat population); in the two groups, 201 patients and 101 patients, respectively, had a BRCA alteration. At 62 months, the duration of imaging-based progression-free survival was significantly longer in the rucaparib group than in the control group, both in the BRCA subgroup (median, 11.2 months and 6.4 months, respectively; hazard ratio, 0.50; 95% confidence interval [CI], 0.36 to 0.69) and in the intention-to-treat group (median, 10.2 months and 6.4 months, respectively; hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001 for both comparisons). In an exploratory analysis in the ATM subgroup, the median duration of imaging-based progression-free survival was 8.1 months in the rucaparib group and 6.8 months in the control group (hazard ratio, 0.95; 95% CI, 0.59 to 1.52). The most frequent adverse events with rucaparib were fatigue and nausea.

Conclusions: The duration of imaging-based progression-free survival was significantly longer with rucaparib than with a control medication among patients who had metastatic, castration-resistant prostate cancer with a BRCA alteration. (Funded by Clovis Oncology; TRITON3 ClinicalTrials.gov number, NCT02975934.).

Figure 1.. Progression-free Survival in Three Trial Populations.

Shown are Kaplan–Meier curves for imaging-based progression-free survival according to independent review in the BRCA subgroup (Panel A), the intention-to-treat population (Panel B), and the ATM subgroup for rucaparib as compared with a control medication (docetaxel or a second-generation androgen-receptor pathway inhibitor [abiraterone acetate or enzalutamide]). Data maturity was 60% in the BRCA subgroup, 64% in the intention-to-treat population, and 74% in the ATM subgroup. The widths of the 95% confidence intervals were not adjusted for multiplicity and cannot be used in place of hypothesis testing. BRCA denotes BRCA1 and BRCA2, and CI confidence interval.

Figure 2.. Comparison of Progression-free Survival between Rucaparib and Control Medications in the BRCA Subgroup.

Shown are Kaplan–Meier curves for rucaparib as compared with a control medication (docetaxel or a second-generation androgen-receptor pathway inhibitor [ARPI]) in the BRCA subgroup. The widths of the 95% confidence intervals were not adjusted for multiplicity and cannot be used in place of hypothesis testing.

Figure 3.. Risk of Disease Progression or Death in the BRCA Subgroup, According to Variable.

Shown is the risk of imaging-based disease progression or death in the BRCA subgroup according to prespecified variables in the rucaparib group as compared with the control group (second-generation ARPI or docetaxel). ECOG denotes Eastern Cooperative Oncology Group.