First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial

Abstract

Preclinical evidence has suggested an interplay between the androgen receptor, which largely drives the growth of prostate cancer cells, and poly(ADP-ribose) polymerase. This association provides a rationale for their co-inhibition for the treatment of metastatic castration-resistant prostate cancer (mCRPC), an area of unmet medical need. The phase 3 TALAPRO-2 study investigated combining the poly(ADP-ribose) polymerase inhibitor talazoparib with enzalutamide versus enzalutamide alone as first-line treatment of mCRPC. Patients were prospectively assessed for tumor alterations in DNA damage response genes involved in homologous recombination repair (HRR). Two cohorts were enrolled sequentially: an all-comers cohort that was enrolled first (cohort 1; N = 805 (169 were HRR-deficient)), followed by an HRR-deficient-only cohort (cohort 2; N = 230). We present results from the alpha-controlled primary analysis for the combined HRR-deficient population (N = 399). Patients were randomized in a 1:1 ratio to talazoparib or placebo, plus enzalutamide. The primary endpoint, radiographic progression-free survival, was met (median not reached at the time of the analysis for the talazoparib group versus 13.8 months for the placebo group; hazard ratio, 0.45; 95% confidence interval, 0.33 to 0.61; P < 0.0001). Data for overall survival, a key secondary endpoint, are immature but favor talazoparib (hazard ratio, 0.69; 95% confidence interval, 0.46 to 1.03; P = 0.07). Common adverse events in the talazoparib group were anemia, fatigue and neutropenia. Combining talazoparib with enzalutamide significantly improved radiographic progression-free survival in patients with mCRPC harboring HRR gene alterations, supporting talazoparib plus enzalutamide as a potential first-line treatment for these patients. ClinicalTrials.gov Identifier: NCT03395197 .

Fig. 1. Trial profile.

Flow diagram showing participant recruitment into the HRR-deficient population, randomization, follow-up and analysis populations.

Fig. 2. rPFS in patients with any HRR gene alteration (assessed by blinded independent central review; HRR-deficient intention-to-treat population).

rPFS was compared between treatment groups using stratified log-rank test. HRs and associated 95% two-sided CIs were estimated by a Cox proportional hazards model. Median time to event was estimated by the Kaplan–Meier method, and 95% CIs were based on the Brookmeyer–Crowley method. The P value is two-sided. NR, not reached at the time of the analysis.

Fig. 3. Subgroup analysis of rPFS.

a,b, Subgroup analysis of rPFS by baseline characteristics (a) and by gene subgroups (b) (assessed by blinded independent central review; HRR-deficient intention-to-treat population). The overall HR for all patients, and by BRCA1/BRCA2 alteration status, was based on a Cox proportional hazards model stratified by the randomization stratification factors. For all other subgroups, the HR was based on an unstratified Cox model with treatment as the only covariate. Data are presented as HRs with two-sided 95% CIs. P values are two sided. The asterisk indicates the inclusion of one patient in each treatment arm who received prior orteronel. †Excludes four patients who did not have HRR gene alterations but were incorrectly randomized to the HRR-deficient population; including these patients resulted in an HR of 0.72 (95% CI, 0.49 to 1.07) for the non-BRCA alterations subgroup. ‡Post hoc exploratory analysis; as this analysis was underpowered, the data are hypothesis-generating and should be interpreted with caution. Gene clustering alteration dominance hierarchy is any BRCA1/BRCA2 alteration (BRCA cluster), then any PALB2 (PALB2 cluster), next any CDK12 (CDK12 cluster), then any ATM (ATM cluster), and finally, any of all other genes (with each patient counted only once). For the single-gene subgroups, only patients bearing alteration(s) in the designated HRR gene and none of the other HRR genes tested are shown, with a prevalence cutoff for display of ≥10 across arms. PS, performance status.

Fig. 4. Secondary efficacy endpoints.

a–e, Secondary efficacy endpoints: overall survival (a), objective response (b), time to PSA progression (c), time to initiation of cytotoxic chemotherapy (d) and PFS2 (e) (HRR-deficient intention-to-treat population). Time-to-event endpoints were compared between treatment groups using a stratified log-rank test. HRs and associated 95% two-sided CIs were estimated by a Cox proportional hazards model. Median time-to-event endpoints were estimated by the Kaplan–Meier method, and 95% CIs were based on the Brookmeyer–Crowley method. P values are two sided. The asterisk denotes that PFS2 was based on investigator assessment (time from randomization to the date of documented progression on the first subsequent antineoplastic therapy or death from any cause, whichever occurs first). CR, complete response; ORR, objective response rate; PD, progressive disease; PFS2, progression-free survival 2; PR, partial response; SD, stable disease.

Extended Data Fig. 1. Study Cohorts and Enrollment.

*An interim analysis (IA) was planned with ~70% of the total required events. The HRRm cohort would be stopped for efficacy if the pre-specified efficacy boundary was crossed (P ≤ 0.003). As the efficacy boundary was crossed at the IA rPFS, this became the final analysis. Survival and safety follow-up is continuing. All other endpoints are final. HRR denotes homologous recombination repair, HRRm HRR mutation-positive, and rPFS radiographic progression-free survival.

Extended Data Fig. 2. Investigator-Assessed rPFS (HRR-Deficient Intention-to-Treat Population).

rPFS was compared between treatment groups using stratified log-rank test. HRs and associated 95% two-sided CIs were estimated by a Cox proportional hazards model. Median time to event was estimated by the Kaplan-Meier method, and 95% CIs based on the Brookmeyer-Crowley method. The P value is two-sided. CI denotes confidence interval, HR hazard ratio, HRR homologous recombination repair, NR not reached at the time of the analysis, and rPFS radiographic progression-free survival.