Phase 3 Study of Talazoparib Plus Enzalutamide Versus Placebo Plus Enzalutamide as First-Line Treatment in Patients With Metastatic Castration-Resistant Prostate Cancer: TALAPRO-2 Japanese Subgroup Analysis

Abstract

Background: In TALAPRO-2, the poly(ADP-ribose) polymerase inhibitor talazoparib plus the androgen receptor-signaling inhibitor enzalutamide improved radiographic progression-free survival (rPFS) versus placebo plus enzalutamide (hazard ratio [HR] = 0.63; 95% CI, 0.51-0.78) in molecularly unselected patients with metastatic castration-resistant prostate cancer (mCRPC). We report an exploratory analysis of efficacy, safety, and pharmacokinetics in Japanese patients enrolled in the TALAPRO-2 study.

Methods: The ongoing, multinational, randomized, double-blind, phase 3 TALAPRO-2 study enrolled patients with mCRPC receiving ongoing androgen deprivation therapy. Patients were prospectively assessed for homologous recombination repair (HRR) gene alterations and randomized 1:1 to receive talazoparib or placebo plus enzalutamide once daily. The primary endpoint was rPFS by blinded independent central review (BICR). Secondary endpoints included overall survival, objective response, safety, and pharmacokinetics.

Results: For the 116 Japanese all-comers patients enrolled in TALAPRO-2, the HR for rPFS was 0.89 (95% CI, 0.45-1.75) for the talazoparib versus placebo arm; among those with HRR-deficient disease, the HR was 0.58 (95% CI, 0.16-2.20). Among patients with BRCA1/2 gene alterations in the HRR-deficient population (n = 10), the HR for rPFS was < 0.01 (95% CI, < 0.01-not reached) for the talazoparib versus placebo arm. In the all-comers population, the objective response rate by BICR was 55% (all complete responses) in the talazoparib arm versus 36% in the placebo arm. The safety profile of talazoparib plus enzalutamide was similar between Japanese patients and the overall all-comers population; no new safety signals were identified. Anemia was the most common grade 3/4 treatment-emergent adverse event (55%) and cause of talazoparib discontinuation (12%). Talazoparib C_trough was comparable across Japanese, Asian, and non-Asian subgroups.

Conclusions: In this exploratory analysis, efficacy outcomes with talazoparib plus enzalutamide in Japanese patients in TALAPRO-2 were consistent with those in the overall all-comers population. The safety profile and pharmacokinetics of the combination were similar between Japanese patients and the overall all-comers population.

Trial registration: ClinicalTrials.gov Identifier: NCT03395197.

Keywords: Japanese; PARP inhibitor; TALAPRO‐2; enzalutamide; mCRPC; talazoparib.

FIGURE 1

rPFS by BICR: (A) Japanese subgroup; (B) overall population (all‐comers intent‐to‐treat population). BICR, blinded independent central review; CI, confidence interval; rPFS, radiographic progression‐free survival. To maintain the overall type I error at or below one‐sided 0.025, alpha for rPFS by BICR was split equally between the all‐comers and the HRR‐deficient populations (one‐sided alpha of 0.0125 for each). Panel B is reprinted from The Lancet, Volume 402, Agarwal et al., Talazoparib plus enzalutamide in men with first‐line metastatic castration‐resistant prostate cancer (TALAPRO‐2): A randomized, placebo‐controlled, Phase 3 trial, pages 291–303, 2023, with permission from Elsevier.

FIGURE 2

rPFS by BICR by (A) baseline characteristics and (B) BRCA1/2 gene alteration status, and HRR gene alteration status (Japanese subgroup of the all‐comers intent‐to‐treat population). BICR, blinded independent central review; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HRR, homologous recombination repair; M0, nonmetastatic; M1, metastatic; NE, not evaluable; PSA, prostate‐specific antigen; rPFS, radiographic progression‐free survival. ^aHazard ratio for all patients was based on a Cox model stratified by the randomization stratification factors. For all subgroups, hazard ratio was based on an unstratified Cox model with treatment as the only covariate. ^bWith or without PSA progression. ^cAll received docetaxel.

FIGURE 3

Objective response rate by BICR (all‐comers population with measurable disease at baseline). BICR, blinded independent central review; CR, complete response; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.

FIGURE 4

(A) Time to PSA progression and (B) time to initiation of cytotoxic chemotherapy (Japanese subgroup of the all‐comers intent‐to‐treat population). CI, confidence interval; NR, not reached; PSA, prostate‐specific antigen.

FIGURE 5

Summary of the most common (≥ 20% in either treatment arm in the Japanese or overall all‐comers safety population) all‐causality TEAEs in the (A) Japanese subgroup and (B) overall all‐comers population. TEAE, treatment‐emergent adverse event. Incidence of TEAEs by all grades, grade 1/2, and grade 3/4 have been independently rounded to whole numbers or to one decimal place if < 1.

FIGURE 6

(A) Incidence of grade 3/4 hematologic TEAEs^a and (B) change in hemoglobin from baseline in the talazoparib plus enzalutamide arm (Japanese subgroup of the all‐comers safety population). MedDRA, Medical Dictionary for Regulatory Activities; SE, standard error; TEAE, treatment‐emergent adverse event. ^aWithin each week, patients with new reports of TEAEs within the clustered preferred term were counted. MedDRA v25.0 coding dictionary applied. Preferred terms clustered for anemia (anemia, hematocrit decreased, hemoglobin decreased, red blood cell count decreased), neutropenia (neutropenia, neutrophil count decreased), and thrombocytopenia (thrombocytopenia, platelet count decreased).

FIGURE 7

Talazoparib C _trough in Japanese, Asian, and non‐Asian patients (all‐comers pharmacokinetics evaluable population). C _trough, plasma concentration at predose in patients following talazoparib 0.5 mg QD and enzalutamide 160 mg; QD, once daily. Closed circles represent individual participant values, open‐colored circles represent the mean, and black circles represent the geometric mean. For geometric mean, zero values have been removed prior to log transformation. Box plots provide the median, first, and third quartiles with whiskers to the last point within 1.5 times the interquartile range. The remaining summary statistics have been calculated using zero values. ^aThe lower limit of quantification is 0.025 ng/mL; concentrations below this value have been set to zero. ^bIncludes patients enrolled in Republic of Korea and China.