A Phase 3 Strategy for Earlier Treatment

For patients with metastatic castration-sensitive prostate cancer (mCSPC) and homologous recombination repair (HRR) gene alterations, treatment intensification remains an important clinical need. At the 2026 ASCO Annual Meeting, investigators presented results from TALAPRO-3, a phase 3 trial evaluating whether adding the PARP inhibitor talazoparib to enzalutamide could improve outcomes when used earlier in the disease course.

The rationale builds on evidence from metastatic castration-resistant prostate cancer, including TALAPRO-2, in which talazoparib plus enzalutamide improved radiographic progression-free survival (rPFS). TALAPRO-3 tested this combination in patients with HRR-altered mCSPC receiving androgen-deprivation therapy.

Trial Design and Patient Population

The double-blind trial randomly assigned 599 patients 1:1 to talazoparib 0.5 mg once daily plus enzalutamide 160 mg once daily or placebo plus enzalutamide. Eligible patients had ECOG performance status 0 or 1 and metastatic disease confirmed by bone scan or soft-tissue imaging. HRR alterations were identified through tumor tissue and/or circulating tumor DNA testing. Stratification factors included de novo versus relapsed disease, high- versus low-volume disease, and BRCA1/2 versus non-BRCA alteration status.

The primary end point was investigator-assessed rPFS. Overall survival (OS) was the alpha-protected key secondary end point; other end points included objective response, duration of response, prostate-specific antigen (PSA) response and progression, time to subsequent systemic therapy, symptomatic skeletal events, safety, and patient-reported outcomes. Baseline characteristics were generally well balanced between treatment groups.

Clinically Meaningful Improvement in rPFS

At the February 18, 2026, data cutoff, median follow-up for rPFS was 37.6 months with talazoparib plus enzalutamide and 37.7 months with placebo plus enzalutamide. The combination reduced the risk of radiographic progression or death by 52% (hazard ratio [HR], 0.481; 95% CI, 0.357-0.647; P<.0001). Median rPFS was not reached with talazoparib plus enzalutamide and was 45.8 months in the control group.

Benefit was observed across prespecified clinical subgroups. In the BRCA1/2-altered subgroup, the risk reduction was 63% (HR, 0.368; 95% CI, 0.222-0.609). In the non-BRCA subgroup, the risk reduction was 43% (HR, 0.567; 95% CI, 0.392-0.819). Post hoc analyses also generally favored the combination across individual HRR gene subgroups, although estimates for less common alterations were limited by small patient numbers.

The interim OS analysis favored talazoparib plus enzalutamide but did not cross the prespecified threshold for statistical significance (HR, 0.767; 95% CI, 0.564-1.044; P=.0905). Secondary efficacy findings aligned with the primary result: the combination significantly delayed PSA progression and initiation of subsequent systemic antineoplastic therapy, and prolonged duration of response among patients with measurable disease.

Safety and Patient-Reported Outcomes

Treatment-emergent adverse events (TEAEs) occurred in nearly all patients in both groups. Grade 3 or 4 TEAEs were more frequent with talazoparib plus enzalutamide than with placebo plus enzalutamide (79% vs 41%). The most common all-cause events with the combination were hematologic, particularly anemia and decreased neutrophil counts, along with fatigue. Anemia occurred in 71% of patients receiving talazoparib plus enzalutamide, including grade 3 or 4 anemia in 41%.

Adverse events were generally managed with dose modifications and supportive measures. Permanent discontinuation of talazoparib or placebo because of an adverse event occurred in 19% and 10% of patients, respectively; 5% of patients discontinued talazoparib because of anemia. Despite the higher hematologic toxicity burden, patient-reported outcomes showed no clinically meaningful differences between treatment groups in global quality of life or symptom burden.

Key Takeaways

TALAPRO-3 demonstrates that adding talazoparib to enzalutamide can substantially delay radiographic progression in patients with HRR-altered mCSPC, with benefit in both BRCA and non-BRCA subgroups. The most common adverse events observed were hematologic (anemia, decreased neutrophil count), and fatigue. These results support the use of talazoparib plus enzalutamide as a potential treatment option in HHR gene-altered mCSPC.

Sources

Agarwal N, Matsubara N, Azad AA, et al. TALAPRO-3: phase 3 study of talazoparib plus enzalutamide versus placebo plus enzalutamide for the treatment of patients with metastatic castration-sensitive prostate cancer harboring homologous recombination repair gene alterations. Presented at: 2026 American Society of Clinical Oncology Annual Meeting. Abstract LBA5007. Slide presentation.

Agarwal N, Matsubara N, Azad AA, et al. TALAPRO-3: Talazoparib (TALA) + enzalutamide (ENZA) compared with placebo (PBO) + ENZA for the treatment of patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) harboring homologous recombination repair (HRR) gene alterations. J Clin Oncol. 2026;44(suppl). Abstract LBA5007. doi:10.1200/JCO.2026.44.17_suppl.LBA5007