Talazoparib Plus Enzalutamide Cuts Progression Risk by 52% in HRR–Altered mCSPC

Adding talazoparib to enzalutamide reduced the risk of radiographic progression or death by 52% compared with enzalutamide alone in men with homologous recombination repair (HRR) gene–altered metastatic castration-sensitive prostate cancer (mCSPC), according to findings from the phase 3 TALAPRO-3 trial (NCT04821622) presented at the 2026 American Society of Clinical Oncology Annual Meeting.¹

The primary end point of investigator-assessed radiographic progression-free survival (rPFS) was met with a highly significant and clinically meaningful result. At a median follow-up of 37.6 months in the talazoparib/enzalutamide arm and 37.7 months in the placebo/enzalutamide arm, the median rPFS was not reached (NR; 95% CI, NR-NR) with talazoparib/enzalutamide vs 45.8 months (95% CI, 37.7-NR) with placebo/enzalutamide (HR, 0.481; 95% CI, 0.357-0.647; P < .0001), representing a 52% reduction in the risk of radiographic progression or death. The 36-month rPFS rate was 76.6% (95% CI, 70.8-81.4) with talazoparib/enzalutamide vs 56.2% (95% CI, 50.0-62.0) with placebo/enzalutamide.

The rPFS benefit was observed across both BRCA1/2-mutated (BRCAm) and non-BRCAm subgroups. In the BRCAm subgroup (talazoparib/enzalutamide, n = 104; placebo/enzalutamide, n = 103), the median rPFS was NR vs 35.1 months (95% CI, 18.6-NR), respectively (HR, 0.368; 95% CI, 0.222-0.609; P < .0001), representing a 63% risk reduction. In the non-BRCAm subgroup (n = 196 each arm), median rPFS was NR in both arms (HR, 0.567; 95% CI, 0.392-0.819; P = .0022), representing a 43% risk reduction. The 36-month rPFS rates were 77.2% vs 48.8% in the BRCAm subgroup and 76.2% vs 60.2% in the non-BRCAm subgroup.¹ A consistent rPFS treatment effect was observed across prespecified subgroups, including disease stage, disease volume, age, site of metastasis, Gleason score, baseline prostate-specific antigen (PSA), ECOG performance status, prior androgen receptor pathway inhibitor (ARPI) use, and geographic region.

“These results support [talazoparib plus enzalutamide] as a potential treatment option for patients with HRR gene–altered mCSPC. And early molecular testing is critically important now in these patients,” said TALAPRO-3 lead investigator Neeraj Agarwal, MD, FASCO, of the Huntsman Cancer Institute at the University of Utah Health.

Overall Survival and Other TALAPRO-3 Efficacy Data

Formal overall survival (OS) testing was conducted per the hierarchical testing approach, given the significant rPFS result. At a median follow-up of 40.5 months in the talazoparib/enzalutamide arm and 41.1 months in the placebo/enzalutamide arm, the median OS was NR in both arms. The interim OS trend favored talazoparib/enzalutamide (HR, 0.767; 95% CI, 0.564-1.044; P = .0905), with 74 OS events in the talazoparib/enzalutamide arm vs 91 in the placebo/enzalutamide arm. The 36-month OS rates were 77.8% (95% CI, 72.5-82.1) and 71.6% (95% CI, 66.0-76.4), respectively.

Additional TALAPRO-3 Secondary End Points

Talazoparib plus enzalutamide significantly improved time to PSA progression (HR, 0.513; 95% CI, 0.370-0.712; P < .0001), with 58 events in the talazoparib/enzalutamide arm vs 96 in the placebo/enzalutamide arm; the median time to PSA progression was NR in both arms. PSA response rates (≥ 50% decline) were 90.5% (95% CI, 86.5-93.5) with talazoparib/enzalutamide vs 86.5% (95% CI, 82.0-90.1) with placebo/enzalutamide (P = .1194). Time to subsequent antineoplastic therapy was also significantly improved (HR, 0.514; 95% CI, 0.378-0.698; P < .0001), with 36-month rates of 78.6% vs 62.0%, respectively.

Among patients with measurable soft tissue disease, the objective response rate was 74.7% (95% CI, 64.8-82.7) with talazoparib/enzalutamide vs 67.0% (95% CI, 57.2-75.5) with placebo/enzalutamide (P = .2925), with a median duration of response of NR vs 27.2 months (95% CI, 19.5-39.6).¹ Docetaxel was the most common subsequent antineoplastic therapy in both arms; notably, olaparib was received by 27% of patients in the placebo/enzalutamide arm vs 9% in the talazoparib/enzalutamide arm, reflecting the lower rate of progression in the combination arm.

Safety in TALAPRO-3

Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 79% of patients in the talazoparib/enzalutamide arm (n = 299) vs 41% in the placebo/enzalutamide arm (n = 295). Serious AEs were reported in 42% vs 32% of patients, respectively. Grade 5 TEAEs occurred in 3% of patients in both arms; treatment-related grade 5 events occurred in 2 patients (< 1%) in the talazoparib/enzalutamide arm; one was due to pancytopenia and the other due to worsening of idiopathic pulmonary fibrosis. There were no grade 5 events in the placebo/enzalutamide arm.

The most common any-grade TEAEs occurring at 15% or greater in the talazoparib/enzalutamide arm were anemia (71%), fatigue (28%), decreased neutrophil count (27%), neutropenia (22%), asthenia (21%), and decreased white blood cell count (21%). AEs of special interest included myelodysplastic syndrome in 3 patients in the talazoparib/enzalutamide arm vs 1 in the placebo/enzalutamide arm, as well as acute myeloid leukemia in 2 vs 0 patients, respectively. Venous embolic and thrombotic events occurred in 7 patients in the talazoparib/enzalutamide arm vs 5 in the placebo/enzalutamide arm.

Given the prominence of anemia, the investigators provided a detailed characterization. At baseline, 43% of patients in the talazoparib arm had grade 1/2 anemia. Median time to onset of grade 3/4 anemia was 3.2 months. Among patients who developed anemia, 40% received packed red blood cell transfusions, with a median of 2 transfusions over the entire duration of talazoparib treatment. The median duration of talazoparib treatment was 34.2 months in patients with grade 3/4 anemia and 35.9 months in those without, indicating that anemia did not substantially curtail treatment duration. Fourteen percent had recurrent grade 3/4 anemia after dose reduction, and only 5% permanently discontinued talazoparib due to anemia. TEAEs were manageable through dose modifications and supportive measures.

Patient-Reported Outcomes in TALAPRO-3

The addition of talazoparib to enzalutamide generally did not result in clinically meaningful differences in patient-reported outcomes compared with enzalutamide alone, with the exception of appetite loss per the EORTC QLQ-C30, which was modestly higher in the talazoparib/enzalutamide arm (estimated difference, 5.2; 95% CI, 2.5-8.0). Differences in global health status/quality of life, physical functioning, role functioning, fatigue, pain, and nausea/vomiting did not exceed the prespecified 5-point threshold for clinical meaningfulness.

TALAPRO-3 Study Design and Patient Characteristics

TALAPRO-3 is a phase 3, double-blind, randomized, placebo-controlled trial.¹ Patients with HRR gene–altered mCSPC, confirmed metastatic disease by bone scan or CT/MRI, an ECOG performance status of 0 or 1, and ongoing androgen deprivation therapy (ADT) with 3 months or fewer of prior ADT with or without ARPI were eligible; prior docetaxel for mCSPC was not permitted. A total of 599 patients were randomly assigned 1:1 to talazoparib 0.5 mg once daily (0.35 mg in patients with moderate renal impairment) plus enzalutamide 160 mg once daily (n = 300) or placebo plus enzalutamide 160 mg once daily (n = 299). Stratification factors were de novo vs relapsed mCSPC, high- vs low-volume disease, and BRCAm vs non-BRCAm. The primary end point was rPFS by investigator assessment; the α-protected key secondary end point was OS. HRR gene alterations were assessed using FoundationOne CDx and FoundationOne Liquid CDx platforms and included mutations in ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C.

Baseline characteristics were well balanced between arms. The median age was 70 years (range, 45-89) in the talazoparib/enzalutamide arm and 69 years (range, 44-86) in the placebo/enzalutamide arm. BRCA1/2 alterations were present in 35% and 34% of patients, respectively. The majority had de novo mCSPC (84% and 85%) and high-volume disease (70% and 71%). A Gleason score of 8 or greater was present in 82% of patients in both arms, and 59% in each arm had bone and soft tissue disease.

Reference

1. 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 17):LBA5007.