TALAPRO-3: Talazoparib plus enzalutamide improves rPFS in HRR gene-altered mCSPC

Treatment with talazoparib (Talzenna) plus enzalutamide (Xtandi) significantly prolonged radiographic progression-free survival (rPFS) vs enzalutamide alone in men with metastatic castration-sensitive prostate cancer (mCSPC) harboring homologous recombination repair (HRR) gene alterations, according to results from the phase 3 TALAPRO-3 trial (NCT04821622).¹

Neeraj Agarwal, MD, FASCO, of Huntsman Cancer Institute at the University of Utah in Salt Lake City, presented the findings during a late-breaking oral session at the 2026 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois. The data were simultaneously published in the New England Journal of Medicine.²

Background and rationale

The phase 3 TALAPRO-2 trial previously demonstrated that adding talazoparib, a poly(ADP-ribose) polymerase inhibitor (PARPi), to enzalutamide, an androgen receptor pathway inhibitor (ARPI), significantly prolonged rPFS and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC), with the greatest benefit observed in patients with HRR gene-altered disease.³ The investigators hypothesized that talazoparib plus enzalutamide (TALA + ENZA) would improve efficacy vs enzalutamide alone in men with HRR gene-altered mCSPC undergoing androgen deprivation therapy (ADT).

Trial design and patient population

TALAPRO-3 was a multicenter, randomized, double-blind, placebo-controlled phase 3 trial. Key eligibility criteria included HRR gene-altered mCSPC confirmed by positive bone scan or metastatic lesion on CT or MRI, ECOG performance status of 0 or 1, ongoing ADT, and no more than 3 months of prior ADT with or without an ARPI for mCSPC. Prior docetaxel for mCSPC was not permitted. HRR gene alterations eligible for enrollment included mutations in ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C.

A total of 599 patients were randomly assigned 1:1 to talazoparib 0.5 mg plus enzalutamide 160 mg once daily (n = 300) or placebo plus enzalutamide 160 mg once daily (n = 299). Randomization was stratified by de novo vs relapsed mCSPC, high vs low volume disease, and BRCA mutation vs non-BRCA mutation subgroups. The primary end point was rPFS by investigator assessment. OS was a key alpha-protected secondary end point, to be formally tested only if rPFS was statistically significant. The study was powered to detect a hazard ratio (HR) of 0.63 using 197 rPFS events.

Baseline characteristics were well balanced between arms. Median age was 70 years (range, 45 to 89) in the TALA + ENZA arm and 69 years (range, 44 to 86) in the placebo plus enzalutamide (PBO + ENZA) arm. Approximately 35% of patients in each arm had BRCA1/2 mutations, 70% had high-volume disease, and 84% had de novo metastatic disease. Beyond BRCA mutations, the most common gene alterations were ATM, CDK12, and CHEK2, and these were evenly distributed between treatment arms.

Primary end point: rPFS

TALAPRO-3 met its primary end point, showing that treatment with TALA + ENZA led to a 52% reduction in the risk of radiographic progression or death vs the enzalutamide control arm (HR, 0.481; 95% CI, 0.357 to 0.647; P < .0001). Median rPFS was not reached in the TALA + ENZA arm (95% CI, not reached [NR] to NR) vs 45.8 months (95% CI, 37.7 to NR) in the PBO + ENZA arm. The median follow-up for rPFS was 37.6 and 37.7 months, respectively. At 36 months, the estimated probability of rPFS was 76.6% (95% CI, 70.8 to 81.4) with TALA + ENZA vs 56.2% (95% CI, 50.0 to 62.0) with PBO + ENZA.

Subgroup analyses by BRCA mutation status demonstrated benefit in both subgroups. In the BRCA1/2-mutated subgroup, TALA + ENZA was associated with a 63% reduction in risk of radiographic progression or death (HR, 0.368; 95% CI, 0.222 to 0.609; P < .0001). The median rPFS was NR vs 35.1 months (95% CI, 18.6 to NR) with PBO + ENZA. In the non-BRCA1/2-mutated subgroup, a 43% reduction in risk was observed (HR, 0.567; 95% CI, 0.392 to 0.819; P = .0022); median rPFS was NR in both arms.

In post hoc analyses, rPFS generally favored TALA + ENZA across prespecified subgroups and across HRR gene subgroups, including ATM and CDK12 mutation subgroups.

Interim overall survival

OS data were immature at the time of analysis, but interim OS trends favored TALA + ENZA. At a median OS follow-up of 40.5 and 41.1 months, respectively, 74 deaths had occurred in the TALA + ENZA arm and 91 in the PBO + ENZA arm (HR, 0.767; 95% CI, 0.564 to 1.044; P = .0905). The estimated 36-month OS probability was 77.8% (95% CI, 72.5 to 82.1) with TALA + ENZA vs 71.6% (95% CI, 66.0 to 76.4) with PBO + ENZA. Median OS was not reached in either arm.

Secondary and exploratory end points

Clinically relevant secondary end points were consistent with the primary rPFS results. Time to PSA progression significantly favored TALA + ENZA, with a 49% reduction in risk of PSA progression (HR, 0.513; 95% CI, 0.370 to 0.712; P < .0001). The PSA response rate (50% decline or greater) was 90.5% (95% CI, 86.5 to 93.5) with TALA + ENZA vs 86.5% (95% CI, 82.0 to 90.1) with PBO + ENZA (P = .1194). Time to subsequent antineoplastic therapy was also prolonged with TALA + ENZA (HR, 0.514; 95% CI, 0.378 to 0.698; P < .0001).

In patients with measurable disease, objective response rates were 74.7% (95% CI, 64.8 to 82.7) with TALA + ENZA vs 67.0% (95% CI, 57.2 to 75.5) with PBO + ENZA (P = .2925). The median duration of response was NR with TALA + ENZA vs 27.2 months (95% CI, 19.5 to 39.6) with PBO + ENZA.

Safety

Grade 3 to 4 treatment-emergent adverse events (TEAEs) occurred in 79% of patients in the TALA + ENZA arm vs 41% in the PBO + ENZA arm. Grade 5 TEAEs were reported in 3% of patients in each arm; treatment-related Grade 5 events occurred in fewer than 1% of patients in the TALA + ENZA arm and 0% in the PBO + ENZA arm. Dose interruption occurred in 69% of patients in the TALA + ENZA arm, and dose reduction in 60%. However, despite frequent dose modifications, more than 80% of patients in the talazoparib arm were able to continue treatment without requiring permanent discontinuation. Permanent discontinuation of talazoparib or placebo due to adverse events occurred in 19% of the TALA + ENZA arm vs 10% of the PBO + ENZA arm.

The most common TEAEs (≥15% of patients) in the TALA + ENZA arm were anemia (71%), fatigue (28%), decreased neutrophil count (27%), neutropenia (22%), asthenia (21%), and decreased white blood cell count (21%). Adverse events of special interest included myelodysplastic syndrome (MDS) in 3 patients in the TALA + ENZA arm vs 1 in the PBO + ENZA arm, acute myeloid leukemia (AML) in 2 patients in the TALA + ENZA arm vs 0 in the PBO + ENZA arm, and venous embolic and thrombotic events in 7 patients in the TALA + ENZA arm vs 5 in the PBO + ENZA arm.

Patient-reported outcomes

No clinically meaningful differences in patient-reported outcomes (PROs) were observed between the TALA + ENZA and PBO + ENZA arms on the EORTC QLQ-C30 global health status/quality of life scale (estimated mean difference, -3.7; 95% CI, -6.5 to -1.0), physical functioning domain (-2.5; 95% CI, -5.1 to 0.1), role functioning domain (-2.7; 95% CI, -6.0 to 0.6), fatigue symptom scale (3.2; 95% CI, 0.2-6.2), pain scale (0.4; 95% CI, -2.4 to 3.2), and nausea/vomiting scale (1.2; 95% CI, 0.2 to 2.3), with the exception of appetite loss, which was worse in the TALA + ENZA arm (5.2; 95% CI, 2.5 to 8.0).

Conclusions

"TALA plus ENZA lead to a clinically meaningful and statistically significant prolongation of rPFS vs active ENZA control in men with HRR gene-altered mCSPC,” Agarwal said in his concluding remarks. “rPFS benefit was consistent across clinical subgroups, including BRCA mutation and non-BRCA mutation subgroups. The interim OS trends in favor of TALA plus ENZA.”

He added that the results support talazoparib plus enzalutamide as a potential treatment option for patients with HRR gene-altered mCSPC and that early molecular testing is critically important in this patient population.

Editor’s note: Agarwal reports relevant disclosures with Pfizer.

REFERENCES

1. Agarwal N, Matsubara A, Azad A, 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 (suppl 17; abstr LBA5007). doi:10.1200/JCO.2026.44.17_suppl.LBA5007
2. Agarwal N, Matsubara A, Azad A, et al. PARP and Androgen-Signaling Inhibition plus ADT in Metastatic Prostate Cancer. N Engl J Med. 2026. doi:10.1056/NEJMoa2604126