Clinical trialPhase 3Prostate cancer

Talazoparib plus enzalutamide in men with metastatic castration-resistant prostate cancer: final overall survival results from the randomised, placebo-controlled, phase 3 TALAPRO-2 trial

The Lancet · 2025805 patients (402 in the talazoparib plus enzalutamide group and 403 in the enzalutamide plus placebo group)

Agarwal N, Azad AA, Carles J, Fay AP, Matsubara N, Szczylik C, et al. The Lancet. 2025. 406:447-460

Study type: Clinical trial
Study name: TALAPRO-2
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled trial (enzalutamide was open-label); 1:1 randomisation
Sample size: 805 patients (402 in the talazoparib plus enzalutamide group and 403 in the enzalutamide plus placebo group)
Source: The Lancet · 2025
Trial registration: NCT03395197

In plain words

In this large study, men with advanced prostate cancer that no longer responded to standard hormone therapy received either enzalutamide plus a drug called talazoparib or enzalutamide plus a placebo (dummy pill). Adding talazoparib helped patients live longer on average (about 45.8 months versus 37.0 months) and stay longer without the disease growing on scans. The benefit was greater in patients with faults in DNA repair genes. Side effects of the combination, especially anaemia and low white blood cells, were more common and need close monitoring.

Key results

HR 0.80 (95% CI 0.66 to 0.96)

Overall survival (whole ITT population)

P=0.016; median follow-up 52.5 months (IQR 48.6 to 56.0)

45.8 months (95% CI 39.4 to 50.8) vs 37.0 months (34.1 to 40.4)

Median overall survival

Talazoparib plus enzalutamide vs enzalutamide plus placebo

HR 0.55 (0.36 to 0.83)

Overall survival in patients with HRR deficiency (n=169)

P=0.0035

HR 0.88 (0.71 to 1.08)

Overall survival in patients without HRR deficiency or with unknown status (n=636)

P=0.22

HR 0.67 (0.55 to 0.81)

Radiographic progression-free survival (updated)

P<0.0001

33.1 months vs 19.5 months

Median rPFS

Talazoparib plus enzalutamide vs enzalutamide plus placebo

Drugs in this study:Enzalutamide (Xtandi)

Dose and schedule cards

Talazoparib + enzalutamide (TALAPRO-2)

First-line mCRPC with HRR gene mutations (FDA label: ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C)Cycle length: ContinuousOn the page “Prostate cancer” · With DNA repair gene mutations (HRR/BRCA): PARP inhibitors in mCSPC and mCRPC

First-line mCRPC with HRR gene mutations (FDA label: ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C)

Drug	Dose	Route	Schedule
Talazoparib	0.5 mg once daily	Oral, with or without food; do not open the capsules	Daily
Enzalutamide	160 mg once daily	Oral	Daily
ADT (GnRH agonist or antagonist, or prior orchiectomy)	Per formulation	—	Continuous

Cycle length: Continuous
Duration: Until progression or unacceptable toxicity

Per the FDA label and the trial. Talazoparib dose reductions: 0.35, 0.25 and 0.1 mg (more than 3 reductions: discontinue); CrCl 30 to 59: 0.35 mg, and CrCl 15 to 29: 0.25 mg. Monthly blood counts; withhold for haemoglobin below 8 (resume at ≥9), platelets below 50,000 (resume at ≥75,000) or neutrophils below 1000 (resume at ≥1500), then resume at a lower dose. Grade 3–4 anaemia occurred in 46% of trial patients.

On the page “Prostate cancer” · With DNA repair gene mutations (HRR/BRCA): PARP inhibitors in mCSPC and mCRPC

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Talazoparib plus enzalutamide

Talazoparib 0.5 mg + enzalutamide 160 mg, both orally once daily, with continued ADT, until radiographic progression or unacceptable toxicity (402 patients). According to the FDA label, talazoparib dose reductions are in steps of 0.35, 0.25 and 0.1 mg, and at creatinine clearance of 30 to 59 mL/min the starting dose is 0.35 mg.

2Enzalutamide plus placebo

Placebo + enzalutamide 160 mg, both orally once daily (403 patients).

Source of the regimen details: ClinicalTrials.gov NCT03395197 and the FDA label for TALZENNA (DailyMed)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

805 men aged 18 years or older (20 years in Japan) with asymptomatic or mildly symptomatic mCRPC (BPI-SF pain score below 4), testosterone ≤50 ng/dL, PSA, soft-tissue or bone progression, ECOG performance status ≤1 and life expectancy ≥12 months, with no prior life-prolonging systemic therapy for castration-resistant disease (prior therapy in the castration-sensitive setting was allowed). Cohort not selected by HRR status; stratified by HRR status and prior therapy in the castration-sensitive setting.

Endpoints

Primary endpoint: radiographic progression-free survival (rPFS) by blinded independent central review. Overall survival (time from randomisation to death from any cause) was a key alpha-protected secondary endpoint (alpha threshold at the final overall survival analysis 0.022 [two-sided]). Both were assessed in the intention-to-treat (ITT) population. Safety was assessed in patients who received at least one dose of study drug.

Safety and side effects

Safety was consistent with the known profile of talazoparib. The most common grade 3 or higher adverse events with talazoparib plus enzalutamide: anaemia (195 patients [49%] versus 18 patients [4%] with enzalutamide plus placebo) and neutropenia (77 patients [19%] versus 6 patients [1%] with enzalutamide plus placebo).

Clinical significance and place in guidelines

Based on these results, the authors consider talazoparib plus enzalutamide a standard-of-care initial treatment option for patients with metastatic castration-resistant prostate cancer. The survival benefit was more pronounced in patients with HRR deficiency and smaller in those without HRR deficiency or with unknown status (P=0.22). Treatment choice should take into account genetic status, the adverse event profile (especially anaemia and neutropenia) and the patient's condition. Regulatory approval status and formal guideline recommendations should be checked separately, as they are not mentioned in the abstract.

Limitations

According to the abstract: enzalutamide was open-label and only talazoparib/placebo was blinded. Results by HRR status are subgroup analyses, and in patients without HRR deficiency or with unknown status the overall survival benefit was not statistically significant. The study was funded by Pfizer. Other limitations should be checked in the full text.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.