Clinical trialPhase 3Prostate cancer

Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial

Lancet · 2023805 patients (cohort not selected by genetics)

Agarwal N, Azad AA, Carles J, Fay AP, Matsubara N, Heinrich D, et al. Lancet. 2023. 402:291-303

A newer report of this study has been published: 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 (2025)

Study type: Clinical trial
Study name: TALAPRO-2
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled trial (open-label enzalutamide)
Sample size: 805 patients (cohort not selected by genetics)
Source: Lancet · 2023
Trial registration: NCT03395197

In plain words

In men whose prostate cancer had become resistant to standard hormone therapy, adding talazoparib tablets to enzalutamide kept the disease under control for longer and, in the final analysis, helped patients live about 9 months longer on average. The greatest benefit was in those with mutations in DNA repair genes. Anaemia (low red blood cells) is the most common side effect and may need a lower dose or a blood transfusion.

Key results

Not reached vs 21.9 months

Radiographic progression-free survival (primary analysis)

HR 0.63; 95% CI 0.51 to 0.78; p<0.0001

45.8 vs 37.0 months

Overall survival (final analysis 2025)

HR 0.80; 95% CI 0.66 to 0.96; p=0.016 (Agarwal et al., Lancet 2025; doi:10.1016/S0140-6736(25)00684-1)

HR 0.55

Overall survival in patients with HRR deficiency

169 patients; 95% CI 0.36 to 0.83

HR 0.88

Overall survival in patients without HRR deficiency or with unknown status

636 patients; 95% CI 0.71 to 1.08 (not significant)

33.1 vs 19.5 months

Updated radiographic progression-free survival

HR 0.67

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 + enzalutamide (402 patients)

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.

2Placebo + enzalutamide (403 patients)

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 outcome: radiographic progression-free survival (blinded independent central review) in the intention-to-treat population. Key alpha-controlled secondary outcome: overall survival.

Safety and side effects

The most common adverse events with talazoparib were anaemia, neutropenia and fatigue. Grade 3-4 anaemia occurred in 46% (185 of 398), improved with dose reduction, and only 8% discontinued talazoparib because of anaemia. In the final analysis, grade 3 or higher anaemia was 49% versus 4% and neutropenia 19% versus 1%.

Clinical significance and place in guidelines

In 2023 the FDA approved talazoparib with enzalutamide for HRR gene-mutated mCRPC; the EMA approved it for patients in whom chemotherapy is not clinically indicated, regardless of HRR status. The final overall survival analysis (2025) strengthened the place of this combination as an initial treatment option for mCRPC, especially in patients with HRR deficiency.

Limitations

Most patients had not previously received an ARPI in the hormone-sensitive setting, whereas today most patients receive an ARPI earlier; the overall survival benefit in patients without HRR deficiency was not significant; anaemia is common and requires blood monitoring.

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.