Talazoparib plus enzalutamide versus placebo plus enzalutamide in metastatic androgen pathway modulator-resistant (castration-resistant) prostate cancer (TALAPRO-2): a biomarker analysis of circulating tumour DNA and cells for prognosis and molecular profiling

Lancet Oncol. 2026 Oct 28:S1470-2045(26)00355-4. doi: 10.1016/S1470-2045(26)00355-4. Online ahead of print.

ABSTRACT

BACKGROUND: The TALAPRO-2 trial showed improved radiographic progression-free survival and overall survival with first-line talazoparib plus enzalutamide versus placebo plus enzalutamide in patients with metastatic androgen pathway modulator-resistant prostate cancer (APMR; also referred to as castration-resistant prostate cancer) unselected for homologous recombination repair (HRR) gene alterations treated. We aimed to assess HRR gene alteration status agreement between prospective solid tumour tissue and circulating tumour DNA (ctDNA) testing, the potential complementary value of prospective and retrospective ctDNA testing, and the prognostic utility of baseline ctDNA burden, changes in ctDNA burden, and circulating tumour cell (CTC) reductions.

METHODS: In TALAPRO-2, a randomised, double-blind, placebo-controlled, phase 3 trial, men aged 18 years or older (≥20 years in Japan) with asymptomatic or mildly symptomatic metastatic APMR prostate cancer and no previous life-prolonging systemic therapy for APMR disease were randomly assigned (1:1) to receive once daily, oral talazoparib 0·5 mg plus enzalutamide 160 mg or placebo plus enzalutamide and stratified by HRR gene alteration status and previous treatment for androgen pathway modulator-naive/sensitive disease. The sponsor, patients, and investigators were masked to allocation of talazoparib or placebo; enzalutamide was open label. In this exploratory analysis, HRR gene alteration status agreement was evaluated in the unselected intention-to-treat cohort between solid tumour tissue prospectively tested using a clinical trial assay based on FoundationOne CDx and retrospectively tested ctDNA samples, collected at screening and assessed using an assay based on FoundationOne Liquid CDx. Tumour burden was categorised as positive or negative (ctDNA tumour fraction detectable or not detectable). Reductions in CTCs, enumerated using CELLSEARCH, were defined as conversion (from five or more cells per 7·5 mL of blood to four or fewer cells per 7·5 mL of blood) or CTC0 (from one or more cells per 7·5 mL of blood to zero). Radiographic progression-free survival was assessed for patients with baseline ctDNA positivity (positive vs negative) and for patients with ctDNA conversion and CTC conversion and CTC0 at week 9 (and week 17 for CTC conversion and CTC0) by treatment group. This trial is registered with ClinicalTrial.gov, NCT03395197 and is active, not recruiting.

FINDINGS: Between Jan 7, 2019, and Sept 17, 2020, 805 patients were enrolled and randomly assigned (402 to talazoparib plus enzalutamide; 403 to placebo plus enzalutamide); median follow-up for radiographic progression-free survival was 24·9 months (IQR 21·9-30·2) for the talazoparib group and 24·6 months (14·4-30·2) for the placebo group. A high concordance in HRR gene alteration status was observed between results from prospectively tested solid tumour tissue samples and retrospectively tested screening ctDNA samples (reported for 739 [92%] of 805 enrolled patients), with 84% (421 of 501) agreement in patients evaluable as either HRR-deficient or HRR-non-deficient by both tests. Median radiographic progression-free survival for positive versus negative ctDNA burden was 21·0 months (95% CI 16·5-not reached [NR]) versus NR (NR-NR), respectively (hazard ratio [HR] 2·46; 95% CI 1·68-3·60; p<0·0001) with talazoparib plus enzalutamide, and 11·0 months (8·4-13·8) versus 33·2 months (30·3-NR), respectively (HR 4·03; 2·85-5·72; p<0·0001) with placebo plus enzalutamide. In both groups, week 9 conversion from positive to negative ctDNA was prognostic of improved radiographic progression-free survival versus remaining ctDNA positive. Patients remaining ctDNA negative had more favourable radiographic progression-free survival versus conversion from positive to negative ctDNA. CTC conversion and CTC0 at week 9 were prognostic for radiographic progression-free survival benefit in both groups.

INTERPRETATION: Our results support broad prognostic utility of ctDNA burden and CTC enumeration in metastatic APMR prostate cancer, including in the context of poly(ADP) ribose polymerase inhibitor therapy.

FUNDING: Pfizer.

PMID:42950862 | DOI:10.1016/S1470-2045(26)00355-4