Phase 2 TALENT Trial: Talazoparib as Monotherapy or With Enzalutamide in HRR-deficient mCRPC

The TALENT trial is a randomized, open‑label, phase 2 trial evaluating whether adding enzalutamide to talazoparib improves outcomes compared with talazoparib alone in men with metastatic castration‑resistant prostate cancer (mCRPC) who have homologous recombination repair (HRR) gene alterations and have progressed after abiraterone‑based therapy. The trial builds on the phase 3 TALAPRO‑2 results, which showed that talazoparib plus enzalutamide significantly prolonged radiographic progression‑free survival (rPFS) versus enzalutamide plus placebo in HRR‑deficient mCRPC, but most patients in that study had not previously received abiraterone. TALENT is designed to test if the PARP–AR inhibition synergy persists in a more contemporary population that has already demonstrated resistance to an androgen‑biosynthesis inhibitor such as abiraterone.

Enrollment is planned for approximately 126 men with mCRPC who have a confirmed pathogenic or likely pathogenic mutation in one of 12 predefined HRR genes, including ATM, and who previously received abiraterone acetate plus prednisone for metastatic hormone‑sensitive or locally advanced prostate cancer and have since experienced disease progression. Importantly, patients with ATM mutations are intentionally limited to about 15% of the total study population. This restriction reflects the growing recognition that ATM‑mutated tumors may respond differently to PARP inhibition compared with other HRR‑deficient subtypes such as BRCA1/2, and that over‑enriching for ATM could skew the overall efficacy signal. By capping the ATM cohort, the trial aims to preserve a balanced representation of HRR gene alterations while still capturing enough ATM‑mutant patients to conduct meaningful exploratory analyses.

Patients are randomized 1:1 to receive either talazoparib  plus enzalutamide plus ongoing androgen deprivation therapy, or talazoparib alone with the same ADT backbone. Treatment continues until disease progression, unacceptable toxicity, a prolonged treatment interruption, or other standard withdrawal criteria. The primary endpoint is investigator‑assessed radiographic progression‑free survival (rPFS), evaluated using RECIST 1.1 for soft‑tissue lesions and PCWG3 criteria for bone disease. Secondary endpoints include time to PSA50 response, time to PSA progression, overall survival, and patient‑reported quality‑of‑life measures.

Exploratory analyses will examine rPFS by HRR gene (BRCA versus non‑BRCA), individual genes, and gene clusters, with particular attention to whether talazoparib–enzalutamide shows a distinct pattern of activity or resistance in ATM‑altered tumors compared with BRCA and other non‑BRCA HRR genes. If positive, TALENT could support earlier use of talazoparib plus enzalutamide in the post‑abiraterone mCRPC setting, especially in patients with HRR‑deficient tumors, while the ATM‑specific subgroup analyses may help refine which molecular subtypes derive the greatest benefit from dual PARP and AR inhibition.

Clinical trial.