Dr Piulats on the Rationale For Evaluating Predictive Biomarkers for Talazoparib/Enzalutamide in mCRPC

Josep Maria Piulats Rodriguez, MD, PhD, chair, Uveal Melanoma, the Spanish Melanoma Group, medical oncologist, Institut Català d’Oncologia–Bellvitge Institute for Biomedical Research, discusses the rationale for conducting a post-hoc analysis evaluating predictive biomarkers for responses with first-line talazoparib (Verzenio) plus enzalutamide (Xtandi) in patients with metastatic castration-resistant prostate cancer (mCRPC).

The phase 3 TALAPRO-2 trial (NCT03395197) evaluated the combination of talazoparib and enzalutamide vs placebo and enzalutamide as first-line therapy in mCRPC, Piulats begins. A key aspect of the TALAPRO-2 trial design was the mandatory determination of homologous recombination repair (HRR) gene status prior to enrollment; however, patients in the trial were unselected for HRR mutations, he notes.

Results from TALAPRO-2 showed that the PARP inhibitor combination significantly improved radiographic progression-free survival (rPFS) vs enzalutamide and placebo in this population, Piulats repotrs. Although the overall study population did experience superior survival outcomes with talazoparib and enzalutamide combination, the most pronounced benefit was observed in patients with HRR mutations. This suggests that the therapeutic effect is particularly concentrated in individuals with HRR-deficient (HRD) tumors, Piulats explains.

Other clinical trials exploring similar PARP inhibitor combinations in mCRPC have also yielded positive outcomes, even when accounting for patients with HRD tumors, Piulats states. This raises questions about whether there may be additional genetic alterations beyond HRD that could explain treatment benefit in specific patients, he says. It remains unclear whether the PARP inhibitor regimen confers a modest benefit across the entire patient population or if there is a substantial benefit specifically in a subset of patients with distinct genetic profiles that have yet to be fully characterized, Piulats explains.

Accordingly, Piulats and colleagues conducted an analysis of a prospectively collected dataset from TALAPRO-2 along with retrospectively analyzed plasma ctDNA to assess the efficacy of talazoparib plus enzalutamide in those harboring 1 or more non-HRR gene mutation who may or may not express an additional HRR gene mutation. Findings presented at the 2024 AACR Annual Meeting suggested that TMPRSS2-ERG and RB1 mutations could serve as candidate predictive biomarkers for differential efficacy with the PARP combination vs enzalutamide and placebo.