Dr Piulats on Validating Predictive Biomarkers for Talazoparib Plus 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 potential next steps to further evaluate whether TMPRSS2-ERG and RB1 are predictive biomarkers for differential efficacy with talazoparib (Verzenio) plus enzalutamide (Xtandi) in patients with metastatic castration-resistant prostate cancer (mCRPC).

Findings from a post-hoc analysis on predictive biomarkers for first-line treatment with the combination regimen vs placebo plus enzalutamide were presented at the 2024 AACR Annual Meeting. This analysis identified several predictive biomarkers, with a focus on TMPRSS2-ERG and RB1, however, since all patients with ERG fusions also had TMPRSS2 fusions, the analysis grouped these mutations together. Significant benefits in progression-free survival (PFS) were observed for patients with TMPRSS2-ERGfusions and RB1 mutations following treatment with the talazoparib and enzalutamide combination.

Because this was a post-hoc analysis, further studies are necessary to validate these results, Piulats states. One area that remains unclear is whether the loss of RB1 directly leads to more aggressive, castration-resistant prostate cancer subtypes, or if this is associated with other factors, particularly due to the proximity of RB1 to BRCA2.

Future research will also incorporate tissue-based results to gain a more comprehensive understanding of the investigation, as the current study only utilized circulating tumor DNA (ctDNA) testing. This approach could help clarify the implications of RB1 loss and its relationship with aggressive cancer subtypes, he adds. Investigators plan the integration of both ctDNA and tissue-based assay datasets to enhance the insights derived from this analysis. This approach could help clarify the implications of RB1 loss and its relationship with aggressive cancer subtypes.

As the field evolves rapidly, there is a need to reanalyze the current landscape of prostate cancer treatment, particularly concerning the role of PARP inhibitors, Piulats says. Ongoing clinical trials in first-line mCRPC are especially pertinent, as many of the cohorts involved have not yet received novel anti-androgens like abiraterone acetate (Zytiga).

For example, the phase 3 TALAPRO-3 trial (NCT04821622) evaluating talazoparib in combination with enzalutamide compared with placebo in combination with enzalutamide in participants with DNA damage repair–deficient mCSPC has completed recruitment. Although this trial will provide valuable data, it may not fully answer the broader questions about the role of PARP inhibitors in this patient population, he explains. Companies, such as AstraZeneca, are initiating clinical trials with PARP1-specific drugs, aiming to identify the best fit for future trials that could offer more definitive answers regarding the use of these agents in prostate cancer treatment, Piulats concludes.