Josep Maria Piulats Rodriguez, MD, PhD, discusses next steps for validating predictive biomarkers of efficacy to treatment with talazoparib plus enzalutamide in mCRPC. 

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 

 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 

. This analysis identified several predictive biomarkers, with a focus on 

 fusions, the analysis grouped these mutations together. Significant benefits in progression-free survival (PFS) were observed for patients with 

 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 

 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.

Videos

Josep Maria Piulats Rodriguez, MD, PhD, discusses the rationale for identifying predictive biomarkers for talazoparib plus enzalutamide in mCRPC.

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 

 mutations could serve as candidate predictive biomarkers for differential efficacy with the PARP combination vs enzalutamide and placebo.

Josep Maria Piulats Rodriguez, MD, discusses an analysis evaluating predictive biomarkers for treatment with talazoparib plus enzalutamide in mCRPC.

Dr Piulats on Predictive Biomarkers for Treatment With 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 findings from a post-hoc analysis evaluating predictive biomarkers for treatment with talazoparib (Verzenio) plus enzalutamide (Xtandi) vs placebo plus enzalutamide as first-line treatment in patients with metastatic castration-resistant prostate cancer.

. In this analysis, investigators identified various genes, 1 of which was excluded from the analysis due to its apparent dependence on the other genes: 

, Piulats begins. Since all patients with 

 fusions, investigators grouped these genes together, Piulats states.

Findings revealed significant benefits with talazoparib plus enzalutamide for the 

 fusion population, particularly in terms of progression-free survival (PFS). Patients with 

 fusions who were treated with placebo plus enzalutamide exhibited a median PFS of 11 months, whereas those receiving talazoparib plus enzalutamide demonstrated an approximate 25.9-month median PFS, Piulats reports; however, because this was a post-hoc analysis, further studies are required to validate these results.

 is a gene known for its role in driving plasticity toward more aggressive prostate cancer subtypes that are resistant to castration, indicating a poor prognosis for patients harboring 

 mutations, Piulats expands. However, the study did not conclusively determine whether this effect directly stems from 

 loss or is associated with other factors, given its proximity to 

, according to Piulats. Further investigations are necessary to elucidate this distinction, Piulats explains. Although only 1 patient with an 

 mutation, both genes are susceptible to loss, potentially influencing the study outcomes, Piulats emphasizes. Notably, since this study used circulating tumor DNA (ctDNA) assays, investigators acknowledged the limitations of liquid-based testing compared with tissue-based testing, he says. Future analyses will incorporate tissue-based results for a comprehensive understanding of these findings, Piulats explains.

Based on feedback received at the 2024 AACR Annual Meeting, investigators plan to merge both the ctDNA and tissue-based assay datasets to gain further insights into these findings, Piulats concludes.

Josep Maria Piulats Rodriguez, MD, discusses an analysis evaluating predictive biomarkers for treatment with talazoparib plus enzalutamide in mCRPC.


Josep Maria Piulats Rodriguez, MD, PhD

Articles

Dr Piulats on Validating Predictive Biomarkers for Talazoparib Plus Enzalutamide in mCRPC

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

Dr Piulats on Predictive Biomarkers for Treatment With Talazoparib/Enzalutamide in mCRPC