Dr Sokolova on Talazoparib Plus Enzalutamide in mCRPC

Alexandra Sokolova, MD, assistant professor, medicine, Division of Hematology/Medical Oncology, School of Medicine, Oregon Health & Science University, discusses key findings from the phase 3 TALAPRO-2 trial (NCT03395197) in patients with metastatic castration-resistant prostate cancer (mCRPC) and unanswered questions regarding the use of PARP inhibitors plus androgen receptor (AR) inhibitors in patients with biomarker-negative disease.

The TALAPRO-2 trial randomized patients with previously untreated mCRPC to receive either talazoparib (Talzenna) plus enzalutamide (Xtandi) or placebo plus enzalutamide, with a primary end point of radiographic progression-free survival (rPFS). Patients in the TALAPRO-2 population were unselected for DNA damage repair (DDR) pathway genetic alterations either directly or indirectly involved with homologous recombination repair. Further subgroup analyses of TALAPRO-2 are necessary to determine the efficacy of talazoparib plus enzalutamide in different patient subgroups, Sokolova says. However, in findings presented at the 2023 Genitourinary Cancers Symposium, the median rPFS was improved in the portion of patients in the TALAPRO-2 population who had DDR-deficient disease vs those without DDR-deficient disease or with unknown DDR disease status, with respective hazard ratios (HRs) of 0.46 and 0.70. In the overall population, the median rPFS was not reached in the talazoparib arm vs 21.9 months in the placebo arm, with an HR of 0.63. Although the overall survival (OS) data are not yet mature, the OS HR was 0.89 in favor of talazoparib.

The significance of these findings for the population of patients with biomarker-negative mCRPC remains to be seen, Sokolova notes. There is a biological rationale for combining PARP inhibitors, such as talazoparib, with AR inhibitors, such as enzalutamide, Sokolova says. AR binds to DDR sites, so inhibiting the AR pathway likely inhibits DDR and causes a DNA DDR-deficient phenotype, Sokolova explains. However, the TALAPRO-2 data are still too immature to provide the rationale for the broad use of talazoparib plus enzalutamide in patients with mCRPC, Sokolova concludes.