Talazoparib added to enzalutamide significantly improved survival and preserved QOL in men with mCRPC harboring homologous recombination repair gene alterations.
Karim Fizazi, MD, PhD
For patients with metastatic castration-resistant prostate cancer (mCRPC), androgen receptor-signaling inhibition with enzalutamide is a standard of care. In addition, PARP inhibitor talazoparib monotherapy showed durable anti-tumor activity in heavily pretreated patients with mCRPC cancer harboring homologous recombination repair gene alterations (HRR-deficient). The aim of the phase 3 TALAPRO-2 trial (NCT03395197) was to evaluate the efficacy and safety of first-line talazoparib plus enzalutamide in men with mCRPC. The results from cohort 2 (HRR-deficient population) were presented at the 2023 ASCO Annual Meeting, held June 2-6 in Chicago, by Karim Fizazi, MD, PhD. Cohort 1 results (non-HRR-deficient and HRR-deficient patients) were previously presented.
In cohort 2, 399 patients were randomly assigned 1:1 to receive either talazoparib/enzalutamide or placebo/enzalutamide. Tumor samples were assessed for HRR gene alteration (ie, BRCA1, BRCA2, PALB2, ATM, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A, and CDK12). The most common alterations were BRCA2, ATM, CDK12, and CHEK2. The primary endpoint was radiographic progression-free survival (rPFS).
The addition of talazoparib to enzalutamide significantly improved rPFS. After a median follow-up of 17 months, median rPFS was not reached in the talazoparib/enzalutamide arm compared with 13.8 months in the placebo/enzalutamide arm (HR, 0.45; P<0.0001). Benefit of talazoparib/enzalutamide was observed in all prespecified subpopulations. Of note, benefit was most prominent in patients with BRCA1/2 gene alterations (HR, 0.20; P<0.0001). Overall survival outcomes demonstrate a clear trend toward a benefit of talazoparib but are not yet mature (HR, 0.69; P=0.68).
Talazoparib had a favorable objective response rate (67.1% vs 40.0%; P=0.0015), time to prostate-specific antigen progression (median 28.6 vs 11.1 months; HR, 0.41; P<0.0001), time to cytotoxic chemotherapy (median not yet reached; HR, 0.46; P=0.0001), and time to clinically meaningful deterioration of QOL (median 27.1 vs 19.3 months; HR, 0.69; P=0.032).
The addition of talazoparib to enzalutamide increased grade 3–4 treatment-related adverse effects (66.2 vs 37.2%), the most common of which leading to dose reduction of talazoparib were anemia (42.9%), neutropenia (15.2%), and thrombocytopenia (5.6%).
“Talazoparib in combination with enzalutamide, if approved, has the potential to become a first-line treatment option for patients with mCRPC and HRR gene alterations,” concluded Dr. Fizazi.
Copyright ©2023 Medicom Medical Publishers
