First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial

Fizazi, K; Azad, AA; Matsubara, N; Carles, J; Fay, AP; De Giorgi, U; Joung, JY; Fong, PCC; Voog, E; Jones, RJ; Shore, ND; Dunshee, C; Zsch&#228;bitz, S; Oldenburg, J; Ye, D; Lin, X; Healy, CG; Di Santo, N; Laird, AD; Zohren, F; Agarwal, N

Author(s): Fizazi, K; Azad, AA; Matsubara, N; Carles, J; Fay, AP; De Giorgi, U; Joung, JY; Fong, PCC; Voog, E; Jones, RJ; Shore, ND; Dunshee, C; Zschäbitz, S; Oldenburg, J; Ye, D; Lin, X; Healy, CG; Di Santo, N; Laird, AD; Zohren, F; Agarwal, N;
Details: Publication Year 2024-01,Volume 30,Issue #1,Page 257-264
Journal Title: Nature Medicine
Publication Type: Research article
Abstract: Preclinical evidence has suggested an interplay between the androgen receptor, which largely drives the growth of prostate cancer cells, and poly(ADP-ribose) polymerase. This association provides a rationale for their co-inhibition for the treatment of metastatic castration-resistant prostate cancer (mCRPC), an area of unmet medical need. The phase 3 TALAPRO-2 study investigated combining the poly(ADP-ribose) polymerase inhibitor talazoparib with enzalutamide versus enzalutamide alone as first-line treatment of mCRPC. Patients were prospectively assessed for tumor alterations in DNA damage response genes involved in homologous recombination repair (HRR). Two cohorts were enrolled sequentially: an all-comers cohort that was enrolled first (cohort 1; N = 805 (169 were HRR-deficient)), followed by an HRR-deficient-only cohort (cohort 2; N = 230). We present results from the alpha-controlled primary analysis for the combined HRR-deficient population (N = 399). Patients were randomized in a 1:1 ratio to talazoparib or placebo, plus enzalutamide. The primary endpoint, radiographic progression-free survival, was met (median not reached at the time of the analysis for the talazoparib group versus 13.8 months for the placebo group; hazard ratio, 0.45; 95% confidence interval, 0.33 to 0.61; P < 0.0001). Data for overall survival, a key secondary endpoint, are immature but favor talazoparib (hazard ratio, 0.69; 95% confidence interval, 0.46 to 1.03; P = 0.07). Common adverse events in the talazoparib group were anemia, fatigue and neutropenia. Combining talazoparib with enzalutamide significantly improved radiographic progression-free survival in patients with mCRPC harboring HRR gene alterations, supporting talazoparib plus enzalutamide as a potential first-line treatment for these patients. ClinicalTrials.gov Identifier: NCT03395197 .
Publisher: Springer Nature
Keywords: Male; Humans; *Prostatic Neoplasms, Castration-Resistant/drug therapy/genetics; Recombinational DNA Repair; *Antineoplastic Agents/therapeutic use; Nitriles; *Benzamides; *Phenylthiohydantoin; *Phthalazines
Department(s): Medical Oncology
Publisher's Version: https://doi.org/10.1038/s41591-023-02704-x
Open Access at Publisher's Site: https://doi.org/10.1038/s41591-023-02704-x
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-02-01 06:31:42

Last Modified: 2024-02-01 06:31:54