Fizazi, Karim 
ORCID: 0000-0002-6068-9474, Azad, Arun A ORCID: 0000-0001-7350-5622, Matsubara, Nobuaki, Carles, Joan, Fay, Andre P, De Giorgi, Ugo, Joung, Jae Young, Fong, Peter CC, Voog, Eric, Jones, Robert J ORCID: 0000-0001-5608-001X et al (show 11 more authors)
(2024)
First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial.
Nature medicine, 30 (1).
pp. 257-264.
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 .
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Humans, Benzamides, Nitriles, Phenylthiohydantoin, Phthalazines, Antineoplastic Agents, Male, Recombinational DNA Repair, Prostatic Neoplasms, Castration-Resistant |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 09 Feb 2024 09:21 |
| Last Modified: | 09 Feb 2024 09:22 |
| DOI: | 10.1038/s41591-023-02704-x |
| Open Access URL: | https://doi.org/10.1038/s41591-023-02704-x |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3178571 |
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