PARP and Androgen-Signaling Inhibition plus ADT in Metastatic Prostate Cancer

Author(s): Neeraj Agarwal, M.D.¹; Nobuaki Matsubara, M.D.²; Arun A. Azad, Ph.D., M.B., B.S.³; Fred Saad, M.D.⁴; Joaquin Mateo, M.D., Ph.D.⁵; Shusuan Jiang, M.D.⁶; Dingwei Ye, M.D.⁷; Eric Voog, M.D.⁸; Neal D. Shore, M.D.⁹; Timuçin Çil, M.D.¹⁰; Christof Vulsteke, M.D., Ph.D.^11,12; Hsiao-Jen Chung, M.D.¹³; Stefanie Zschäbitz, M.D.¹⁴; A. Douglas Laird, Ph.D.¹⁵; Xiaoxi Zhang, Ph.D.¹⁶; Prachi Nandoskar, M.B., B.S.¹⁵; Sarah Fenech Chetcuti, M.D.¹⁷; Fong Wang, M.D., Ph.D., M.P.H.¹⁵; Karim Fizazi, M.D., Ph.D.¹⁸;

Source: DOI: 10.1056/NEJMoa2604126

Dr. Anjan Patel's Thoughts

Moving PARP inhibition earlier into the hormone-sensitive androgen pathway modulation–sensitive (APMS) setting, this trial shows talazoparib plus enzalutamide cuts the risk of progression or death in half (HR 0.48) in HRR-altered metastatic prostate cancer, with an impressive 3-year progression-free survival (PFS) of 77% versus 56%. The benefit extends beyond BRCA1/2 to ATM and CDK12 as well, which is clinically meaningful given that two-thirds of this population was non-BRCA.

BACKGROUND

A previous trial involving patients with metastatic prostate cancer that was resistant to androgen pathway modulation (formerly referred to as castration-resistant) showed that adding talazoparib to enzalutamide significantly improved imaging-based progression-free survival and overall survival, with the greatest benefit observed in the cohort with alterations in homologous recombination repair genes.

METHODS

In this ongoing, phase 3, double-blind trial assessing talazoparib in patients with metastatic androgen pathway modulation–sensitive [APMS] prostate cancer harboring alterations in homologous recombination repair genes, we randomly assigned patients in a 1:1 ratio to receive talazoparib a dose of 0.5 mg plus enzalutamide a dose of 160 mg once daily (talazoparib group) or placebo plus enzalutamide a dose of 160 mg once daily (control group). Randomization was stratified according to disease status (new or relapsed), disease volume (high or low), and BRCA (vs. non-BRCA) mutation status. The primary end point was investigator-assessed imaging-based progression-free survival. The key secondary end point was overall survival.

RESULTS

A total of 300 patients were assigned to the talazoparib group and 299 to the control group. 3 years, progression-free survival was 77% in the talazoparib group and 56% in the control group (hazard ratio for disease progression or death, 0.48; 95% confidence interval [CI], 0.36 to 0.65; P

CONCLUSIONS

Talazoparib added to enzalutamide led to significantly better imaging-based progression-free survival than placebo plus enzalutamide among patients with metastatic APMS prostate cancer harboring alterations in homologous recombination repair genes. Serious adverse events were more common with talazoparib plus enzalutamide than with placebo plus enzalutamide. (Funded by Pfizer; TALAPRO-3 ClinicalTrials.gov number, NCT04821622.)

Author Affiliations

¹Huntsman Cancer Institute, University of Utah, Salt Lake City; ²National Cancer Center Hospital East, Chiba, Japan; ³Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; ⁴Centre Hospitalier de l’Université de Montréal, University of Montreal, Montreal; ⁵Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona; ⁶Hunan Cancer Hospital, Changsha, China; ⁷Fudan University Shanghai Cancer Center, Shanghai; ⁸Clinique Victor Hugo, Centre Jean Bernard, Le Mans, France; ⁹START Carolinas/Carolina Urologic Research Center, Myrtle Beach, SC; ¹⁰Adana City Education and Research Hospital, Adana Faculty of Medicine, University of Health Sciences, Adana, Turkey; ¹¹Integrated Cancer Center Ghent, AZ Maria Middelares, Ghent, Belgium; ¹²Center for Oncological Research, University of Antwerp, Antwerp, Belgium; ¹³Taipei Veterans General Hospital, Taipei, Taiwan; ¹⁴Department of Medical Oncology, Heidelberg University Hospital, and Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany; ¹⁵Pfizer, South San Francisco, CA; ¹⁶Pfizer, New York; ¹⁷Pfizer, Berlin; ¹⁸Centre Oscar Lambret, University of Paris-Saclay, Lille, France

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