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PARP Inhibitors Have Comparable Efficacy with Platinum Chemotherapy in Patients with BRCA-positive Metastatic Castration-resistant Prostate Cancer. A Systematic Review and Meta-analysis - Beyond the Abstract

Advancements in molecular diagnostics and targeted therapies of the past years brought the era of precision medicine in prostate cancer care. The evolving accessibility and global adoption of BRCA testing provide healthcare practitioners with a valuable tool to tailor treatment algorithms to individual patient needs.

In prostate cancer, BRCA-positive patients represent a distinct subtype with earlier onset disease, and more aggressive behavior, suggesting that these patients are not only molecularly but also prognostically different. In addition, loss-of-function mutations of the BRCA genes might impact the tumor’s sensitivity to different systemic treatments. While the association between alterations in homologous recombinant repair genes and improved response to Poly (ADP-ribose) polymerase (PARP) inhibitors is well documented, much less is known about their sensitivity to other prostate cancer treatments.

Therefore, we addressed the question of whether BRCA-positive metastatic castration-resistant prostate cancer (mCRPC) patients show different sensitivity to on-label prostate cancer treatments. For this purpose, we conducted two meta-analyses; one for the comparison of different PARP inhibitors among themselves and with platinum chemotherapy, and a second comparing treatment efficacy between docetaxel, abiraterone, and enzalutamide. In our more recent study, we found comparable efficacy between PARP inhibitors (niraparib, olaparib, and talazoparib) and carboplatin in terms of PSA50 response rates and overall survival.1 This suggests platinum as a viable treatment option for individuals with BRCA-positive mCRPC. Furthermore, our data demonstrate comparable efficacy among different PARP inhibitors in terms of progression-free and overall survival. In the second, formerly published meta-analysis, we found that docetaxel, abiraterone, and enzalutamide are all active in BRCA-positive prostate cancer patients.2 However, our systematic review and meta-analysis suggest that enzalutamide provides a higher PSA50 rate and superior PFS.

These findings are particularly interesting in the context of diverse outcomes observed in combination studies of PARP inhibitors and androgen receptor pathway inhibitors (MAGNITUDE, PROpel, TALAPRO-2).3-5 Overall, the two studies suggest that the type of PARP inhibitor may not substantially contribute to differences observed in the aforementioned trials; instead, the choice of combination partner may hold significance. Additionally, the question of which conventional doublet treatment (ADT plus abiraterone, docetaxel, or enzalutamide) provides the most benefit for BRCA-positive prostate cancer patients remains of high importance for treatment in earlier disease stages (e.g.: metastatic hormone sensitive disease).1

Written by: Tibor Szarvas,1,2 Péter Nyirády,1 Boris Hadaschik,2 and Tamás Fazekas1,3

  1. Department of Urology, Semmelweis University, Budapest, Hungary
  2. Department of Urology, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany
  3. Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
References:

  1. Fazekas T, Széles ÁD, Teutsch B, Csizmarik A, Vékony B, Kói T, Ács N, Hegyi P, Hadaschik B, Nyirády P, Szarvas T. Poly (ADP-ribose) Polymerase Inhibitors Have Comparable Efficacy with Platinum Chemotherapy in Patients with BRCA-positive Metastatic Castration-resistant Prostate Cancer. A Systematic Review and Meta-analysis. Eur Urol Oncol. 2023 Sep 16:S2588-9311(23)00174-8.
  2. Fazekas T, Széles ÁD, Teutsch B, Csizmarik A, Vékony B, Kói T, Ács N, Hegyi P, Hadaschik B, Nyirády P, Szarvas T. Therapeutic sensitivity to standard treatments in BRCA positive metastatic castration-resistant prostate cancer patients-a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2023;26:665-672. doi:10.1038/s41391-022-00626-2
  3. Chi KN, Sandhu S, Smith MR, Attard G, Saad M, Olmos D, Castro E, Roubaud G, Pereira de Santana Gomes AJ, Small EJ, Rathkopf DE, Gurney H, Jung W, Mason GE, Dibaj S, Wu D, Diorio B, Urtishak K, Del Corral A, Francis P, Kim W, Efstathiou E. Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial. Ann Oncol. 2023;34:772-782.
  4. Saad F, Clarke NW, Oya M, Shore N, Procopio G, Guedes JD, Arslan C, Mehra N, Parnis F, Brown E, Schlürmann F, Joung JY, Sugimoto M, Sartor O, Liu YZ, Poehlein C, Barker L, Del Rosario PM, Armstrong AJ. Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24:1094-1108
  5. Agarwal N, Azad AA, Carles J, Fay AP, Matsubara N, Heinrich D, Szczylik C, De Giorgi U, Young Joung J, Fong PCC, Voog E, Jones RJ, Shore ND, Dunshee C, Zschäbitz S, Oldenburg J, Lin X, Healy CG, Di Santo N, Zohren F, Fizazi K. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. 2023 Jul 22;402(10398):291-303. 
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