Combining next-generation hormonal therapy with PARP inhibition in metastatic castration-resistant prostate cancer

In a paradigm of precision oncology, elegant preclinical work showed that inhibition of poly(ADP-ribose) polymerase (PARP) proteins can exploit a deficiency of cancer cells to repair DNA double-strand breaks through homologous recombination repair (HRR), 1 Lord CJ Ashworth A PARP inhibitors: synthetic lethality in the clinic. Science. 2017; 355: 1152-1158 Crossref PubMed Scopus (1528) Google Scholar and the resulting synthetic lethality was first shown to be clinically effective in ovarian cancer carrying a germline deleterious mutation in BRCA1 or BRCA2, key HRR genes. 2 Banerjee S Moore KN Colombo N et al. Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021; 22: 1721-1731 Summary Full Text Full Text PDF PubMed Scopus (122) Google Scholar For prostate cancer, the discovery of alterations in BRCA2 and other HRR-related genes in up to 20% of advanced disease 3 Robinson D Van Allen EM Wu YM et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015; 161: 1215-1228 Summary Full Text Full Text PDF PubMed Scopus (2180) Google Scholar led to the development of several biomarker-driven trials of PARP inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC) 4 Abida W Patnaik A Campbell D et al. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin Oncol. 2020; 38: 3763-3772 Crossref PubMed Scopus (363) Google Scholar , 5 de Bono JS Mehra N Scagliotti GV et al. Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Oncol. 2021; 22: 1250-1264 Summary Full Text Full Text PDF PubMed Scopus (110) Google Scholar , 6 Hussain M Mateo J Fizazi K et al. Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med. 2020; 383: 2345-2357 Crossref PubMed Scopus (342) Google Scholar , 7 Smith MR Scher HI Sandhu S et al. Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2022; 23: 362-373 Summary Full Text Full Text PDF PubMed Scopus (63) Google Scholar and to the regulatory approval of rucaparib and olaparib as monotherapy for the treatment of mCRPC harbouring mutations in BRCA2 and other HRR genes. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trialTalazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in rPFS versus standard of care enzalutamide as first-line treatment for patients with mCRPC. Final overall survival data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumour HRR gene alterations. Full-Text PDF