Adding PARP inhibitor to an androgen-receptor signaling inhibitor in metastatic prostate cancer: what are we missing?

Homologous recombination repair (HRR) genes, including BRCA1/2, are mutated in up to 25-30% of metastatic prostate cancer patients [ 1 Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215-1228. doi: 10.1016/j.cell.2015.05.001. Erratum in: Cell. 2015 Jul 16;162(2):454 Google Scholar ], defining a specific subgroup that could derive an important therapeutic benefit from targeted therapy with PARP inhibitors (PARPi). Single-agent PARPi showed to be effective in metastatic castration-resistant prostate cancer (mCRPC) patients; to date, two main phase III clinical trials, namely the PROfound and the TRITON3 trials, reported a prolonged radiographic progression-free survival (rPFS) and overall survival (OS) of olaparib and rucaparib, respectively, over physician’s choice control therapy in BRCA1/2 mutated (BRCA1/2+) patients [ 2 Hussain M. Mateo J. Fizazi K. et al. PROfound Trial Investigators. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020; 383: 2345-2357 Crossref PubMed Scopus (0) Google Scholar , 3 Fizazi K. Piulats J.M. Reaume M.N. et al. TRITON3 Investigators. Rucaparib or Physician's Choice in Metastatic Prostate Cancer. N Engl J Med. 2023; 388: 719-732 Crossref Scopus (8) Google Scholar ]. The subsequent step in clinical research was the investigation of combining PARPi and androgen-receptor signaling inhibitor (ARSI) in first-line mCRPC, based on favorable preclinical data supporting the synergy between these two pathways and the non-overlapping safety profiles of the drugs [ 4 Asim M. Tarish F. Zecchini H.I. et al. Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer. Nat Commun. 2017; 8: 374 Crossref PubMed Scopus (124) Google Scholar ].