Integrating PARP Inhibitors in mCRPC Therapy: Current Strategies and Emerging Trends

Bicky Thapa,1,* Navonil De Sarkar,2– 4,* Subhajit Giri,2,3 Komal Sharma,2– 4 Mingee Kim,5 Deepak Kilari1 1Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; 2Medical College of Wisconsin Cancer Center, Milwaukee, WI, USA; 3Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA; 4Data Science Institute, Medical College of Wisconsin, Milwaukee, WI, USA; 5School of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA*These authors Contributed equally to this workCorrespondence: Deepak Kilari, Email [email protected]: Metastatic castrate-resistant prostate cancer (mCRPC) is associated with poor prognosis. DNA damage response (DDR) genes are commonly altered in mCRPC rendering them as promising therapeutic targets. Poly (ADP ribose) polymerase inhibitors (PARPi) demonstrated antitumor activity in mCRPC patients with DDR gene mutations through synthetic lethality. Multiple clinical trials with PARPi monotherapy exhibited encouraging clinical outcomes in selected patients with mCRPC. More recently, three Phase III randomized clinical trials (RCTs) combining PARPi with androgen receptor signaling inhibitors (ARSIs) demonstrated improved antitumor activity compared to ARSI monotherapy in mCRPC patients as the first-line therapy. Clinical benefit was more pronounced in patients harboring DDR alterations, specifically BRCA1/2. Interestingly, antitumor activity was also observed irrespective of DDR gene mutations, highlighting BRCAness phenotype with androgen receptor blockade resulting in synergistic activity between ARSIs and PARPi. In this review, we discuss the clinical efficacy and safety data of the combination of PARPi plus ARSI in all Phase 3 randomized controlled trials (RCTs), emphasizing strategies for patient selection and highlighting emerging trends based on clinical trial data.Keywords: PARP inhibitors, talazoparib, ARSI, DDR genes, HRD, metastatic CRPC