Advanced prostate cancer (PCa) is enriched for alterations in DNA damage repair genes; poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a class of drugs that have demonstrated effectiveness in PCa, particularly in tumors with alterations in BRCA1/2 and other homologous recombination repair (HRR) genes, acting through a synthetic lethal mechanism. To prevent or delay drug resistance, and to expand the patient population that can benefit from this class of drug, combination treatment strategies have been developed in preclinical and clinical studies.
This review examines the latest developments in clinical trials testing PARPi for advanced PCa and their emerging role in earlier disease settings. Furthermore, it discusses the critical role of careful patient selection and identification of additional biomarkers to enhance treatment efficacy.
Two PARPi (olaparib and rucaparib) have been approved as monotherapy in metastatic castration-resistant PCa, thereby establishing the first biomarker-guided drug indications in PCa. Several combinations of PARPi with androgen receptor pathway inhibitors have now also been approved. Anemia and fatigue are the main adverse events associated with this drug class in clinical trials; gastrointestinal toxicities are common but usually manageble.
PARPi are active against PCa with HRR mutations, especially in those with germline or somatic BRCA1/2 mutations. There is still a need to further optimize patient stratification strategies, particularly for combination approaches. Future research should focus on refining predictive biomarkers, improving treatment delivery strategies, and exploring the potential benefits of PARPi in earlier stages of the disease.
Here, we summarize the results from clinical trials testing different poly (ADP-ribose) polymerase inhibitors (PARPi), a novel targeted drug class, in prostate cancer. Overall, the data from these trials confirm the efficacy of this drug class in those metastatic prostate cancers that show specific gene alterations, such as mutations in the BRCA1/2 genes. Several studies combining PARPi with other standard drugs for prostate cancer suggest that there may be efficacy in larger patient populations, but some of these data still need validation in longer follow-up analyses.
European urology oncology. 2024 Dec 04 [Epub ahead of print]
Francesca Zacchi, Wassim Abida, Emmanuel S Antonarakis, Alan H Bryce, Elena Castro, Heather H Cheng, Shahneen Shandhu, Joaquin Mateo
Section of Innovation Biomedicine-Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, Verona, Italy., Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Medicine, University of Minnesota, Masonic Cancer Center, Minneapolis, MN, USA., Department of Medical Oncology and Developmental Therapeutics, City of Hope, Goodyear, AZ, USA., Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain., Department of Medicine, Division of Hematology and Oncology, University of Washington, Seattle, WA, USA; Fred Hutchinson Cancer Center, Seattle, WA, USA., Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia., Vall d'Hebron Institute of Oncology, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. Electronic address: .