First-line combination treatment with PARP and androgen receptor-signaling inhibitors in HRR-deficient mCRPC: Applying clinical study findings to clinical practice in the United States.

Metastatic castration-resistant prostate cancer (mCRPC) remains incurable and develops from biochemically recurrent PC treated with androgen deprivation therapy (ADT) following definitive therapy for localized PC, or from metastatic castration-sensitive PC (mCSPC). In the mCSPC setting, treatment intensification of ADT plus androgen receptor (AR)-signaling inhibitors (ARSIs), with or without chemotherapy, improves outcomes vs ADT alone. Despite multiple phase 3 trials demonstrating a survival benefit of treatment intensification in PC, there remains high use of ADT monotherapy in real-world clinical practice. Prior studies indicate that co-inhibition of AR and poly(ADP-ribose) polymerase (PARP) may result in enhanced benefit in treating tumors regardless of alterations in DNA damage response genes involved either directly or indirectly in homologous recombination repair (HRR). Three recent phase 3 studies evaluated the combination of a PARP inhibitor (PARPi) with an ARSI as first-line treatment for mCRPC: TALAPRO-2, talazoparib plus enzalutamide; PROpel, olaparib plus abiraterone acetate and prednisone (AAP); and MAGNITUDE, niraparib plus AAP. Results from these studies have led to the recent approval in the United States of talazoparib plus enzalutamide for the treatment of mCRPC with any HRR alteration, and of both olaparib and niraparib indicated in combination with AAP for the treatment of mCRPC with BRCA alterations.

Here, we review the newly approved PARPi plus ARSI treatments within the context of the mCRPC treatment landscape, provide an overview of practical considerations for the combinations in clinical practice, highlight the importance of HRR testing, and discuss the benefits of treatment intensification for patients with mCRPC.

Cancer treatment reviews. 2024 Mar 29 [Epub ahead of print]

Rana R McKay, Alicia K Morgans, Neal D Shore, Curtis Dunshee, Geeta Devgan, Neeraj Agarwal

Moores Cancer Center, University of California San Diego, 3855 Health Sciences Drive, La Jolla, CA 92037, USA. Electronic address: ., Harvard Medical School, Dana-Farber Cancer Institute, 450 Brookline Ave, Dana 09-930, Boston, MA 02215, USA. Electronic address: ., Carolina Urologic Research Center, 823 82nd Parkway, Suite B, Myrtle Beach, SC 29572, USA. Electronic address: ., Urology Specialists, 2260 W. Orange Grove Road, Tucson, AZ 85741, USA. Electronic address: ., Pfizer Inc., 66 Hudson Blvd East, New York, NY 10001, USA. Electronic address: ., Huntsman Cancer Institute (NCI-CCC), University of Utah, 2000 Circle of Hope Drive, Suite 5726, Salt Lake City, UT 84112, USA. Electronic address: .