2. UroToday Home
  3. Recent Abstracts
  4. Urologic Oncology
  5. Prostate Cancer

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 - Beyond the Abstract

While most patients with prostate cancer are diagnosed with localized disease, a subset will develop metastatic disease, and subsequently castration-resistant prostate cancer (mCRPC), which remains incurable. Additionally, an increasing number of patients will present with de novo metastatic prostate cancer, known as metastatic castration-sensitive prostate cancer (mCSPC), and may progress to mCRPC. In the mCSPC setting, treatment intensification of androgen deprivation therapy (ADT) with androgen receptor (AR) pathway inhibitors (ARPIs; alternatively called androgen receptor signaling inhibitors or ARSIs), with or without docetaxel, has improved overall survival versus ADT alone. However, real-world evidence indicates that many men with mCSPC do not receive such treatment intensification.

Preclinical and clinical evidence suggests that co-inhibition of the AR pathway and poly(ADP-ribose) polymerase (PARP) may result in enhanced benefit in the treatment of mCRPC regardless of alterations in DNA damage response genes involved either directly or indirectly in homologous recombination repair (HRR). We explore the results of three phase 3 clinical trials (TALAPRO-2, PROpel, and MAGNITUDE) investigating this premise in the first-line mCRPC setting. We also discuss the newly approved combination treatments within the context of the current treatment landscape for mCRPC in the United States (US) and consider practical clinical considerations for administering a PARP inhibitor (PARPi) with an ARPI, including the importance of HRR testing, treatment intensification, and management of adverse events (AEs).

TALAPRO-2, which investigated talazoparib plus enzalutamide in patients who were prospectively tested for HRR gene alterations, demonstrated that the combination improved radiographic progression-free survival (rPFS) versus enzalutamide alone in both the all-comers and the HRR-deficient populations. In PROpel, which investigated olaparib plus abiraterone acetate and prednisone (AAP) in patients who were retrospectively assessed for HRR gene alterations, the combination also improved rPFS in the non–HRR-deficient and HRR-deficient populations. MAGNITUDE, which investigated niraparib plus AAP in patients prospectively tested for HRR gene alterations, found that the combination improved rPFS in the HRR-deficient population but futility was declared for the non–HRR-deficient population. Overall survival was immature at the time of this review for TALAPRO-2 and MAGNITUDE. For all patients in PROpel, improved median overall survival was noted for the combination treatment but statistical significance was not reached. Across all three studies, the greatest rPFS benefit was seen in patients whose tumors harbored BRCA gene alterations. Subsequent approvals in the US were of talazoparib plus enzalutamide for the treatment of mCRPC with any HRR gene alterations and of olaparib and niraparib, both in combination with AAP, for the treatment of mCRPC with BRCA alterations.

The results of these phase 3 trials highlight the importance of HRR screening for patients with advanced prostate cancer, to ensure that patients who may benefit from these therapies are identified. Testing for HRR deficiency at the time of initial diagnosis of advanced prostate cancer, without waiting for the onset of mCRPC, is key to avoiding a false negative result, which may occur from using old tissue samples with degraded DNA or samples with a low quantity of DNA. Testing blood samples for circulating tumor DNA presents a promising alternative to the “gold standard” of tumor tissue testing, with the caveat that the results should be interpreted with an understanding of the potential for a false-negative or -positive test result.

There is currently underutilization of treatment intensification and treatment sequencing (e.g., treatment with enzalutamide followed by abiraterone) for patients with metastatic prostate cancer. In the all-comers cohort of TALAPRO-2, and PROpel and MAGNITUDE, less than a quarter of patients received docetaxel and/or an ARPI before enrollment. Real-world studies in the US show that up to half of patients do not receive any life-prolonging therapy after their first-line treatment for metastatic prostate cancer. Based on the efficacy of PARPi monotherapy after an ARPI in the PROfound study, and of upfront PARPi plus ARPI combination therapy vs sequencing in the BRCAAWAY study, there is a compelling rationale to use a PARPi plus an ARPI upfront, particularly in individuals with select HRR gene alterations. However, treatment intensification may increase the risk of AEs, and the safety profile of treatment combination needs to be discussed and reviewed with the patient and caregiver team. Anemia was the most common of any grade and grade ≥3 AE in TALAPRO-2, PROpel, and MAGNITUDE; anemia was actively managed by supportive care and dose modification.

In the rapidly evolving treatment landscape for patients with mCRPC, it is important to reassess treatment plans and help each patient make informed decisions on their treatment pathway based on their medical history and genetic testing. In the US, the combination of PARPi and ARPIs is a promising new standard-of-care option for patients with select HRR gene alterations (talazoparib plus enzalutamide) and specifically BRCA alterations (olaparib plus AAP or niraparib plus AAP or talazoparib plus enzalutamide) in the first-line mCRPC setting.

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 - Beyond the Abstract



Written by: Rana R. McKay,a Alicia K. Morgans,b Neal D. Shore,c Curtis Dunshee,d Geeta Devgan,e and Neeraj Agarwalf 

  1. Moores Cancer Center, University of California San Diego, 3855 Health Sciences Drive, La Jolla, CA 92037, USA
  2. Harvard Medical School, Dana-Farber Cancer Institute, 450 Brookline Ave, Dana 09-930, Boston, MA 02215, USA
  3. Carolina Urologic Research Center, 823 82nd Parkway, Myrtle Beach, SC 29572, USA
  4. Arizona Urology Specialists, 2260 W. Orange Grove Road, Tucson, AZ 85741, USA
  5. Pfizer Inc., 66 Hudson Blvd East, New York, NY 10001, USA
  6. Huntsman Cancer Institute (NCI-CCC), University of Utah, 2000 Circle of Hope Drive, Suite 5726, Salt Lake City, UT 84112, USA
Disclosures: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R.R.M. reports a consulting or advisory board role for AstraZeneca, AVEO Pharmaceuticals, Bayer, Blue Earth Diagnostics, Bristol Myers Squibb, Calithera, Caris, Dendreon, Eisai, Eli Lilly, Exelixis, Janssen, Merck, MOMA, Myovant, Novartis, Pfizer, Sanofi, Seagen, Sorrento Therapeutics, Telix, and Tempus; and research funding (to her institution) from AstraZeneca, Artera, Bayer, Bristol Myers Squibb, Exelixis, Oncternal, and Tempus. A.K.M. reports a consulting role for Antev, Astellas, AstraZeneca, Bayer, Exelixis, Janssen, Lantheus, Merck, Myovant, Novartis, Pfizer, Sanofi, and Telix; and research funding from Bayer, Lantheus, Myovant, Pfizer, and Sanofi. N.D.S. reports a consulting or advisory role for AbbVie, Alessa Therapeutics, AIkido, Amgen, Arquer, Asieris, Astellas Pharma, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, CG Oncology, Clarity Pharmaceuticals, Clovis Oncology, Dendreon, Exact Imaging, Exact Sciences, FerGene, Ferring, FIZE Medical, Foundation Medicine, GenesisCare, Genentech, Guardant Health, ImmunityBio, Incyte, Invitae, Janssen, Lantheus, Lilly, Mdxhealth, Merck, Minomic, Myovant Sciences, Myriad Genetics, Nymox, Pacific Edge Biotechnology, Pfizer, Photocure, PlatformQ, Profound, Promaxo, Propella Therapeutics, Protara, Sanofi, Sesen Bio, Specialty Networks, Telix Pharmaceuticals, Tolmar, UroGen Pharma, Vaxiion, and Vessi; providing expert testimony for Ferring; and leadership or other fiduciary role in other board, society, committee, or advocacy group with Photocure. C.D. reports participation on advisory boards for Astellas Pharma, Bayer, Janssen, and Pfizer; and research funding from AstraZeneca, Bayer, Dendreon, Hengrui Pharmaceuticals, Janssen, Laekna Therapeutics, Myovant Sciences, and Pfizer. G.D. is an employee of Pfizer and may hold Pfizer stock/stock options. N.A. has received an honorarium for consultancy before May 2021 from Astellas Pharma, AstraZeneca, AVEO, Bayer, Bristol Myers Squibb, Calithera Biosciences, Eisai, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead Sciences, Immunomedics, Janssen, Lilly, and MEI Pharma; and research funding (to his institution) from Arvinas, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Calithera Biosciences, Celldex, Clovis Oncology, CRISPR Therapeutics, Eisai, EMD Serono, Exelixis, Genentech, Gilead Sciences, GlaxoSmithKline, Immunomedics, Janssen, Lava, Lilly, Merck, Nektar, Neoleukin, Novartis, ORIC Pharmaceuticals, Pfizer, Rexahn, Roche, Sanofi, Seagen, Takeda, and TRACON.

Acknowledgments: This work was sponsored by Pfizer Inc. and medical writing support was provided by Annette Smith, PhD, on behalf of CMC Affinity, a division of IPG Health Medical Communications, and was funded by Pfizer.

Read the Abstract