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Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer

Chi KN 1 , Rathkopf D 2 , Smith MR 3 , Efstathiou E 4 , Attard G 5 , Olmos D 6 Show all authors , Lee JY 7 , Small EJ 8 , Pereira de Santana Gomes AJ 9 , Roubaud G 10 , Saad M 11 , Zurawski B 12 , Sakalo V 13 , Mason GE 14 , Francis P 15 , Wang G 14 , Wu D 16 , Diorio B 17 , Lopez-Gitlitz A 16 , Sandhu S 18 , MAGNITUDE Principal Investigators

Affiliations 

  • 1 BC Cancer - Vancouver Center, University of British Columbia, Vancouver, BC, Canada
  • 2 Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York, NY
  • 3 Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA
  • 4 Houston Methodist Cancer Center, Houston, TX
  • 5 University College London, London, UK
  • 6 Department of Medical Oncology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
  • 7 Department of Urology Cancer Center, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
  • 8 Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA
  • 9 Liga Norte Riograndense Contra o Câncer, Natal, Brazil
  • 10 Department of Medical Oncology, Institut Bergonié, Bordeaux, France
  • 11 Department of Clinical Oncology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 12 Department of Outpatient Chemotherapy, Professor Franciszek Lukaszczyk Oncology Center, Bydgoszcz, Poland
  • 13 Kyiv City Clinical Oncology Center and Academician O.F. Vozianov Institute of Urology of the National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine
  • 14 Janssen Research & Development, LLC, Spring House, PA
  • 15 Janssen Research & Development, LLC, Raritan, NJ
  • 16 Janssen Research & Development, LLC, Los Angeles, CA
  • 17 Janssen Research & Development, LLC, Titusville, NJ
  • 18 Peter MacCallum Cancer Centre and the University of Melbourne, Melbourne, Australia
J Clin Oncol, 2023 Jun 20;41(18):3339-3351.
PMID: 36952634 DOI: 10.1200/JCO.22.01649

Abstract

PURPOSE: Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with current standard-of-care therapies. Homologous recombination repair (HRR) gene alterations, including BRCA1/2 alterations, can sensitize cancer cells to poly (ADP-ribose) polymerase inhibition, which may improve outcomes in treatment-naïve mCRPC when combined with androgen receptor signaling inhibition.

METHODS: MAGNITUDE (ClinicalTrials.gov identifier: NCT03748641) is a phase III, randomized, double-blinded study that evaluates niraparib and abiraterone acetate plus prednisone (niraparib + AAP) in patients with (HRR+, n = 423) or without (HRR-, n = 247) HRR-associated gene alterations, as prospectively determined by tissue/plasma-based assays. Patients were assigned 1:1 to receive niraparib + AAP or placebo + AAP. The primary end point, radiographic progression-free survival (rPFS) assessed by central review, was evaluated first in the BRCA1/2 subgroup and then in the full HRR+ cohort, with secondary end points analyzed for the full HRR+ cohort if rPFS was statistically significant. A futility analysis was preplanned in the HRR- cohort.

RESULTS: Median rPFS in the BRCA1/2 subgroup was significantly longer in the niraparib + AAP group compared with the placebo + AAP group (16.6 v 10.9 months; hazard ratio [HR], 0.53; 95% CI, 0.36 to 0.79; P = .001). In the overall HRR+ cohort, rPFS was significantly longer in the niraparib + AAP group compared with the placebo + AAP group (16.5 v 13.7 months; HR, 0.73; 95% CI, 0.56 to 0.96; P = .022). These findings were supported by improvement in the secondary end points of time to symptomatic progression and time to initiation of cytotoxic chemotherapy. In the HRR- cohort, futility was declared per the prespecified criteria. Treatment with niraparib + AAP was tolerable, with anemia and hypertension as the most reported grade ≥ 3 adverse events.

CONCLUSION: Combination treatment with niraparib + AAP significantly lengthened rPFS in patients with HRR+ mCRPC compared with standard-of-care AAP.

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* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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