Results of Phase 3 Clinical Trial Being Published Online in New England Journal of Medicine
Treatment with an investigational androgen receptor inhibitor significantly delayed the development of metastasis in patients with prostate cancer that had become resistant to standard androgen-deprivation therapy. The results of a multi-institutional, phase 3 clinical trial of apalutamide – led by investigators from Massachusetts General Hospital (MGH) and University of California San Francisco (UCSF) – are receiving early release publication in the New England Journal of Medicine to coincide with a presentation today at the American Society for Clinical Oncology Genitourinary Cancers (ASCO-GU) Symposium.
“Our study found that apalutamide treatment markedly improved metastasis-free survival and other clinical outcomes in men with castration-resistant prostate cancers and no detectable metastases,” says Matthew Smith, MD, PhD, of the MGH Cancer Center, corresponding author of the NEJM report. “At this time, there are no approved treatments for men in that situation, so we need to wait until their disease progresses to add the standard therapies that have been approved for metastatic disease.”
Senior author Eric Small, MD, deputy director of the Helen Diller Family Comprehensive Cancer Center at UCSF, who presented the data at the ASCO-GU Symposium, says, “This trial’s results suggest that the availability of apalutamide should offer men with nonmetastatic, castration-resistant prostate cancer a treatment that can delay or prevent the development of metastases and other complications associated with disease progression.”
Androgen-deprivation therapy, either through surgical removal of the testicles or the use of drugs that suppress testosterone production, is standard treatment for men with metastatic prostate cancer and is also used for nonmetastatic cancer. Unfortunately, androgen deprivation stops working for almost all patients, leading to what is called castration-resistant disease. In such patients whose cancer has not yet spread, a rapid rise in prostate-specific antigen (PSA) levels warns of the near-term development of metastases, the major cause of complications and death from prostate cancer.
Apalutamide binds to the androgen receptor, blocking its activation by testosterone and other androgens. Apalutamide is being developed by The Janssen Pharmaceutical Companies of Johnson & Johnson, which sponsored this study. A previous phase 2 clinical trial of apalutamide for men with nonmetastatic, castration-resistant prostate cancer at high risk of progression showed that the drug was well tolerated and achieved responses in most patients.
The current trial was conducted at 322 sites in 26 countries in North America, Europe and the Asia-Pacific. More than 1,200 patients enrolled in the trial between October 2013 and December 2016. All participants had nonmetastatic prostate cancer that had stopped responding to androgen-deprivation therapy and a rapid PSA doubling time, indicating an elevated risk for metastasis. Participants were randomized to receive a daily oral dose of either apalutamide or a placebo and were evaluated every 16 weeks for signs of disease progression.
The NEJM study reports results based on data gathered by May 19, 2017. The average progression-free survival – the time from randomization to the first evidence of metastasis – was 40.5 months for participants receiving apalutamide, compared with 16.2 months for those taking a placebo. Taking apalutamide also reduced other signs of disease progression – including development of imaging-confirmed metastasis or symptoms such as bone pain -- and death from any cause. Members of the apalutamide group who continued to benefit from the drug were able to continue treatment, and members of the placebo group could begin receiving apalutamide on an open-label basis.
Small is professor of Medicine and chief of the Division of Hematology and Oncology at UCSF. He holds the Doris and Donald Fisher Distinguished Professorship in Clinical Cancer Research and the Stanford W. Ascherman and Norman R. Ascherman Endowed Chair at UCSF. Smith is director of the Genitourinary Malignancies Program and holds the Claire and John Bertucci Endowed Chair in Genitourinary Cancers in the MGH Cancer Center and is a professor of Medicine at Harvard Medical School
Several additional phase 3 trials of apalutamide are currently underway for other prostate cancer disease states, including studies of both earlier and later stage disease.
The NEJM report was co-authored by 16 additional investigators – from academic medical centers and from Janssen Research & Development – in nine countries.
UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospitals in San Francisco and Oakland – and other partner and affiliated hospitals and healthcare providers throughout the Bay Area.
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $900 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2017 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."