A newly developed drug called apalutamide can delay the progression of a hard-to-treat form of prostate cancer, research shows. The drug, an investigational androgen receptor inhibitor, was the focus of a multi-institutional, phase 3 clinical trial led by investigators from Massachusetts General Hospital (MGH) and University of California, San Francisco (UCSF).

“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. 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,"

corresponding author Matthew Smith, MD, PhD, of the MGH Cancer Center, said.

Androgen-deprivation Therapy

Androgen-deprivation therapy, either through the use of drugs that suppress testosterone production, or surgical removal of the testicles, is standard treatment for men with metastatic prostate cancer and is also used for non-metastatic 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.

Prostate cancer is the second most deadly form of the disease for men in the US, and the American Cancer Society anticipates that it will kill nearly 30,000 people this year alone while another 164,000 are diagnosed. Most forms of prostate cancer grow slowly, meaning they may not be detectable for many years.


Apalutamide works by binding 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.

Apalutamide is similar to enzalutamide both structurally and pharmacologically . Enzalutamide was approved by the Food and Drug Administration for medical use in the United States in August 2012.

This trial, conducted at 322 sites in 26 countries in North American, Europe and the Asia-Pacific, involved more than 1,200 patients 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.

As of 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.

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 current report was co-authored by 16 additional investigators - from academic medical centers and from Janssen Research & Development - in nine countries.

“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,"

said senior author Eric Small, MD, deputy director of the Helen Diller Family Comprehensive Cancer Center at UCSF.

Matthew R. Smith, M.D., Ph.D., Fred Saad, M.D., Simon Chowdhury, M.B., B.S., Ph.D., Stéphane Oudard, M.D., Ph.D., Boris A. Hadaschik, M.D., Julie N. Graff, M.D., David Olmos, M.D., Ph.D., Paul N. Mainwaring, M.B., B.S., M.D., Ji Youl Lee, M.D., Hiroji Uemura, M.D., Ph.D., Angela Lopez-Gitlitz, M.D., Géralyn C. Trudel, Ph.D., Byron M. Espina, B.S., Youyi Shu, Ph.D., Youn C. Park, Ph.D., Wayne R. Rackoff, M.D., Margaret K. Yu, M.D., and Eric J. Small, M.D. for the SPARTAN Investigators Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer NEJM February 8, 2018 DOI: 10.1056/NEJMoa1715546

Image: Castration resistant prostate cancer, human tissue' by Mateus Crespo, The Institute of Cancer Research. CC BY

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