For most prostate cancer patients, androgen-deprivation therapy, either through surgical removal of the testicles or the use of drugs that suppress testosterone production, is the standard treatment.
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.
Now, the results of a phase 3 clinical trial co-led by Harvard Medical School investigators based at Massachusetts General Hospital show that treatment with apalutamide, an investigational androgen receptor inhibitor, significantly delayed the development of metastasis in castration-resistant prostate cancer patients.
The average progression-free survival—the time from treatment to the first evidence of metastasis—was 40.5 months for participants receiving apalutamide, compared with 16.2 months for those taking a placebo.
“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,” said Matthew Smith, HMS professor of medicine at Mass General and corresponding author of the study, published online in the New England Journal of Medicine.
“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,” Smith added.
Apalutamide binds to the androgen receptor, blocking its activation by testosterone and other androgens. 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 American, 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.
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.
“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, professor of medicine at the University of California San Francisco.
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.