New clinical trial design cuts the time needed to assess experimental treatments for prostate cancer

Every year, 50,000 to 60,000 men with prostate cancer in the United States find themselves in a precarious position: after being treated with surgery or radiation, and despite being given hormonal therapy that should eradicate any remaining traces of cancer, their prostate-specific antigen (PSA) levels climb or stay elevated. That’s called nonmetastatic castration-resistant prostate cancer (nmCRPC), and the term “castration” is used because hormonal therapy blocks testosterone, a hormone produced by the testicles that makes prostate cancer cells grow faster. Since prostate cancer cells leach PSA into blood, elevated levels of this protein in men on hormonal therapy suggest the disease is still lurking, and that metastatic tumors will eventually appear elsewhere in the body.

The first treatment for this condition, called apalutamide, was approved earlier this year by the FDA. But in approving the drug, FDA officials also relied on a newer, faster, and more practical measure to find out if the drug was working in clinical trials. The gold standard for confirming effectiveness in clinical research is overall survival, referring to how long patients live on experimental treatment before dying of their disease. If overall survival among patients on an experimental drug is significantly longer than it is in control patients treated with an older drug or placebo, then the experimental drug is deemed superior and approval typically follows.

But what happens if overall survival differences between the treatment and control groups take many years to ascertain? That’s been a tricky problem for clinical research in nmCRPC, because men can live with it for so long before any new tumors appear. The transition to metastatic cancer comes with pain and worsening symptoms, so it has to be delayed for as long as possible. But when tumors are still confined to the prostate, reaching the overall survival endpoint can take 10 to 15 years — a prohibitive time frame for pharmaceutical companies.

So during the apalutamide clinical trial, investigators dropped overall survival in favor of a different measure: metastasis-free survival (MFS). As the term implies, MFS simply refers to how long men with nmCRPC live on treatment before new tumors appear. According to the results, MFS in men given apalutamide lasted approximately 40 months, compared to 16 months in a control group of men given standard treatments plus placebo. Whether MFS predicts longer overall survival still isn’t known, but some experts are optimistic that it does.

Writing in the New England Journal of Medicine last June, FDA officials spelled out prospects for MFS in future prostate cancer clinical trials. Most important, they emphasized, is that delays in metastasis from treatment should be “clinically meaningful,” or in other words, long enough to justify the costs and potential risks. (During an earlier trial exploring MFS differences in nmCRPC patients that was completed in 2012, the experimental treatment delayed metastasis to the bones by just four months. An FDA advisory committee concluded that treatment benefits weren’t worth the risks, and so the experimental drug was never approved.)

How long is long enough with MFS? FDA officials wouldn’t say. But Dr. Maha Hussain, a professor of hematology and oncology at Northwestern University’s Feinberg School of Medicine in Chicago, IL, and a member of the aforementioned advisory committee, was quoted in the cancer research trade press saying “a minimum of one year.”

Whether MFS will be used in clinical trials focused on diseases other than prostate cancer still isn’t known. Experts are grappling with associated technical issues, including the adequacy of existing technology to detect metastatic tumors while they’re still very small. But the FDA editorial ended on an encouraging note. “Future agents may be approved on the basis of MFS… if the safety profile is acceptable for a medication taken in the long term.”

 

Charlie Schmidt