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Clinical Trials Point to New Options for Advanced Prostate Cancer

Two more treatments for men with advanced prostate cancer could soon be available, according to updated findings from two phase III clinical trials presented in San Francisco last week at the 2012 Genitourinary Cancers Symposium.

In the trials, the investigational agents MDV3100 and radium-223 (Alpharadin) improved overall survival in men with metastatic castrate-resistant prostate cancer—that is, cancer that no longer responds to treatments that dramatically diminish the testosterone available in the body to fuel tumor growth.

The drugs, which work by different mechanisms of action, also controlled the growth of bone metastases—the most common site of tumor spread in prostate cancer—and caused few serious side effects. Both trials were stopped early because of the survival improvements, and the investigational drugs were offered to patients who had not received them during the trials.

If the Food and Drug Administration (FDA) approves both drugs, which several researchers said is likely, the number of approved treatments for men with advanced castrate-resistant prostate cancer would rise to six—up from only a single approved agent, the chemotherapy drug docetaxel, in 2004.

        FDA-Approved Drugs for Treating Advanced Prostate Cancer

The FDA is reviewing MDV3100 and radium-223 under the fast-track designation for treatment of men with metastatic castrate-resistant prostate cancer. The fast track designation is used to expedite the review of drugs for serious conditions for which there is an unmet medical need.

"This is a very exciting time," said Dr. Leonard Gomella of the Thomas Jefferson University Kimmel Cancer Center, who was not involved in either trial. "We have so many new options for patients with advanced castrate-resistant prostate cancer, agents with different mechanisms of action to treat the cancer in different ways. It's very good news for patients."

Different Agents, Similar Results

More than 900 patients with advanced prostate cancer that had spread only to the bones were enrolled in the smaller of the two trials, dubbed ALSYMPCA, which compared treatment with radium-223 plus best supportive care to placebo plus best supportive care.

Radium-223, developed by the Norwegian company Algeta, is the first of a class of drugs called alpha-particle emitters to advance this far into clinical studies. Because it is a "calcium mimic"— like calcium, it targets areas of bone undergoing changes such as those induced by tumors—the drug is designed to target bone metastases, the trial's lead investigator, Dr. A. Oliver Sartor of the Tulane University Cancer Center, said during a press briefing.

Once in the bone, radium-223 emits very low levels of alpha radiation, which travels less than 100 microns, or approximately four one-thousandths of an inch. The drug radiates the tumors and surrounding areas "in a very localized fashion," Dr. Sartor said, "like a little bomb going off but [one] that doesn't affect surrounding tissues very much at all."

The results presented last week were from an interim analysis of 805 patients in the trial. The analysis showed a median overall survival of 14 months in patients treated with radium-223 versus 11.2 months in patients treated with placebo. Patients who received radium-223 also lived significantly longer before experiencing bone-related events such as fractures or spinal compressions, a median of 13.6 months compared with 8.4 months for those in the placebo group.

Delaying the onset of bone events is clinically important, said Dr. Philip Saylor of Massachusetts General Hospital, who was not involved in the trial. "Such an overwhelming burden of the disease takes place in the skeleton," Dr. Saylor said. It's also a promising sign, he continued, that radium-223 doesn't appear to cause bone marrow suppression, a problem that has been seen with investigational beta-particle emitters.

The other trial, AFFIRM, tested MDV3100, a drug that targets androgen receptors on cells.

Until fairly recently, the prevailing thought was that prostate tumors that continued to grow despite extremely low levels of testosterone in the body were using a mechanism that does not involve testosterone. But laboratory studies have convincingly shown that tumor cells "have their own mechanisms for making androgens at the local tumor site or figuring out ways to turn on androgen receptors to help them grow," Dr. Gomella explained.

MDV3100—which is being co-developed by San Francisco-based Medivation, Inc. and Tokyo-based Astellas Pharma, Inc.—works by two routes, preventing testosterone from binding to androgen receptors and, within the cell, preventing the androgen receptor from initiating the production of proteins that induce tumor growth.

Nearly 1,200 men, all of whom had castrate-resistant prostate cancer that had progressed after treatment with docetaxel, took part in AFFIRM. The median overall survival was 18.4 months for patients treated with MDV3100 and 13.6 months for those treated with placebo.

Approximately one-third of patients treated with MDV3100 had partial or complete shrinkage of their tumors, compared with 1.3 percent of patients in the control arm, explained the trial's lead investigator, Dr. Howard Scher of Memorial Sloan-Kettering Cancer Center. Treatment with MDV3100 also substantially lengthened the amount of time patients lived without the progression of metastatic tumors (as measured by imaging studies), 8.3 months compared with 2.9 months.

The results, Dr. Scher noted, "will likely position" MDV3100 as the initial treatment in patients with advanced castrate-resistant prostate cancer whose disease progresses after docetaxel treatment.

Next Steps: Treatment Sequencing and Combinations

With several options for treating castrate-resistant prostate cancer, much of the discussion among researchers and clinicians centers on how best to use them—in particular, in what order.

Given the different mechanisms of action and survival improvements seen with MDV3100 and radium-223, using the drugs sequentially could be a particularly promising approach, Dr. Nicholas Vogelzang of the Comprehensive Cancer Centers of Nevada said during the press briefing.

Dr. Sartor agreed. "Whether there are additive or even synergistic benefits will have to be demonstrated in trials," he said, "but it's plausible that combinations or sequential use of these agents may add even more value than what we've seen here."

Combining approved and investigational agents is also high on the research agenda. In asymptomatic patients, combining immunotherapeutic treatments like sipuleucel-T with newer androgen-directed therapies may be a valuable approach, Dr. Gomella said. In patients with progressive disease, treatments that incorporate chemotherapy combined with radium-223 may be particularly effective.

"Of course this is all theory," he said. "But we're very excited that we can even be talking about these theories right now."

—Carmen Phillips