FDA Approves Apalutamide for Some Men with Prostate Cancer

March 8, 2018, by NCI Staff

Cancer (purple) such as prostate cancer often spreads to the bone (orange), causing bone pain and fractures.
Credit: National Cancer Institute

On February 14, the Food and Drug Administration (FDA) approved apalutamide (Erleada) for men with prostate cancer that has not spread (nonmetastatic) and is resistant to standard hormone therapy, also called androgen deprivation therapy (ADT).

Treatment with apalutamide decreased the risk of metastasis or death by more than 70% compared with placebo, the trial that led to the approval showed.

"These are very dramatic results and, in many ways, exceeded our expectations," said lead investigator Matthew Smith, M.D., Ph.D., of Massachusetts General Hospital Cancer Center. The treatment "will be an important option" for men with prostate cancer in this setting, he added.

"We're learning that using hormone therapy earlier in men with prostate cancer can delay metastasis and probably improve survival. But the balance of benefits and potential side effects will need to be evaluated on a patient-by-patient basis," said William Dahut, M.D., head of the Prostate Cancer Clinical Research Section of NCI's Center for Cancer Research.

A New Option After Hormone Therapy Resistance

Men with prostate cancer that has not spread may be treated with ADT. These treatments block the body's production and use of male sex hormones (known as androgens) that drive prostate cancer growth. But most prostate cancers eventually become castration resistant, meaning the tumor begins to grow again despite androgen deprivation.

In the past, men with nonmetastatic castration-resistant prostate cancer continued ADT and were carefully observed for signs that the cancer had spread, at which point they could receive therapies for metastatic prostate cancer.

"The prevention of metastases represents an important unmet medical need," trial co-investigator Eric Small, M.D., of the University of California, San Francisco, said at the 2018 Genitourinary Cancers Symposium.

In an earlier phase 2 trial funded by NCI, Dr. Smith and his colleagues found that apalutamide had anticancer activity against castration-resistant prostate cancer. Apalutamide prevents androgens from binding to androgen receptors on cells and triggering cell growth.

In the phase 3 trial (dubbed SPARTAN) that led to the FDA approval, men with castration-resistant prostate cancer and no metastatic disease detectable by standard imaging tests were randomly assigned to receive apalutamide or placebo in addition to ongoing ADT. All participants were at high risk of metastasis based on rapidly rising prostate specific antigen (PSA) levels. The study was sponsored by Janssen Pharmaceutical Companies, the manufacturer of apalutamide.

The median length of time from the start of treatment to when tumors spread or the patient died (metastasis-free survival) was 16 months in the placebo group and 40 months in the apalutamide group. Men treated with apalutamide also went longer without worsening symptoms of cancer progression. Even when their cancer progressed on apalutamide and they went on to receive another therapy, these men had longer time to progression with the subsequent treatment than men in the placebo group.

The median length of time patients were alive after the start of treatment (overall survival) was 39 months for those who received placebo and had not been reached at the time of the study analysis for those who received apalutamide. An early analysis suggests that apalutamide may reduce the risk of death from prostate cancer, but longer patient follow-up is needed before the researchers can confirm this.

More patients in the apalutamide group than the placebo group had weight loss, fatigue, rash, falls, and bone fractures. In the apalutamide group, approximately 11% of patients discontinued treatment due to side effects, compared with 7% in the placebo group. Serious side effects were associated with the death of 1 subject in the placebo group and 10 subjects in the apalutamide group.

The researchers found no differences in quality-of-life scores reported by participants between the groups, and the scores did not get worse during treatment.

Apalutamide is the first drug to be approved by FDA based on an improvement in metastasis-free survival. Traditionally, most approvals are based on an improvement in progression-free survival or overall survival.

"This new precedent for FDA approval may permit drugs to reach the clinic more quickly," Dr. Dahut explained.

Another Potential Option for Prostate Cancer

Results from a separate clinical trial that was also reported at the 2018 Genitourinary Cancers Symposium suggest that there may soon be another potential treatment option for men with nonmetastatic castration-resistant prostate cancer.

The PROSPER trial showed that enzalutamide (Xtandi), a hormone therapy that also counteracts castration resistance, reduced the risk of metastasis or death by 71% compared with placebo. Compared with placebo, enzalutamide delayed the median time before study subjects needed a different treatment because their cancer had gotten worse (18 months versus 40 months). At the time of analysis, patients were not followed long enough for the investigators to determine the median overall survival.

Enzalutamide caused side effects in a greater percentage of patients than did placebo (87% versus 77%). The most common serious side effects of enzalutamide were high blood pressure, fatigue, and blood in the urine. After the study treatment was completed, 32 patients who received enzalutamide died of unknown causes, compared with 4 patients who received placebo.

Enzalutamide is FDA-approved to treat metastatic castration-resistant prostate cancer but it is not currently approved to treat men with nonmetastatic castration-resistant prostate cancer.

Considering results from the SPARTAN and PROSPER trials, it is evident that "using these more intense hormonal therapies earlier can definitely prevent the development of metastasis," Dr. Dahut said.

"But treating asymptomatic patients carries a certain burden of proof wherein benefit must clearly outweigh risk," Philip Kantoff, M.D., of Memorial Sloan Kettering Cancer Center, noted in a discussion of the two trials at the symposium.

It is not clear whether longer metastasis-free survival translates to benefits such as fewer symptoms or longer overall survival in these men, Dr. Kantoff explained. While it seems that both apalutamide and enzalutamide may ultimately prolong overall survival, there is not yet enough data to know for sure. "To me the clinical benefit is not yet fully determined in both studies," he concluded.

New Imaging Techniques May Change Diagnoses

While apalutamide—and, potentially, enzalutamide—gives men with nonmetastatic castration resistant disease a new treatment option, this patient population may decrease in the future, Dr. Dahut noted. That’s because traditional imaging techniques such as a CAT scan may not be able to detect tiny metastatic tumors, he explained. But a technique being used in research studies called molecular imaging can catch smaller tumors. If molecular imaging tests become part of clinical care, more men with prostate cancer might be classified as having metastatic disease.

"It's highly likely that apalutamide would be active" in men with metastatic castration-resistant prostate cancer, Dr. Dahut speculated. Trials to evaluate apalutamide in this patient population are already underway, Dr. Smith noted.