April 2, 2018/Cancer

FDA Approval of Apalutamide: Practical Implications

The first approved treatment for men with nonmetastatic castration-resistant prostate cancer (M0CRPC)

650×450 Apalutamide 2

With the recent FDA approval of apalutamide for the treatment of patients with nonmetastatic castration-resistant prostate cancer (M0CRPC), urologists and medical oncologists for the first time have an approved treatment for men with M0CRPC.


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“We now have an agent that we can use in patients with M0 (zero metastases) stage of the disease,” says Cleveland Clinic medical genitourinary oncologist Jorge A. Garcia, MD, FACP. “Treating CRPC in this early stage improves metastasis-free survival, that includes time-to-disease progression (radiographic, serologic and clinical). Treatment with apalutamide in the M0 setting also delays time to chemotherapy. When we look at the impact of apalutamide on the progression-free survival (PFS) of subsequent therapy, patients who receive apalutamide also appear to do better compared to those who received placebo.

“All of these endpoints are quite powerful and likely to lead to survival improvement in a significant number of patients,” he continues. “We now have to wait for the data to mature to really see if this is indeed the case.” Dr. Garcia, The Kerscher Family Chair for Clinical Prostate Cancer Research, has joint appointments in Hematology and Oncology and Urology departments at Taussig Cancer Institute and Glickman Urological & Kidney Institute, respectively.

Possible game-changers

Robert Abouassaly, MD, Department of Urology, agrees that approval of apalutamide, a competitive inhibitor of the androgen receptor, will have a major impact on treatment of patients with M0CRPC.

“Apalutamide will be a new treatment option for patients with M0CRPC who have failed initial androgen deprivation therapy,” says Dr. Abouassaly. “I think that this drug, and other drugs like apalutamide, could be game-changers for prostate cancer because they show effectiveness earlier and earlier in the course of the disease.”

A phase 2 study at Cleveland Clinic led by Dr. Garcia is also looking at apalutamide given in combination with luteinizing hormone-releasing hormone (LHRH) for four weeks prior to surgery in patients with high-risk prostate cancer.

“These are patients with high-risk localized prostate cancer (i.e., Gleason score 8-10) who are considering local curative treatment with surgery and have not yet been treated with androgen deprivation therapy, so they are not yet castration-resistant,” Dr. Abouassaly says.


Dr. Garcia notes that M0CRPC has been traditionally difficult to treat primarily due to a lack of established standard treatments.

“Standard treatment hasn’t been available for men with M0CRPC because these patients are healthy with no symptoms of disease,” he explains. “Furthermore, it is very hard to offer systemic therapy without knowing if it will lead to survival improvement or delay the appearance of radiographic findings or clinical symptoms. Therefore, in the past, most patients with rising prostate-specific antigen levels in the M0CRPC setting used to be observed, undergo systemic therapy on clinical trials or we would use secondary hormonal manipulations with older androgen receptor inhibitors such as bicalutamide or nilutamide.

SPARTAN trial demonstrates multiple benefits of apalutamide

Approval of apalutamide was based on a multicenter phase 3 clinical trial (SPARTAN trial) conducted in 1,207 men with M0CRPC randomized in a ratio of 2:1 to receive either 240 mg daily apalutamide (n = 806) or placebo (n = 401). Results were reported in the New England Journal of Medicine in early 2018. MFS served as the primary endpoint and was defined as the time from randomization to first distant metastasis, or death.

“This is one of several trials to use a new generation antiandrogen in patients without metastatic disease,” Dr. Abouassaly points out. “The study only included patients at increased risk of developing metastases and the results showed a significant advantage to using apalutamide — the median time to metastasis development was 40.5 months in patients treated with apalutamide compared to 16.2. months in patients taking placebo.”

Dr. Garcia notes that the trial “showed a 72 percent relative risk reduction in time to distant metastasis or death, with a hazard ratio of 0.28 and a statistically significant P value (P < 0.001).

“The benefits of apalutamide were also evident from the results obtained for all secondary endpoints, including time to metastasis, progression-free survival, and time to symptomatic progression (P < 0.001 for all comparisons),” says Dr. Garcia.


“Although apalutamide was associated with a 30 percent reduction in the risk of death, in the interim analysis this finding was not statistically significant,” he says. “But it is very important to recognize that the lack of significance in the survival benefit does not mean that this agent is not powerful and effective, because the primary endpoint of this clinical trial was MFS – an endpoint that was selected as a surrogate for survival benefit.”

Practical benefits of apalutamide

In conclusion, Dr. Garcia points out several practical benefits of apalutamide treatment, including ease of administration and the drug’s early action.

“For practitioners who treat men with M0CRPC, it is very important to recognize that (i) apalutamide is an oral agent, and (ii) it may make it possible to maintain patients free of symptoms, because this agent acts before the disease can be objectively measured and before symptoms appear.”

He also emphasizes that practitioners can’t assume oral agents such as apalutamide don’t have side effects. “In the SPARTAN trial, apalutamide was associated with higher rates of rash, fatigue, arthralgia, weight loss, falls and fracture when compared to placebo. The majority of adverse events were grade (G) 1 or 2, thus manageable by most physicians. What is important here is to understand the published data to allow early recognition of side effects so we don’t compromise the quality of life of our M0CRPC patients.”

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