Apalutamide Received FDA Approval for Nonmetastatic Hormone-Resistant Prostate Cancer

The United States Food and Drug Administration, FDA , on 14 February 2018 approved treatment for prostate cancer no longer responding to conventional hormonal therapy, with rising PSA and therefore a high risk of metastasis to other organs, using apalutamide (brand name Erleada ).

This Is the First FDA-Approved Treatment for Nonmetastatic Hormone-Resistant Prostate Cancer

For the first time, the FDA used metastasis-free survival as a primary endpoint in its decision-making. Metastasis-free survival is the time from diagnosis of early or locally advanced nonmetastatic disease until the first metastasis. Particularly in prostate cancer follow-up, it is a newly used intermediate measure to predict overall survival. Prostate cancer patients live a long time, so waiting for overall survival to measure a new drug’s effect greatly prolongs clinical trials. Intermediate endpoints are therefore needed. Metastasis-free survival resembles disease-free survival, but disease-free survival considers local recurrence, whereas the former considers the first distant organ metastasis.

What Is Apalutamide?

Apalutamide, brand name Erleada, was first discovered in 2010. It prevents androgens such as testosterone and dihydrotestosterone from binding to androgen receptors abundant in prostate cells, blocking these male hormones’ effects on the prostate and other tissues.

Every year worldwide, 1.1 million new prostate cancer diagnoses occur, with approximately 300 thousand deaths annually. In the United States, 5-year survival is 98.6%, clearly showing the scale of treatment success. At diagnosis, 91% of prostate cancers are early-stage, and approximately 10% to 20% of early-stage cancers are hormone (castration)-resistant. Among hormone-resistant patients, 16% show no metastases at diagnosis.

Prostate Cancer Cells Becoming Hormone/Castration-Resistant

For early-stage prostate cancer, a local treatment is used as the main approach, such as surgery, internal radiotherapy, external radiotherapy, HIFU, cryoablation (freezing treatment) . Active surveillance without treatment is also an option for early-stage, low-risk disease. Alongside these treatments, for intermediate- or high-risk patients, conventional hormonal therapies are started. At this stage, prostate cancer cells are sensitive to hormone suppression. Some patients may develop rising PSA without distant organ metastasis, as discussed above; this is called nonmetastatic hormone-resistant prostate cancer . Before apalutamide, no approved treatment existed for these patients, who were monitored on conventional hormonal treatment until distant metastases developed.

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The SPARTAN Study That Led to Apalutamide Approval

Approval was based on 1207 patients with nonmetastatic castration-resistant prostate cancer assessed in the multicenter, double-blind SPARTAN clinical trial . Patients were divided into two arms in a 2-to-1 ratio: the 806-patient group received standard androgen suppression plus oral apalutamide once daily at 240 mg, while the 401-patient arm received standard treatment plus placebo .

The main efficacy endpoint was metastasis-free survival, defined as time until the first distant metastasis (bone or soft tissue lesions, or spread to lymph nodes outside the pelvis) or death from any cause, whichever occurred first.

The results showed median metastasis-free survival of 40.5 months with apalutamide and 16.2 months with placebo.

Common side effects occurring in at least 10% of patients included fatigue, hypertension, rash, diarrhea, nausea, weight loss, arthralgia, falls, hot flashes, decreased appetite, fractures and peripheral edema.

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The recommended apalutamide dose is 240 mg orally once daily (four 60 mg tablets).

Apalutamide’s success in nonmetastatic hormone-resistant prostate cancer is particularly noteworthy. However, newer imaging technologies such as PSMA-PET may detect some metastases earlier and reduce the number of patients in this intermediate category, enabling men to receive treatments already approved for these cancers.

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