FDA Approval for Rising PSA in Nonmetastatic, Hormone-Sensitive Prostate Cancer

For patients at high risk of metastasis who have biochemical recurrence (rising PSA) of nonmetastatic, castration-sensitive (responsive to hormone suppression) prostate cancer , enzalutamide (Xtandi, Astellas Pharma) received US Food and Drug Administration (FDA) approval on November 16, 2023.

For prostate cancer patients in this setting—nonmetastatic, castration-sensitive disease with biochemical recurrence—this represents the first FDA approval .

What Is Biochemical Recurrence?

Biochemical recurrence refers to an increase in prostate-specific antigen (PSA) levels measured through blood tests, particularly after prostate cancer treatment. A rise in PSA after treatment may indicate that the cancer has recurred or remains active in the body. However, not every PSA increase signifies biochemical recurrence; generally, doubling of PSA over a specified period, such as 6-9 months, is considered biochemical recurrence.

PSA is expected to fall to an undetectable level after treatments such as radical prostatectomy (surgical removal of the prostate) or radiotherapy. However, if PSA subsequently rises beyond a particular threshold, this is regarded as biochemical recurrence and may generally mean that the cancer has recurred locally or spread to other parts of the body (metastasized). This rise usually occurs without any tumor finding detectable on imaging.

Diagnosing biochemical recurrence is an important step in following patients who have received cancer treatment and generally indicates that treatment needs to be adjusted or new treatment options considered.

What Is Castration-Sensitive Prostate Cancer?

Castration-sensitive prostate cancer responds favorably to androgen-deprivation therapy (ADT), which deprives the body of male hormones (androgens). Androgens, particularly testosterone, promote prostate cancer cell growth and proliferation. Castration sensitivity means the cancer cells lose their ability to grow and spread when exposed to low levels of these hormones.

Over time, some prostate cancers may become resistant to hormone therapy; these are called "castration-resistant prostate cancer" (CRPC). This means the cancer can now grow even in an environment with low testosterone, generally indicating a need to consider more aggressive treatment approaches. Early success can be achieved in treating castration-sensitive prostate cancer, slowing or stopping disease progression.

FDA Approval Based on the EMBARK Study

Enzalutamide's efficacy was evaluated in EMBARK, a randomized, controlled clinical trial of 1068 patients with nonmetastatic, castration-sensitive prostate cancer and high-risk biochemical recurrence. All had previously undergone radical prostatectomy or radiotherapy with curative intent, had a PSA doubling time of ≤ 9 months, and were ineligible for salvage radiotherapy at enrollment.

Patients were randomized 1:1:1 to one of 3 arms:

• Combination Treatment Arm: Patients received enzalutamide (160 mg once daily) plus leuprolide. This was a blinded arm, meaning neither patients nor doctors knew which treatment was being given.
• Enzalutamide Monotherapy (Single-Agent Treatment) Arm: Patients received open-label enzalutamide alone (160 mg once daily). "Open-label" means that both patients and doctors knew which treatment was being given.
• Placebo Arm: Patients received placebo (an inactive substance, once daily) plus leuprolide. This was also a blinded arm.

The main efficacy outcome was metastasis-free survival (MFS) for enzalutamide plus leuprolide versus placebo plus leuprolide, assessed by blinded independent central review. Additional efficacy outcomes were MFS for enzalutamide monotherapy versus placebo plus leuprolide, and overall survival (OS).

Results

• Enzalutamide plus leuprolide significantly improved MFS compared with placebo plus leuprolide, with the median not reached in either arm (hazard ratio 0.42; 95% CI: 0.30, 0.61; p-value<0.0001). The combination reduced the risk of metastasis by 58%.
• Enzalutamide monotherapy also significantly improved MFS compared with placebo plus leuprolide (hazard ratio 0.63; 95% CI: 0.46, 0.87; p-value = 0.0049). Enzalutamide alone reduced the risk of metastasis by 37%.

Overall survival data were immature at analysis, with a death rate of 12% across the entire patient population.

The most common adverse effects (in 20% or more) among patients receiving enzalutamide plus leuprolide were hot flashes, musculoskeletal pain, fatigue, falls, and hemorrhage. With enzalutamide monotherapy, the most common adverse effects were fatigue, gynecomastia, musculoskeletal pain, breast tenderness, hot flashes, and hemorrhage.

The recommended enzalutamide dose is 160 mg orally once daily, with or without food, until disease progression or unacceptable toxicity. Enzalutamide may be given with or without a GnRH analog. Treatment may be suspended if PSA becomes undetectable (< 0.2 ng/mL) after 36 weeks of treatment. It may be restarted when PSA rises to ≥ 2.0 ng/mL in patients who previously underwent radical prostatectomy, or ≥ 5.0 ng/mL in those who previously received radiation therapy.

This review was conducted under Project Orbis, an FDA Oncology Center of Excellence initiative providing a framework for concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with Health Canada and Switzerland's Swissmedic. Reviews of the applications by other regulatory agencies are ongoing.

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