China National Medical Products Administration Approves Enzalutamide

The China National Medical Products Administration (NMPA) has approved Astellasnew drug application (NDA) for enzalutamide (Xtandi®; previously known as MDV3100).

Enzalutamide is an oral, once-daily androgen receptor signaling inhibitor, for the treatment of adult men with metastatic castration-resistant prostate cancer (CRPC) who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy (ADT) in whom chemotherapy is not yet clinically indicated.

Prostate cancer is considered metastatic once the cancer has spread outside of the prostate gland to other parts of the body. [1] Metastatic CRPC is fatal, with a median survival of approximately 3-4 years for men starting treatment with ADT. [2]

Chinese approval
The approval of enzalutamide by the Chinese regulator is based on the Asian multinational PREVAIL study (also known as 9785-CL-0232), a phase III, randomized, double-blind, placebo controlled efficacy and safety study of enzalutamide in men with metastatic castration-resistant prostate cancer. The study enrolled 388 participants who were not previously treated with cytotoxic chemotherapy.

As part of the approval process, the regulators also considered data from a trial (Protocol 9785-CL-0013) in asymptomatic or mildly symptomatic patients with progressive metastatic prostate cancer who had disease progression despite ADT and a single-dose pharmacokinetic study in healthy Chinese volunteers . [3]

In these studies the researchers evaluated oral enzalutamide (160 mg/day) versus placebo plus gonadotropin-releasing hormone (GnRH) therapy or after bilateral orchiectomy. The study, involving Asian patients including approximately 200 Chinese patients, showed consistent results with those in the global pivotal Phase III PREVAIL study in the same target population. [4]

“Currently the treatment options are limited in China for men with metastatic castration-resistant prostate cancer,” note Andrew Krivoshik, MD., Ph.D., Senior Vice President and Global Therapeutic Area Head, Oncology Development, Astellas.

“The approval of enzalutamide in China brings us one step closer to offering physicians a meaningful treatment option in an area where there is a high medical need,” Krivoshik added.

Trials
Participating patients treated with enzalutamide demonstrated a statistically significant reduction in the risk of Prostate Specific Antigen (PSA) progression (Hazard Ratio of 0.38 [95% confidence interval: 0.27, 0.52], P < 0.0001).

The median time to PSA progression was 8.31 months in the enzalutamide group versus 2.86 months in the placebo group. Treatment with enzalutamide also resulted in a statistically significant reduction in risk of radiographic disease progression or death compared with treatment with placebo with a Hazard Ratio (HR) of 0.31 (95% confidence interval: 0.20, 0.46; P<0.0001).

Additionally, treatment with enzalutamide showed a statistically significant improvement in overall survival compared to treatment with placebo, with a 67% decrease in the risk of death (HR 0.33, [95% CI: 0.16, 0.67]; P=0.0015).

The safety profile observed in the Asian PREVAIL study was generally consistent with previous clinical studies in patients with metastatic CRPC. [2] The most common adverse reactions (≥10%) that occurred more frequently (≥2% over placebo) in the enzalutamide-treated patients from the randomized placebo-controlled clinical trials were asthenia/fatigue, decreased appetite, hot flush, arthralgia, dizziness/vertigo, hypertension, headache, and decreased weight.

In addition to the Asian PREVAIL data involving a Chinese sub-population, the approval was supported by results from the global Phase III PREVAIL trial, which were published in the New England Journal of Medicine in 2014.

The Phase III PREVAIL trial was a double-blind, placebo-controlled, multi-national trial that enrolled 1,717 patients and randomly assigned patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The patients were enrolled at sites in the United States, Canada, Europe, Australia, Russia, Israel and Asia including Japan. [4]

The Phase III study was stopped after a planned interim analysis demonstrating a benefit of the active treatment. In this global study, the researchers found that a rate of radiographic progression-free survival (PFS) at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001).

Based on the results of the global PREVAIL study, the researchers concluded that enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. This conclusion resulted in the adoption of enzalutamide as a standard of care for men with metastatic CRPC in countries where it is available.

Milestone
Prostate cancer is the second most common cancer in men worldwide [5] and in China it has become the most common tumor in male urinary malignancies. [6]

“The approval of enzalutamide is an important milestone. Tens of thousands of Chinese patients with metastatic castration-resistant prostate cancer could potentially benefit from the reduced risk of disease progression and death found in the Asian PREVAIL study,” said Hiroshi Hamaguchi, President, Astellas Greater China Commercial.

“The approval also demonstrates a significant step forward for Astellas, with enzalutamide being the first Astellas oncology treatment approved in China,” Hamaguchi concluded.

References
[1] American Society of Clinical Oncology. ASCO Answers: Prostate Cancer (2018). Online. Last accessed November 2019.
[2] Mottet N, et al. Updated Guidelines for Metastatic Hormone-sensitive Prostate Cancer: Abiraterone Acetate Combined with Castration Is Another Standard. Eur Urol. 2018;3:316-321.
[3] An Asian Study to Evaluate Efficacy and Safety of Oral Enzalutamide in Progressive Metastatic Prostate Cancer Participants. Online. Last accessed September 2019.
[4] Beer T, Armstrong A et al. Enzalutamide in Metastatic Prostate Cancer before Chemotherapy. N Engl J Med 2014; 371:424-433.
[5] American Cancer Society. Key Statistics for Prostate Cancer. Online. Last accessed September 2019.
[6] Chinese guidelines for diagnosis and treatment of prostate cancer 2018. Chin J Cancer Res. 2019 Feb; 31(1): 67–83.