By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved the first treatment for non-metastatic, castration-resistant prostate cancer (NM-CRPC). Apalutamide is a second-generation nonsteroidal androgen receptor inhibitor. Currently approved androgen receptor inhibitors (e.g., bicalutamide, enzalutamide) are approved for metastatic prostate cancer. Apalutamide demonstrates high affinity to the androgen receptor and favorable activity in CRPC xenograft models.1,2 The FDA granted the treatment priority review. It is marketed as Erleada.
Apalutamide is indicated for the treatment of patients with NM-CRPC.3
The recommended dose is 240 mg (four 60 mg tablets) orally once daily.3 It may be taken without regard to meals. Patients also should receive a gonadotropin-releasing hormone analog (e.g., leuprolide, goserelin) concurrently or should have undergone bilateral orchiectomy. Apalutamide is available as 60 mg tablets.
Apalutamide is the first FDA-approved treatment for NM-CRPC.
Fall and fractures have been associated with apalutamide (falls: 16% for apalutamide vs. 9% for placebo; fractures: 12% for apalutamide vs. 7% for fractures).3 Other adverse reactions include fatigue, arthralgia, rash, and hypothyroidism.1,2 Two subjects developed a seizure (0.2%) in the clinical trial, compared to none in the placebo group.
Efficacy and safety of apalutamide were evaluated in a double-blind, randomized, placebo-controlled trial in subjects with NM-CRPC (Selective Prostate Androgen Receptor Targeting with ARN-509).3,4 Subjects were at high risk for development of metastasis and exhibited local or regional node disease (class N0) or presented with malignant pelvic lymph nodes that measured < 2 cm in the short axis (N1) and were located below the aortic bifurcation. Androgen-deprivation therapy continued throughout the trial. Subjects were randomized 2:1 to apalutamide (240 mg daily; n = 806) or placebo (n = 401). The primary efficacy endpoint was time to first detection of metastasis (metastasis-free survival) or death from any cause. Subjects were stratified by Prostate Specific Antigen (PSA) Doubling Time (≤ 6 months or > 6 months), use of bone-sparing agents, and locoregional disease. Median metastatic-free survival was 40.5 months for apalutamide vs. 16.2 months for placebo (hazard ratio, 0.28; 95% confidence interval, 0.23-0.35). The benefit was seen across the different subgroups (e.g., high PSA levels, short PSA doubling time, or local or regional nodal disease at baseline). In addition, there was significant improvement in time to metastasis, progression-free survival, and time to symptomatic progression. Data were not mature enough to estimate overall survival.
Prostate cancer is the second most commonly diagnosed cancer in men and is the second leading cause of cancer death among American men.5 Chemical or surgical castration is an effective treatment for castration-sensitive disease; however, 10-20% of prostate cancers are castration-resistant, and among those patients, about 16% show no evidence of metastatic disease at the time of castration-resistant diagnosis. CRPC progresses clinically, radiographically, or biochemically despite castrate levels of serum testosterone (< 50 ng/dL).6 Apalutamide offers a potentially promising new oral option for NM-CRPC at high risk for metastasis. Although survival benefit has not been demonstrated, the FDA approved the drug using a new endpoint of “median metastasis-free survival.” More data from SPARTAN and further studies will demonstrate whether this translates to survival benefit. The cost of apalutamide is $10,920 for a 30-day supply.
- Cancian M, Renzulli JF 2nd. Nonmetastatic castration-resistant prostate cancer: A modern perspective. Urology 2018 Jan 31. pii: S0090-4295(18)30044-X. doi: 10.1016/j.urology.2018.01.010. [Epub ahead of print].
- Clegg NJ, et al. ARN-509: A novel antiandrogen for prostate cancer treatment. Cancer Res 2012;72:1494-1503.
- Erleada Prescribing Information. Janssen Products, LP, February 2018.
- Smith MR, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 2018 Feb 8. doi: 10.1056/NEJMoa1715546. [Epub ahead of print].
- Luo J, et al. Treatment of nonmetastatic castration-resistant prostate cancer. Oncology (Williston Park) 2016;30:336-344.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer. Feb. 14, 2018. Available at: . Accessed March 8, 2018.