Apalutamide is the first non-metastatic, castration-resistant prostate cancer (NM-CRPC) treatment approved by the FDA.1 The approval is based upon data from the phase III SPARTAN study, which was presented at the 2018 Genitourinary Cancers Symposium and published in the New England Journal of Medicine.1-3 It is the first time any drug has been approved by using the endpoint of metastasis-free survival (MFS).1
Among men with NM-CRPC, a rapidly rising prostate-specific antigen (PSA) predicts time to first bone metastasis and survival.4,5 Given the lack of clinical trials in NM-CRPC, the unmet need remains significant in this subgroup of patients.6
“There is a population of men with prostate cancer who have no visible evidence of spread but who have a rise in their blood markers. These patients can have a poor prognosis, and until now, the optimal management of their cancer remained an enigma,” said Dr. Sumanta K. Pal of the City of Hope Comprehensive Cancer Center, US, at the 2018 Genitourinary Cancers Symposium.7
Apalutamide is a next-generation androgen receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR, which prevents AR translocation, DNA binding, and AR-mediated transcription.3 In the phase II study, apalutamide resulted in durable PSA responses in men with NM-CRPC, leading to a further investigation in the phase III SPARTAN study.3
SPARTAN enrolled a total of 1,207 men with NM-CRPC and a PSA doubling time of 10 months or less during continuous androgen-deprivation therapy (bilateral orchiectomy or gonadotropin-releasing hormone [GnRH] analogue agonists or antagonists). “Prior data has shown that these are the patients most at risk for developing metastases and death,” said lead study author, Prof. Eric J. Small of the University of California, US.2,3 Patients were randomly assigned in a 2:1 ratio to receive apalutamide 240mg or placebo.3 After the first detection of distant metastasis, patients were allowed to receive abiraterone acetate plus prednisone.3
Dr. Richard Pazdur, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, described the novel primary endpoint used in SPARTAN. “This approval is the first to use the endpoint of MFS, measuring the length of time that tumors did not spread to other parts of the body or that death occurred after starting treatment.”1
In the planned primary analysis of SPARTAN, the median MFS was 40.5 months in the apalutamide arm vs. 16.2 months in the placebo arm, this translates into a 72% reduction in the risk of distant metastasis or death (HR=0.28; 95% CI: 0.23-0.35; p<0.001).3 The clinical benefit with apalutamide was consistently seen across prespecified subgroups regardless of their age, PSA doubling time, and local or regional nodal disease at trial entry.3
“The SPARTAN trial results demonstrated impressive clinical benefits in patients with NM-CRPC,” said co-principal investigator, Dr. Matthew Smith, Director of the Genitourinary Malignancies Program at the Massachusetts General Hospital Cancer Center, Professor of Medicine at Harvard Medical School, US. “As an oncologist and clinical investigator, I know how devastating it can be for patients and their families to hear that the cancer has spread. With this approval, doctors now have the chance to offer hope for delaying metastases in patients with CRPC.”8
Remarkable results were also shown by another AR inhibitor, enzalutamide, in its phase III PROSPER trial. In combination with androgen-deprivation therapy, the median MFS in men with NM-CRPC who received enzalutamide was 36.6 months, as compared to 14.7 months in those receiving androgen-deprivation therapy alone (HR=0.29; 95% CI: 0.24-0.35; p<0.0001).9 If approved by the FDA, enzalutamide would become the second approved therapy for men with NM-CRPC.
1. FDA approves new treatment for a certain type of prostate cancer using novel clinical trial endpoint. FDA News Release. 2018 (Accessed February 27, 2018, at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm596768.htm).
2. Apalutamide Delays Metastasis by Over 2 Years in Prostate Cancer. OncLive. 2018 (Accessed February 27, 2018, at http://www.onclive.com/conference-coverage/gu-2018/apalutamide-delays-metastasis-by-over-2-years-in-prostate-cancer).
3. Smith MR, Saad F, Chowdhury S, et al. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. N Engl J Med. 2018 [Epub ahead of print].
4. Smith MR, Kabbinavar F, Saad F, et al. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol. 2005;23(13):2918-25.
5. Smith MR, Saad F, Oudard S, et al. Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time. J Clin Oncol. 2013;31(30):3800-6.
6. Gomella Discusses Apalutamide Approval and Other Progress in Prostate Cancer. OncLive. 2018 (Accessed February 27, 2018, at http://www.onclive.com/web-exclusives/gomella-discusses-apalutamide-approval-and-other-progress-in-prostate-cancer).
7. FDA Approves Apalutamide for Nonmetastatic Castration-Resistant Prostate Cancer. OncLive. 2018 (Accessed February 27, 2018, at http://www.onclive.com/web-exclusives/fda-approves-apalutamide-for-nonmetastatic-castrationresistant-prostate-cancer).
8. ERLEADA (apalutamide), a Next-Generation Androgen Receptor Inhibitor, Granted U.S. FDA Approval for the Treatment of Patients with Non-Metastatic Castration-Resistant Prostate Cancer. PR Newswire. 2018 (Accessed February 27, 2018, at https://www.prnewswire.com/news-releases/erleada-apalutamide-a-next-generation-androgen-receptor-inhibitor-granted-us-fda-approval-for-the-treatment-of-patients-with-non-metastatic-castration-resistant-prostate-cancer-300598990.html).
9. Enzalutamide More Than Doubles MFS for Nonmetastatic CRPC. OncLive. 2018 (Accessed February 27, 2018, at http://www.onclive.com/conference-coverage/gu-2018/enzalutamide-more-than-doubles-mfs-for-nonmetastatic-crpc).