Janssen Pharmaceutical has submitted a Marketing Authorization Application to the European Medicines Agency (EMA) for apalutamide, an investigational, next generation oral androgen receptor (AR) inhibitor for the treatment of patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC).
The submission is based on data from the pivotal SPARTAN Phase 3 clinical trial which assessed the safety and efficacy of apalutamide versus placebo in men with nmCRPC who have a rapidly rising prostate specific antigen (PSA) level, despite receiving continuous androgen deprivation therapy (ADT). The SPARTAN clinical trial showed a significantly decreased risk of distant metastasis or death (definition of the primary endpoint, metastasis free survival) by 72 percent, compared to placebo in combination with ADT (HR = 0.28; 95% CI, 0.23-0.35; P < 0.0001) and improved median metastasis-free survival (MFS) by over two years (difference of 24.3 months) in patients with nmCRPC whose PSA is rapidly rising. The results were presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) in San Francisco (Abstract 161). Study findings were simultaneously published in The New England Journal of Medicine.
“The results of the SPARTAN trial are the first to show that metastases can be delayed in patients with castration-resistant prostate cancer, suggesting that apalutamide could become a new standard of care for patients with high-risk non-metastatic CRPC,” said Dr. Simon Chowdhury, Consultant Medical Oncologist, Guy's and St Thomas' Hospitals, and a SPARTAN study investigator.
SPARTAN, a Phase 3, randomized, double-blind, placebo-controlled, multicenter study, enrolled 1,207 patients with non-metastatic castration-resistant prostate cancer and was conducted at 332 sites in 26 countries in North America, Europe, Asia-Pacific and Australia. Patients were randomized 2:1 to receive apalutamide in combination with androgen deprivation therapy (ADT) (n = 806), or placebo in combination with ADT (n = 401).
Apalutamide in combination with ADT decreased the risk of distant metastasis or death by 72 percent, compared to placebo in combination with ADT (HR = 0.28; 95% CI, 0.23-0.35; P < 0.0001). The median MFS was 40.5 months for apalutamide in combination with ADT compared to 16.2 months for placebo in combination with ADT, prolonging MFS by over two years. MFS benefit was consistently seen across all subgroups of patients.
In addition to significantly improving metastasis free survival, apalutamide in combination with ADT, compared to placebo in combination with ADT, demonstrated clinical improvement across all secondary endpoints, with statistically significant improvements in time to metastasis (TTM; median of 40.5 months in the apalutamide arm compared to median of 16.6 months in the placebo arm) and progression-free survival (PFS; median of 40.5 months compared to median of 14.7 months in the placebo arm). Treatment with apalutamide significantly decreased the risk of symptomatic progression by 55 percent compared with placebo (HR = 0.447; 95% CI: 0.315, 0.634; P <0.0001). Apalutamide was associated with a 30 percent risk reduction of death compared to placebo at this early interim analysis for overall survival (OS) (HR = 0.70; P = 0.07).1 In exploratory endpoints, apalutamide in combination with ADT, compared to placebo in combination with ADT, also achieved a 94 percent risk reduction in time to PSA progression (HR = 0.06; 95% CI, 0.05-0.08; P <0.0001), and a 51 percent risk reduction in second progression-free survival (PFS2) (HR = 0.49; P < 0.001). The combination of apalutamide and ADT was tolerable, with maintenance of overall health-related quality of life.
The most common Grade 3/4 treatment-emergent adverse events (TEAEs) for apalutamide in combination with ADT versus placebo in combination with ADT were rash (5.2 percent vs. 0.3 percent), fall (1.7 percent vs. 0.8 percent) and fracture (2.7 percent vs. 0.8 percent). Treatment discontinuation due to adverse events was 11 percent in the apalutamide arm compared to 7 percent in the placebo arm. Rates of serious adverse events (SAEs) were similar in the apalutamide in combination with ADT arm versus placebo in combination with ADT arm (25 percent vs. 23 percent respectively).
Non-metastatic castration-resistant prostate cancer (CRPC) refers to a disease stage when the cancer no longer responds to medical or surgical treatments that lower testosterone, but has not yet been discovered in other parts of the body using a bone scan or CT scan. Features include: lack of detectable metastatic disease; rapidly rising prostate-specific antigen while on androgen deprivation therapy (ADT) and serum testosterone level below 50 ng/dL. Ninety percent of patients with non-metastatic CRPC will eventually develop bone metastases, which can lead to pain, fractures and spinal cord compression. The relative 5-year survival rate for patients with distant stage castration sensitive or castration resistant prostate cancer is 30 percent. While it is critical to delay the onset of metastasis in patients with non-metastatic CRPC, there are currently no FDA or EMA approved treatments.