November 10, 2020 - The China National Medical Products Administration has approved enzalutamide for the treatment of adult patients with nonmetastatic castration-resistant prostate cancer who are at a higher risk of metastasis.
The China National Medical Products Administration has approved enzalutamide (Xtandi) for the treatment of adult patients with nonmetastatic castration-resistant prostate cancer (CRPC) who are at a higher risk of metastasis, according to an announcement from Astellas Pharma.1
The regulatory decision was based on data from the phase 3 PROSPER trial (NCT02003924), which showed that the combination of enzalutamide and androgen deprivation therapy (ADT) led to a 71% reduction in the risk of metastases or death versus ADT alone in patients with nonmetastatic CRPC.2 The median metastasis-free survival (MFS) was 36.6 months with enzalutamide/ADT versus 14.7 months with ADT alone (HR, 0.29; 95% CI, 0.24-0.35; P <.0001).
“In order to maintain quality of life for men with nonmetastatic prostate cancer, new treatments are needed to delay the progression of prostate cancer and prevent it from spreading to other areas in the body,” Andrew Krivoshik, MD, PhD, senior vice president and global therapeutic area head of Oncology Development at Astellas, stated in a press release. “In clinical studies, enzalutamide significantly reduced the risk of the cancer spreading or death compared to placebo alone.”
In the double-blind phase 3 PROSPER trial, 1401 patients with asymptomatic nonmetastatic CRPC were randomized to receive either enzalutamide at 160 mg daily plus ADT (n= 933) or a matching sugar pill placebo (n = 468). ADT was comprised of gonadotropin-releasing hormone agonist/antagonist. All patients enrolled to the study had testosterone levels of 50 ng/dL or less, a prostate-specific antigen (PSA) doubling time of 10 months or less, and a PSA of 2 ng/mL or more.
The primary end point of the trial was MFS within 112 days of treatment discontinuation. Secondary end points included PSA, time to next antineoplastic therapy, and overall survival (OS). The median duration of treatment in the investigational and control arms was 18.4 months and 11.1 months, respectively.
Additional results showed that the time to the first use of a subsequent antineoplastic therapy was longer in the enzalutamide arm than in the placebo arm, 39.6 months versus 17.7 months, respectively (HR, 0.21; P <.001). This therapy was used in 15% versus 48% of patients in the investigational and control arms, respectively. The time to PSA progression was also prolonged with enzalutamide versus placebo, at 37.2 months versus 3.9 months, respectively (HR, 0.07; P <.001). PSA progression was reported in 22% on the investigational arm versus 69% on the control arm.
At the first interim analysis of OS, 11% (n = 103) of patients who received enzalutamide/ADT died versus 13% (n = 62) of those who received ADT/placebo. Updated data showed that as of October 15, 2019, 31% (n = 288) versus 38% (n = 178) in the investigational and placebo arms, respectively, had died.3 The median OS was 67.0 months (95% CI, 64.0–not reached) with enzalutamide/ADT versus 56.3 months (95% CI, 54.4-63.0) with ADT/placebo (HR, 0.73; 95% CI, 0.61-0.89; P =.001).
Additional results from PROSPER were presented during the 2020 ESMO Virtual Congress and showed that nadir PSA was significantly associated with MFS in patients with nonmetastatic CRPC and a rapidly rising PSA who received enzalutamide.4 By the 17th week of treatment, 79% of men enrolled on the trial experienced a PSA decline of 50% or greater from baseline, with 23% demonstrating a PSA value of less than 0.2 ng/mL; these changes were found to be significantly associated with MFS.
Additionally, a PSA decline of 50% or greater, 90% or greater, and less than 0.2 ng/mL at any time on the study was significantly linked with a 88%, 74%, and 80%, respectively, reduced risk of development of metastasis or death in those who had received enzalutamide (all P <.0001). A PSA decline of 50% or greater showed the strongest prognostic effect versus the other PSA thresholds examined.
With regard to safety, significantly more adverse effects (AEs) were reported in the investigational arm compared with the control arm, at 87% versus 77%, respectively. Grade 3 AEs were reported in 31% of those on the enzalutamide arm versus 23% of those on the placebo arm. The grade 3 or higher toxicities more commonly reported in the investigational arm versus the control arm were hypertension (5% vs 2%, respectively) and fatigue (3% vs 1%).
Nine percent of patients on the enzalutamide/ADT arm experienced toxicities that resulted in treatment discontinuation versus 6% of those on the ADT/placebo arm. Moreover, 5% of patients versus 3% of patients on the investigational and control arms, respectively, reported major cardiovascular events. Three seizures were reported in the investigational arm versus none in the control arm.
“Enzalutamide in nonmetastatic CRPC provides patients and their doctors with an important new option for the treatment of their advancing prostate cancer,” Hiroshi Hamaguchi, president of Greater China Commercial at Astellas. “We look forward to serving more patients and physicians as we expand our work in prostate cancer and continue to grow the Astellas oncology program in China.”
In July 2018, the FDA approved enzalutamide for the treatment of patients with nonmetastatic CRPC based on data from PROSPER. In 2012, the FDA initially approved enzalutamide as a treatment of men with metastatic CRPC following docetaxel. The indication was expanded in 2014 to include treatment with enzalutamide before chemotherapy.