FDA Grants Priority Review to Enzalutamide for Metastatic Hormone-Sensitive Prostate Cancer

The FDA has granted a priority review to a supplemental New Drug Application for a new indication for enzalutamide as a treatment for men with metastatic hormone-sensitive prostate cancer.

The FDA has granted a priority review to a supplemental New Drug Application (sNDA) for a new indication for enzalutamide (Xtandi) as a treatment for men with metastatic hormone-sensitive prostate cancer (mHSPC).1

The sNDA is supported by findings from the phase III ARCHES trial as well as data from the phase III ENZAMET trial, both of which demonstrated improved outcomes for patients with the use of enzalutamide. The FDA has set a target action date for a decision on the sNDA by the fourth quarter of 2019.

“We are pleased to receive the Priority Review designation, which reflects the need for more treatment options for men living with metastatic hormone-sensitive prostate cancer,” said Chris Boshoff, MD, PhD, chief development officer of oncology, Pfizer Global Product Development, in a press release. Pfizer and Astellas Pharma are jointly developing and commercializing the androgen receptor inhibitor. “The submission is supported by a strong data package, including 2 phase III trials investigating Xtandi in men living with this form of prostate cancer.”

The international, double-blind ARCHES trial explored the addition of enzalutamide to androgen deprivation therapy (ADT) compared with ADT alone in men with mHSPC. The trial enrolled 1150 men with mHSPC who were randomized 1:1 to receive either 160 mg/day of enzalutamide or placebo plus ADT.2

The primary endpoint of radiographic progression-free survival (PFS) was met, showing a 61% reduction in the risk of radiographic progression or death with the addition of enzalutamide. At a median follow-up of 14.4 months, the median rPFS was not reached in the enzalutamide arm compared with 19.0 months in the ADT and placebo arm (HR, 0.39; 95% CI, 0.30-0.50;P<.001).

The PFS benefit seen with the addition of enzalutamide was consistent across patient subgroups, including in those with a high volume of disease (HR, 0.43) and those who had received prior docetaxel therapy (HR, 0.52).

In the enzalutamide arm, the objective response rate (ORR) was 83.1%, consisting of a complete response (CR) rate of 36.7%, compared with an ORR of 63.7% and a CR rate of 23.1% in the ADT and placebo arm.

Enzalutamide also demonstrated an improvement in the median time to prostate-specific antigen (PSA) progression, although the median time was not reached in either treatment arm (HR, 0.19; 95% CI, 0.13-0.26;P<.001). The median overall survival (OS) was also not reached in either arm as of this interim analysis, but demonstrated a 19% improvement in the risk of death with the use of enzalutamide (HR, 0.81; 95% CI, 0.53-1.25;P= .3361).

Treatment with enzalutamide also delayed the time to castration resistance (not reached vs 13.8 months; HR, 0.28; 95% CI, 0.22-0.36;P<.001) and the time to first symptomatic skeletal related event (HR, 0.52; 95% CI, 0.33-0.80;P= .0026).

The median treatment duration was 12.8 months (range, 0.2-26.6) in the enzalutamide and ADT arm compared with 11.6 months (range, 0.2-24.6) in the ADT and placebo arm.

The rate of adverse events (AEs) and serious AEs were similar between the 2 treatment arms (AEs, 85.1% vs 85.9%; serious AEs, 18.2% vs 19.5%). The most common any-grade AEs with enzalutamide were hot flash (27.1%), fatigue (19.6%), and arthralgia (12.2%). In the enzalutamide arm, the most common grade ≥3 AEs of special interest were hypertension (3.3%), fatigue (1.7%), second primary malignancies (1.6%), and musculoskeletal events (1.6%).

Treatment discontinuation occurred in 23.5% of patients in the enzalutamide arm compared with 42.0% in the ADT and placebo arm. Fourteen and 10 AEs led to death in the enzalutamide and ADT-alone arms, respectively.

The open-label, randomized ENZAMET trial explored the use of enzalutamide compared with a standard nonsteroidal antiandrogen (NSAA) therapy both with testosterone suppression. A total of 1125 men were randomized 1:1 to either 160 mg of daily enzalutamide or bicalutamide, nilutamide, or flutamide as part of the standard-care arm.3

The primary endpoint was OS, which was improved with the use of enzalutamide compared with the standard NSAAs (HR, 0.67; 95% CI, 0.52-0.86;P= .002). At 3 years, the estimated OS rate was 80% in the enzalutamide group compared with 72% in the standard NSAA group.

The time until clinical PSA rise, clinical progression, or death was significantly increased with enzalutamide compared to the other NSAAs (HR, 0.39; 95% CI, 0.33-0.47;P<.001). Clinical PFS also showed a significant benefit with enzalutamide (HR, 0.40; 95% CI, 0.33-0.49;P<.001).

According to data presented at the 2019 ASCO Annual Meeting, among the men with a high volume of disease on imaging scans (n = 596), those who received enzalutamide had a 3-year OS rate of 71% compared with 63% with another NSAA (HR, 0.74; 95% CI, 0.55-1.01). The 3-year OS rates were 89% and 82% (HR, 0.48; 95% CI, 0.28-0.80), respectively, in men with a low volume of disease (n = 529).4

In the subgroup of men who received planned concurrent docetaxel, the OS rates were similar regardless of treatment (HR, 0.90; 95% CI, 0.62-1.31). Of these patients, 71% had a high volume of disease. There was a more significant difference in survival in men who did not receive planned early docetaxel (HR, 0.53; 95% CI, 0.37-0.75). Only 37% of these patients had a high volume of disease.

At 3 years, 62% of patients in the enzalutamide arm were still receiving treatment compared with 34% in the standard-care group.3

The rate of grade ≥3 and serious AEs were slightly increased with enzalutamide compared with the standard NSAAs. The most common grade ≥3 AEs with enzalutamide were febrile neutropenia (7% vs 6% with standard NSAAs), hypertension (8% vs 4%, respectively), neutrophil count decrease (6% vs 3%), fatigue (6% vs 1%), and syncope (4% vs 1%). Seizures occurred in 7 patients in the enzalutamide arm compared with none in the standard-care group.

“The complementary data from the ARCHES and ENZAMET trials in men with mHSPC take us another step closer to understanding Xtandi’s full potential in helping address unmet needs in prostate cancer,” Andrew Krivoshik, MD, PhD, senior vice president and oncology therapeutic area head at Astellas, said in a press release. “Xtandi is a current standard of care in castration-resistant prostate cancer and we look forward to working with the FDA to potentially make Xtandi available to men earlier in their prostate cancer journey.”

Data from both trials have also been submitted to the European Medicines Agency and the Pharmaceuticals and Medical Devices Agency in Japan for potential approval.


  1. U.S. FDA Grants XTANDI&reg; (enzalutamide) Application Priority Review for the Treatment of Men with Metastatic Hormone-Sensitive Prostate Cancer [press release]. Tokyo and New York: Astellas Pharma Inc. and Pfizer Inc.; August 21, 2019. https://bwnews.pr/2Zjti3p. Accessed August 21, 2019.
  2. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer [published online July 22, 2019].J Clin Oncol.doi: 10.1200/JCO.19.00799.
  3. Davis ID, Martin AJ, Stockler MR, et al; ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer.N Engl J Med. 2019;381:121-131. doi: 10.1056/NEJMoa1903835.
  4. Sweeney C, Martin AJ, Zielinski RR, et al. Overall survival (OS) results of a phase III randomized trial of standard-of-care therapy with or without enzalutamide for metastatic hormone-sensitive prostate cancer (mHSPC): ENZAMET (ANZUP 1304), an ANZUP-led international cooperative group trial.J Clin Oncol. 2019;37(suppl; abstr LBA2).