FDA Approves Enzalutamide for Metastatic Castration-Sensitive Prostate Cancer


The FDA has approved a supplemental new drug application for enzalutamide (Xtandi) for the treatment of patients with metastatic castration-sensitive prostate cancer.

The FDA has approved a supplemental new drug application for enzalutamide (Xtandi) for the treatment of patients with metastatic castration-sensitive prostate cancer.

The approval is based on findings from the phase III ARCHES trial, in which the median radiographic progression-free survival (rPFS) in men with metastatic castration-sensitive prostate cancer was not reached with enzalutamide plus androgen deprivation therapy (ADT) and was 19.45 months with placebo and ADT, translating to a 61% reduction in risk of radiographic progression or death with enzalutamide (HR, 0.39; 95% CI, 0.30-0.50; P <.0001).1

"Men with metastatic castration-sensitive prostate cancer face complex treatment decisions and it is critical for physicians and patients to have as much information as possible when deciding on all of the options available," lead study investigator Andrew Armstrong, MD, professor of medicine, surgery, pharmacology and cancer biology, director of Research in the Duke Cancer Institute's Center for Prostate and Urologic Cancers, stated in a press release. "The research supporting the FDA approval and updated treatment guidelines provide physicians and patients with compelling evidence to consider enzalutamide as a treatment option for men with this disease."

The international, double-blind ARCHES trial enrolled 1150 patients with histologically verified metastatic castration-sensitive prostate cancer across North America, Europe, and the Asia-Pacific region who were randomized to receive enzalutamide at 160 mg daily or placebo. Men with both low- and high-volume disease, as well as patients who received recent treatment with docetaxel but did not have disease progression were enrolled.

Patients were allowed to receive prior androgen deprivation therapy (ADT) ≤3 months; those who received prior docetaxel could have had ADT for up to 6 months. The primary endpoint was rPFS, defined as the time to radiographic progression of disease either by soft tissue or confirmed bone scan criteria or death from any cause within 24 weeks of treatment discontinuation, whichever occurred first.

At initial diagnosis, 70% in the enzalutamide arm and 63% in the placebo arm had distant metastasis; 62% and 65%, respectively, had high disease volume; and 67% and 65%, respectively, had a Gleason score ≥8. Across the overall study population, approximately 18% of patients received prior docetaxel in the hormone-sensitive setting and the median duration of prior ADT at study entry was 1.6 months. Of those with confirmed metastases at screening, nearly half had bone only metastases with about 9% having soft tissue only metastases.

Enzalutamide plus ADT was also associated with a reduction in the risk of time to PSA progression by 81% (HR, 0.19; 95% CI, 0.13-0.26; P <.0001) and the time to initiation of new antineoplastic therapy by 72% (HR, 0.28; 95% CI, 0.20-0.40; P <.0001) compared with ADT alone.

An interim analysis of OS showed that the median OS has not been reached in either arm, with 39 deaths in the enzalutamide arm and 45 in the placebo arm. OS data were not mature at the time of final rPFS analysis.

The 12-month event-free rate estimate for rPFS was 84% in the enzalutamide/ADT arm and 64% in the placebo/ADT arm, with a median that has not been reached for enzalutamide. At the data cutoff date of October 14, 2018, the majority of the events were radiographic progression events—77 in the enzalutamide arm and 185 in the placebo arm. With a median follow-up of 14.4 months, the median duration of therapy was 12.8 months for enzalutamide plus ADT versus 11.6 months for placebo plus ADT.

A complete response (disappearance of all lesions on imaging) was attained by 36.7% of enzalutamide-treated patients versus 23.1% of placebo recipients. The overall response rate favored enzalutamide over placebo (83.1% vs 63.7%; P <.0001).

The safety profile of enzalutamide was consistent with prior studies of the androgen receptor inhibitor. The proportion of patients who had to discontinue study was similar between enzalutamide and placebo (7.2% vs 5.2%) and the rate of grade ≥3 adverse events (AEs) was also similar (24.3% vs 25.6%).

The safety analysis of the ARCHES trial is generally consistent with the safety profile of enzalutamide that has been observed in prior clinical trials. In ARCHES, the most common adverse events (≥5%) that were reported more frequently in patients treated with enzalutamide plus ADT versus placebo/ADT included hot flush (27% vs 22%, respectively), asthenic conditions (24% vs 20%), hypertension (8.0% vs 5.6%), fractures (6.5% vs 4.2%), and musculoskeletal pain (6.3% vs 4.0%).

"Enzalutamide has been established as a standard of care for men with castration-resistant prostate cancer and has been prescribed to more than 420,000 patients worldwide since it was first approved in 2012," Andrew Krivoshik, MD, PhD, senior vice president and oncology therapeutic area head at Astellas, which co-develops enzalutamide with Pfizer. "This approval in metastatic castration-sensitive prostate cancer means physicians can now offer Xtandi to men earlier in their advanced prostate cancer treatment journey."


  1. Xtandi (Enzalutamide) approved by U.S. FDA for the treatment of metastatic castration-sensitive prostate cancer [news release]. Pfizer. Published December 16, 2019. https://bit.ly/2tpujIV. Accessed December 16, 2019.
  2. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. Phase 3 study of androgen deprivation therapy (ADT) with enzalutamide (ENZA) or placebo (PBO) in metastatic hormone-sensitive prostate cancer (mHSPC): The ARCHES trial. J Clin Oncol. 2019;37(suppl 7, abstr 687). doi: 10.1200/JCO.2019.37.7_suppl.687.
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