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

The FDA has granted a priority review designation to a supplemental new drug application for enzalutamide (Xtandi) for the treatment of men with metastatic hormone-sensitive prostate cancer (mHSPC), according to Astellas Pharma Inc. and Pfizer Inc., the codevelopers of the androgen receptor inhibitor.

The designation, which will expedite the development and review of enzalutamide in this setting, is based on data from the phase III ARCHES and ENZAMET trials. The ARCHES study showed that at a median follow-up of 14.4 months, median radiographic progression-free survival (rPFS) in men with mHSPC was not reached in the enzalutamide arm and was 19.45 months in the placebo arm, 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

In the phase III ENZAMET trial, the 3-year overall survival (OS) rate in men with mHSPC was 80% in patients treated with enzalutamide plus standard of care (SOC) compared with 72% among those who received a different nonsteroidal antiandrogen (NSAA; HR, 0.67; 95% CI, 0.52-0.86; P = .002).²

"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," said 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."

ARCHES

The international, double-blind ARCHES trial enrolled 1150 patients with histologically verified mHSPC 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. A final OS analysis will be conducted after approximately 342 deaths.

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%).

Following the unblinding at the end of double-blind treatment and the significant positive outcome on the primary endpoint, all patients in the placebo group are being offered enzalutamide in an open-label extension protocol.

ENZAMET

The international, randomized phase III ENZAMET trial was led by the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group. The trial enrolled 1125 men with mHSPC between March 2014 and March 2017. These men were randomized 1:1 to receive either enzalutamide or 1 of 3 first-generation NSAAs (bicalutamide [Casodex], nilutamide [Nilandron], or flutamide [Eulexin]) plus a testosterone-suppressing medicine. Less than half of the men (n = 503) received early doses of docetaxel. Patients were evaluated every 12 weeks and at progression could receive therapy for castration-resistant prostate cancer at the investigator’s discretion.

ADT was allowed in the study up to 120 days prior to randomization, but intermittent ADT dosing was not allowed.

Randomization was stratified by volume of disease, planned early docetaxel use, planned anti-resorptive therapy, comorbidity score, performance status, and study site. A high volume of disease was considered the existence of visceral metastases and/or ≥4 bone metastases, with at least 1 of these beyond the pelvis and vertebral column.

The study authors noted that the 2 treatment arms were well balanced at baseline. The median age was 69 years across the 2 treatment arms.

As of the first interim analysis on February 28, 2019, when the criteria of 235 deaths had been met, patients had been followed for a median of 33 months. At 3 years, 64% of patients assigned to receive enzalutamide were still on the study treatment compared with 36% in the other NSAA arm.

The time until clinical prostate-specific antigen (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). Looking only at clinical progression also showed a significant benefit with enzalutamide (HR, 0.40; 95% CI, 0.33-0.49; P <.001). There was a 60% decreased rate of progression at any one time.

Among 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).

In the subgroup of men who received planned concurrent docetaxel, the OS rates were similar regardless of treatment (HR, 0.90; 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.

Selected AEs included hypertension of grade 2 seen in 4% of those treated with another NSAA and in 8% treated with enzalutamide and of grade 3 in 5% versus 11%, respectively. Grade 2 (14% vs 25%) and grade 3 (1% vs 6%) fatigue, grade 2 (1% vs 5%) and grade 3 (<1% vs 1%) falls, grade 1/2 concentration impairment (1% vs 4%), syncope (1% vs 4%), and seizure (0% vs 1%) were also noted. The rate of selected AEs per year of treatment exposure was 34% (95% CI, 29%-40%) with enzalutamide compared with 33% (95% CI, 28%-39%) with other NSAAs.

References

1. 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.
2. 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). doi: 10.1200/JCO.2019.37.18_suppl.LBA2.