Enzalutamide Approved in Europe for Metastatic Hormone-Sensitive Prostate Cancer

The European Commission has approved enzalutamide for the treatment of adult patients with metastatic hormone-sensitive prostate cancer.

The European Commission (EC) has approved enzalutamide (Xtandi) for the treatment of adult patients with metastatic hormone-sensitive prostate cancer (mHSPC), according to an announcement from Astellas Pharma Inc.1

With this additional indication, the antiandrogen medication is the only oral treatment that has been given the green light by the EC to treat 3 types of advanced prostate cancer: nonmetastatic, metastatic and castration resistant, and metastatic hormone sensitive.

The regulatory decision was based on findings from the phase 3 ARCHES trial, which demonstrated that enzalutamide, when paired with androgen deprivation therapy (ADT), resulted in a significant 61% reduction in the risk of radiographic progression or death compared with placebo/ADT in 1150 patients with mHSPC (HR, 0.39; 95% CI, 0.30-0.50; P <.0001).2 The radiographic progression-free survival (rPFS) was not reached in the investigative arm vs 19.45 months in the control arm.

“[Patients with] mHSPC have limited options and, unfortunately, there is a poor prognosis for many men,” Andrew Armstrong, MD, professor of medicine, surgery, pharmacology and cancer biology; director of research at the Center for Prostate and Urologic Cancers at Duke Cancer Institute; and lead investigator of ARCHES, stated in a press release. “The research supporting this approval provides clinical evidence showing how enzalutamide can help improve outcomes for men with mHSPC, which gives healthcare professionals in Europe the option to offer the treatment across the advanced prostate cancer disease continuum.”

ARCHES evaluated the safety and efficacy of enzalutamide in combination with ADT in patients with mHSPC. The trial enrolled patients with mHSPC and histologically confirmed adenocarcinoma, an ECOG performance status of 0 or 1, who had a current ADT duration of 3 months or less unless previous docetaxel was received; if the chemotherapy agent had been received, they had to have an ADT duration of 6 months or less.

In total, 1150 patients with mHSPC who met the eligibility criteria were randomized 1:1 to receive either enzalutamide at a daily dose of 160 mg plus ADT (n = 574) or placebo plus ADT (n = 576). Stratification was based on volume of disease (low vs high) and previous docetaxel (none, 1 to 5 cycles, or 6 cycles). The primary end point of the research was rPFS.

The median age of the patients enrolled to ARCHES was 70 years, most were from Europe, and 63.5% had high disease volume. Moreover, 66.5% were noted to have distant metastasis at the time of their initial diagnosis. The median duration of prior ADT was 1.6 months in both treatment arms. Also, the median prostate-specific antigen (PSA) in the enzalutamide arm was 5.4 ng/mL vs 5.1 ng/mL in the placebo arm.

The time to PSA progression had not been reached in either treatment arm (HR, 0.19; 95% CI, 0.13-0.26; P <.0001). The undetectable PSA rate in the enzalutamide arm was 68.1% (95% CI, 63.9-72.1) vs 17.6% (95% CI, 14.4-21.2) in the placebo arm, which translated to a 50.5% rate difference (95% CI, 45.3-55.7; P <.0001).

Moreover, enzalutamide plus ADT elicited an objective response rate of 83.1% (95% CI, 76.7%-88.3%) compared with 63.7% (95% CI, 56.3%-70.7%) with placebo/ADT; this translated to a rate difference of 19.3% (95% CI, 10.4-4.28; P <.0001). Additionally, the addition of the antiandrogen to ADT also resulted in a significant 72% reduction in the risk of beginning a new antineoplastic therapy compared with placebo plus ADT.

Results from a post-hoc analysis of ARCHES presented during the 2020 ESMO Virtual Congress indicated that efficacy varied by PSA levels at baseline.3 Of the 1146 patients who had available baseline PSA values, 135 had ≤0.2 μg/L, 388 had >0.2 to 4 μg/L, and 623 patients had >4 μg/L; the rPFS for each of these subgroups was 0.60 months, 0.32 months, and 0.41 months, respectively.

The time to PSA progression in these subsets was 0.21 months, 0.12 months, 0.21 months, respectively. Additionally, the time to castration resistance was 0.43 months, 0.26 months, and 0.27 months, respectively.

Enzalutamide in combination with ADT also resulted in maintained health-related quality of life (HRQoL) and low symptom burden compared with placebo plus ADT in this patient population.4 Patient-reported outcome scores reflected high HrQoL and low pain at baseline. Moreover, no statistically significant differences were reported in the time to first (TTFD) and first confirmed clinically meaningful deterioration in HRQoL and pain between the treatment arms in terms of QLQ-PR25 and FACT-P scores (nominal P >.05).

Enzalutamide did lead to a significant delay in the TTFD in worst pain by about 3.0 months (nominal P = .032), pain severity (nominal P = .021), and EQ-5D-5 L visual analogue scale score (nominal P = .0070) compared with placebo.

Safety data from the trial proved to be comparable to what has been previously reported with the antiandrogen in patients with castration-resistant prostate cancer. Rates of grade 3 or higher adverse effects were similar between the investigative and control arms, at 24.3% and 25.6%, respectively.


  1. Astellas’ XTANDI (enzalutamide) approved by European Commission for men with metastatic hormone-sensitive prostate cancer. News release. Astellas Pharma Inc. May 4, 2021. Accessed May 4, 2021. https://bit.ly/3vL1i5n
  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):687. doi:10.1200/JCO.2019.37.7_suppl.687
  3. Alcarez A, Szmulewitz RZ, Shore N, et al. ARCHES – the role of androgen deprivation therapy (ADT) with enzalutamide (ENZA) or placebo (PBO) in metastatic hormone-sensitive prostate cancer (mHSPC): post hoc analyses of efficacy by baseline prostate-specific antigen (PSA) levels. Ann Oncol. 2020;31(suppl 4):S523-S524. doi:10.1016/j.annonc.2020.08.894
  4. Stenzl A, Dunshee C, Giorgi UD, et al. Effect of enzalutamide plus androgen deprivation therapy on health-related quality of life in patients with metastatic hormone-sensitive prostate cancer: an analysis of the ARCHES randomised, placebo-controlled, phase 3 study. Eur Urol. 2020(20):30194-30199. doi:10.1016/j.eururo.2020.03.019