Enzalutamide Granted Positive EU Opinion for Metastatic Hormone-Sensitive Prostate Cancer

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion to recommend an additional indication of enzalutamide (Xtandi) for the treatment of adult patients with metastatic hormone-sensitive prostate cancer (mHSPC).¹

The recommendation is based on data from the pivotal phase 3 ARCHES trial (NCT02677896), where enzalutamide plus androgen deprivation therapy (ADT) resulted in an improvement in radiographic progression-free survival (rPFS) vs placebo/ADT; it was not reached (NR; 95% CI, NR–NR) in the investigative arm vs 19.45 months (95% CI, 16.59-NR) in the control arm (HR, 0.39; 95% CI, 0.30-0.50; P <.0001).²

“This positive opinion from the CHMP is testament to our continuing commitment to addressing unmet needs for men with advanced prostate cancer,” Andrew Krivoshik, MD, PhD, senior vice president and Global Therapeutic Area Head, Oncology Development, at Astellas, stated in the press release. “We are excited to be another step closer to approval of enzalutamide for the treatment of men with mHSPC.”

In the ARCHES trial, investigators set out to examine the safety and efficacy of enzalutamide plus ADT in patients with mHSCPC based on the hypothesis that the combination would prolong rPFS over ADT alone in this population.

To be eligible for enrollment, patients had to have mHSPC and histologically confirmed adenocarcinoma, an ECOG performance status of 0 to 1, with a current ADT duration of 3 months or less unless prior docetaxel was received; if it had been, then they had to have a ADT duration of 6 months or less.

A total of 1150 patients with mHSPC were randomized 1:1 to receive enzalutamide at 160 mg/day plus ADT (n = 574) or placebo plus ADT (n = 576). Patients were stratified based on volume of disease (low vs high) and prior docetaxel for their disease (none, 1 to 5, or 6 cycles). The primary end point of the trial was rPFS.

The median age of participants across the arms was 70 years, the majority were from Europe, 63.5% had high disease volume, and 66.5% had distant metastasis at the time of their initial diagnosis. Eighteen percent of patients received prior docetaxel, 91% had prior ADT, and 38% had prior antiandrogens. The median duration of previous ADT was 1.6 months in both arms. The median prostate-specific antigen (PSA) in the investigative arm was 5.4 ng/mL vs 5.1 ng/mL in the control arm.

Additional results indicated that the time to PSA progression had not yet been reached in either arm (HR, 0.19; 95% CI, 0.13-0.26; P <.0001). The undetectable PSA rates in the investigative and control arms was 68.1% (95% CI, 63.9-72.1) vs 17.6% (95% CI, 14.4-21.2), translating to a 50.5% rate difference (95% CI, 45.3-55.7; P <.0001). Additionally, the objective response rate with enzalutamide/ADT was 83.1% (95% CI, 76.7%-88.3%) vs 63.7% (95% CI, 56.3%-70.7%), translating to a rate difference of 19.3% (95% CI, 10.4-28.2; P <.0001).

Notably, the addition of enzalutamide to ADT significantly reduced the risk of starting a new antineoplastic therapy by 72% vs placebo/ADT.

A post-hoc analysis of the trial presented during the 2020 ESMO Virtual Congress showed efficacy outcomes by various baseline PSA levels.³ In the overall population with available baseline PSA values (n = 1146/1150), 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 subgroups was 0.60 months, 0.32 months, and 0.41 months, respectively.

Moreover, the time to PSA progression was 0.21 months, 0.12 months, and 0.21 months, respectively. Results also indicated that the time to castration resistance was 0.43 months, 0.26 months, and 0.27 months, respectively.

Regarding safety, the profile of enzalutamide proved to be consistent with what has been observed in prior clinical trials done in patients with castration-resistant prostate cancer (CRPC). The incidence of grade 3 or higher adverse effects reported in the trial proved to be similar between the arms, at 24.3% vs 25.6%, respectively.

Enzalutamide is approved in the European Union for use in adult patients with high-risk, nonmetastatic CRPC and adult patients with metastatic CRPC in whom chemotherapy is not yet indicated or after progressive disease on, or after, docetaxel.

The agent is also approved in the United States for use in both nonmetastatic and metastatic CRPC, and in patients with mHSPC. Enzalutamide is indicated for patients with prostate cancer who have distant metastasis in Japan, which includes those with mHSPC and CRPC.

References

1. Astellas receives positive CHMP opinion for XTANDI (enzalutamide) for patients with metastatic hormone-sensitive prostate cancer. News release. Astellas Pharma, Inc. March 29, 2021. Accessed March 30, 2021. https://bit.ly/3foFV4H
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