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The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of enzalutamide (Xtandi) for the treatment of adult men with metastatic castration-sensitive prostate cancer.1
The CHMP based its recommendation on data from the phase 3 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; P <.0001).2,3
The European Commission will now review the CHMP recommendation and make a final decision.
"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, Astellas, stated in a press release. "We are excited to be another step closer to approval of enzalutamide for the treatment of men with metastatic hormone-sensitive prostate cancer in Europe."
The 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.
Prior ADT for ≤3 months was allowed; patients with prior docetaxel were allowed to have received up to 6 months of ADT. 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.
Distant metastasis at diagnosis was reported in 70% in the enzalutamide arm and 63% in the placebo arm; 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.
The enzalutamide arm also showed a reduction in the risk of time to PSA progression by 81% (HR, 0.19; P <.0001) and the time to initiation of new antineoplastic therapy by 72% (HR, 0.28; P <.0001) compared with ADT alone.
At 12 months, the 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).
No new safety signals emerged with 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%).
1. Astellas Receives Positive CHMP Opinion for XTANDI™ (enzalutamide) for Patients with Metastatic Hormone-Sensitive Prostate Cancer. Published online March 26, 2021. Accessed March 26, 2021.
2. 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.
3. 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. https://bit.ly/2PAr10g.