Previously, the interim analysis of the ENZAMET trial indicated that adding enzalutamide to testosterone suppression provided an early overall survival (OS) benefit in patients with hormone-sensitive prostate cancer (HSPC). Recently published in The Lancet, the planned primary OS analysis of this trial confirms a sustained improvement in OS of HSPC patients receiving enzalutamide plus testosterone suppression, compared to those receiving testosterone suppression alone. These findings suggest that enzalutamide plus testosterone suppression should be considered as a viable treatment option for eligible HSPC patients.
Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival (OS) in men with castration-resistant prostate cancer, regardless of whether it was used before or after docetaxel chemotherapy. The phase III ENZAMET trial evaluated whether adding enzalutamide to first-line therapy would delay the emergence of castration resistance and thereby improve OS in patients with hormone-sensitive prostate cancer (HSPC). The interim analysis of this trial, which compared testosterone suppression plus either enzalutamide or standard nonsteroidal antiandrogen therapy, showed an early OS benefit with enzalutamide. Recently, the planned primary OS analysis of the ENZAMET trial was reported, with the goal of determining the benefit of enzalutamide treatment in various prognostic subgroups and in patients receiving concurrent docetaxel.
The international phase III ENZAMET trial was conducted at 83 sites in Australia, Canada, Ireland, New Zealand, the UK, and the USA. Eligible participants were males aged ≥18 years with metastatic HSPC and an Eastern Cooperative Oncology Group performance status score of 0-2. In total, 1,125 participants were randomly assigned (1:1) to receive testosterone suppression plus oral enzalutamide (160 mg once per day) or a weaker standard oral non-steroidal antiandrogen (bicalutamide, nilutamide, or flutamide; control group) until clinical disease progression or prohibitive toxicity. Testosterone suppression was allowed up to 12 weeks before randomisation and for up to 24 months as adjuvant therapy. Concurrent docetaxel was allowed for up to six cycles once every 3 weeks. The primary endpoint was OS. This planned analysis was triggered by reaching 470 deaths.
After a median follow-up of 68 months, the median OS was not reached (HR[95%CI]: 0.70 [0.58-0.84]; p<0.0001), with 5-year OS rates of 57% vs. 67% in the control and enzalutamide groups, respectively. OS benefits with enzalutamide were consistent across predefined prognostic subgroups, including synchronous and metachronous high-volume or low-volume disease, and planned use of concurrent docetaxel. The most common grade 3-4 adverse events were febrile neutropenia associated with docetaxel use (6% in both arms), fatigue (1% vs. 6% in the control and enzalutamide groups, respectively) and hypertension (6% vs. 10%). The incidence of grade 1-3 memory impairment was 4% vs. 13%. No deaths were attributed to study treatment.
In conclusion, the recently reported primary OS analysis of the ENZAMET trial provides evidence that adding enzalutamide to standard of care treatment leads to a significant and sustained improvement in OS for patients with metastatic HSPC. These findings suggest that this treatment regimen should be considered as a viable treatment option for eligible patients with metastatic HSPC.
Sweeney CJ, Martin AJ, Stockler MR, et al. Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial. Lancet Oncol. 2023;24(4):323-34.