Enzalutamide prolongs upfront survival in hormone-sensitive metastatic prostate cancer

The non-steroidal antiandrogen ensalutamide plus standard therapy increased the 3-year survival rate in men with mHSPC to 80% compared to 72% achieved with other non-steroidal antiandrogens. This was confirmed by an interim analysis of the phase III ENZAMET study.

A look at a "hard-and-early" strategy for long-term control of prostate cancer

The non-steroidal antiandrogen enzalutamide plus standard therapy increased the 3-year survival rate in men with mHSPC to 80% compared to 72% achieved with other non-steroidal antiandrogens. This was confirmed by an interim analysis of the phase III ENZAMET study.

Nonsteroidal antiandrogen enzalutamide plus standard therapy increased 3-year survival to 80% in men with metastatic hormone-sensitive prostate cancer (mHSPC) compared to 72% achieved with other non-steroidal antiandrogens. This was the result of an interim analysis of the phase III ENZAMET study conducted by the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group. 

The results were presented by Christopher Sweeney, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, USA, in the plenary session on June 2 at the annual meeting of ASCO (American Society of Clinical Oncology) 2019 (Source 1) and published in parallel in the New England Journal of Medicine (Source 2).

Until 2014, metastatic hormone-sensitive prostate cancer was treated exclusively with testosterone suppression without or with non-steroidal antiandrogens. However, men with a high tumor load had shorter survival times. The therapy results improved with the early use of docetaxel. The administration of abiraterone in addition to testosterone suppression also prolonged survival.

Enzalutamide is an orally applicable androgen receptor inhibitor that is also effective in resistance to first-generation non-steroidal antiandrogens such as bicalutamide, nilutamide, and flutamide. Studies had shown that enzalutamide prolonged overall survival (OS) in patients with castration-resistant prostate cancer regardless of whether it had been used before or after docetaxel treatment.

A head-to-head comparison in ENZAMET

The Phase III ENZAMET study (Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer) was based on the hypothesis that enzalutamide, in addition to testosterone suppression, can prolong the OS by inhibiting the androgen receptor more than first-line mHSPC therapy compared to standard antiandrogen therapy.

Patients with mHSPC stratified by metastatic volume, docetaxel use, ECOG-PS, antiresorptive therapy, comorbidities and study center were enrolled in the open, international, randomized phase III study. All patients were treated for testosterone suppression with Goserelin, Leuprolide or Degarelix. 563 patients additionally received enzalutamide (160mg/day), 562 patients were additionally treated with bicalutamide, nilutamide or flutamide. 503 men received docetaxel. The primary endpoint was overall survival.

Sweeny presented the results of a pre-planned interim analysis after 235 deaths and a median follow-up of 34 months. 134 deaths occurred in the comparison arm, 102 in the enzalutamide arm. After 3 years, 80% of the men in the enzalutamide arm were still alive, compared to 72% in the comparison arm (hazard ratio 0.67, p = 0.002). Enzalutamide thus reduced the relative mortality risk by 33%. The secondary endpoint, progression-free survival (time to PSA increase, clinical progression or death), was also significantly better with enzalutamide with an HR of 0.39 than with the comparatives.

The positive effect of enzalutamide on OS was most pronounced in patients who were not treated with docetaxel. The 3-year survival rate was 83% here and 70% for the comparative antiandrogens. In patients with docetaxel, enzalutamide showed no survival benefit. In men with a high tumor load, the 3-year survival rate with enzalutamide was 71%, with the other antiandrogens 64%. In men with a low tumor load, the 3-year survival rate with enzalutamide was 90%, with the other antiandrogens 82%. Enzalutamide was, therefore, most effective in men with a low tumor load who did not receive docetaxel.

At the time of the first data analysis, 64% of the patients still took enzalutamide, 34% the comparative antiandrogens.

Severe adverse effects occurred in 42% of the patients with enzalutamide and in 34% with reference substances. Enzalutamide led more frequently to Grade 2 and 3 hypertension, fatigue and syncope. There was also an increase in seizures. Therefore, according to Sweeney, the question always arises as to whether the patients are fit enough for enzalutamide.

"Doctors and patients with prostate cancer now have a new treatment option with enzalutamide, especially for men who do not tolerate chemotherapy or have a low tumor load," said Sweeney in a press statement.

Multiple options for upfront therapy intensification

The revolution in intensified upfront therapy for prostate cancer began in 2015 with the upfront dose of docetaxel, according to Tanya Barauskas Dorff, City of Hope Cancer Center, Duarte, California, discussant of the ENZAMET study at the ASCO 2019 plenary session, followed by the upfront dose of Abiraterone in 2017 and now validation with ENZAMET.

Dorff pointed out that the results in the control arm with a 3-year survival of 72% were better than had originally been assumed with 65%. Only 50% of the planned events had occurred. The ENZALUTAMIDE results were confirmed by the results of the TITAN study, also presented at ASCO 2019, in which the androgen receptor inhibitor apalutamide, in addition to testosterone suppression, prolonged PFS and overall survival of patients with mHSPC compared to placebo.

Dorff emphasized that a "hard-and-early" strategy is important for the long-term control of prostate cancer. However, there is no evidence for the simultaneous use of docetaxel and enzalutamide. The different options for upfront intensification - abiraterone, docetaxel, apalutamide, and enzalutamide - are, in her opinion, equivalent: "There is no evidence that one is superior to the other".

1. Sweeny C, et al. Overall survival (OS) results of 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. 2019 ASCO Annual Meeting, Chicago, May 31 to June 4, 2019, Abstract LBA2. https://meetinglibrary.asco.org/record/174531/abstract
2. Davis ID, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. published online on 2 June 2019. https://www.nejm.org/doi/full/10.1056/NEJMoa1903835