Enzalutamide shows potential survival benefit in metastatic hormone-sensitive prostate cancer
Men with metastatic hormone-sensitive prostate cancer (mHSPC) who receive testosterone suppression therapy may have a better survival outcome with the addition of enzalutamide over other non-steroidal anti-androgen (NSAA) therapies, according to the phase III ENZAMET* trial.
The results showed a 33 percent reduced risk of mortality and a 61 percent reduced risk of progression to castration-resistant prostate cancer with enzalutamide, said study author Professor Christopher Sweeney from the Dana-Farber Cancer Institute in Boston, Massachusetts, US.
A total of 1,125 men (median age, 69 years) with mHSPC and ECOG performance status 0–2 were randomized to receive testosterone suppression in addition to standard (first generation) NSAA (bicalutamide, nilutamide, or flutamide; n=562) or enzalutamide (160 mg/day; n=563) and were evaluated every 12 weeks. Patients could have received up to two cycles of docetaxel and 12 weeks of testosterone suppression before randomization.
Forty-four and 45 percent of standard therapy and enzalutamide recipients, respectively, had planned docetaxel treatment, with 159 and 181 patients, respectively, receiving the full six-cycle course. Volume of metastases was well balanced between groups with 53 and 52 percent of standard therapy and enzalutamide recipients, respectively, having high-volume disease.
After a median follow up of 34 months, overall survival (OS) was greater among enzalutamide compared with standard therapy recipients (3-year OS, 80 percent vs 72 percent, hazard ratio [HR], 0.67, 95 percent confidence interval [CI], 0.52–0.86; p=0.002). [ASCO 2019, abstract LBA2; N Engl J Med 2019;doi:10.1056/NEJMoa1903835]
Progression-free survival (PFS) also appeared to favour men who received enzalutamide over standard therapy, be it in terms of time to clinical progression** (3-year PFS, 68 percent vs 41 percent, HR, 0.40, 95 percent CI, 0.33–0.49) or time to increase in PSA***, clinical progression, or death (3-year PFS, 67 percent vs 37 percent, HR, 0.39, 95 percent CI, 0.33–0.47; p<0.001 for both).
Adverse events (AEs) that occurred more frequently among enzalutamide than standard therapy recipients included grade 3 hypertension (8 percent vs 4 percent), fatigue (6 percent vs 1 percent), and syncope (4 percent vs 1 percent). Seven enzalutamide recipients experienced seizures compared with none in the standard treatment group.
When AE incidence was limited to the first 6 months, the incidence of neutropenic fever, sensory neuropathy, grade 1–2 watery eyes, and grade 2 fatigue was higher among patients who received docetaxel (vs no docetaxel), regardless of whether they received enzalutamide or standard therapy.
“It is of note, there were more expected toxicities seen with enzalutamide alone, and more docetaxel-related toxicity with the addition of enzalutamide,” said Sweeney.
While treatment discontinuations occurred among more patients in the standard vs the enzalutamide arm, AE-related treatment discontinuations occurred more frequently in enzalutamide than standard therapy recipients (16 percent vs 4 percent).
More patients in the standard therapy than enzalutamide group received subsequent life-prolonging anticancer therapies (85 percent vs 67 percent) due to the higher incidence of clinical progression in the standard therapy group.
“The high-level conclusion is early enzalutamide improved time to progression and OS when added to standard mHSPC therapy. The clinical interpretation of this data is enzalutamide added to testosterone suppression represents an appropriate option for men with metastatic prostate cancer commencing testosterone suppression,” said Sweeney.
“The analyses of treatment effects on clinical PFS according to the volume of disease and planned early docetaxel treatment showed consistently smaller effects of enzalutamide in patients with high-volume disease and in those with early docetaxel treatment,” said Sweeney and co-authors. “Our current data support the claim that early enzalutamide prolongs survival within 3 years in the entire trial population but provide limited support that it prolongs OS within 3 years in patients who received early docetaxel treatment.”
“For patients who are candidates for docetaxel when starting testosterone suppression, quality of life analyses and longer follow-up are needed to determine whether the delay in progression with concurrent enzalutamide results in a meaningful clinical benefit, and/or is compounded by subsequent castration-resistant prostate cancer therapy and prolonged survival beyond 3 years,” Sweeney said.