Adding Xtandi (enzalutamide) to standard androgen deprivation therapy (ADT) significantly prolonged life by nearly a year for men with high-risk, non-metastatic castration-resistant prostate cancer (CRPC), final data from a Phase 3 clinical trial show.
The results, “Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer,” were published in the New England Journal of Medicine and presented at the 2020 American Society of Clinical Oncology (ASCO) annual meeting — held virtually due to the COVID-19 pandemic.
“Overall survival is a critical endpoint in evaluating a prostate cancer medicine,” Cora N. Sternberg, MD, the study’s first author and clinical director of the Englander Institute for Precision Medicine at Weill Cornell Medicine, in New York, said in a press release.
“These results add to the body of evidence supporting Xtandi’s potential to reduce the risk of death in men with castration-resistant prostate cancer,” she added.
Xtandi, an oral hormone therapy developed by Pfizer and Astellas Pharma, is currently approved in the U.S. and in Europe to treat three types of advanced prostate cancer: high-risk non-metastatic CRPC, metastatic CRPC, and metastatic castration-sensitive prostate cancer (mCSPC).
Its approval for the treatment of men with high-risk non-metastatic CRPC was based on data from the PROSPER Phase 3 clinical trial (NCT02003924), which evaluated whether adding Xtandi to standard ADT was superior to ADT alone.
The trial enrolled 1,401 men with non-metastatic CRPC and rapidly rising prostate-specific antigen (PSA) levels — a marker of disease progression — at more than 300 clinical sites across 32 countries.
Participants, who had no symptoms or other evidence of metastasis, were randomly assigned to either 160 mg of Xtandi (933 patients) or a placebo (468 patients) once daily, in addition to ADT.
The trial’s main goal was to assess metastasis-free survival, or the time until cancer spreading or death from any cause. Secondary goals included overall survival, time to PSA-based disease progression, time to first use of a subsequent anti-cancer therapy (including chemotherapy), and safety.
Results of a primary interim analysis in 2017 showed that adding Xtandi to ADT significantly prolonged metastasis-free survival and the time to use of new anti-cancer therapy by nearly two years (both 21.9 months), and the time to PSA-based progression by almost three years (33.3 months), compared with ADT alone.
At a median follow-up of 23 months (nearly two years), median overall survival had not been reached in either group, meaning that more than half of men were still alive.
At this point, men in the placebo group were allowed to cross over to the Xtandi group, which 87 of the 114 people still on a placebo chose to do. These men received Xtandi for a median of 14.5 months.
At final data cut-off date (October 2019), patients had been followed for a median of 48 months (four years), with a median treatment duration of 33.9 months in the Xtandi group and 14.2 months in the placebo group.
Results showed that 288 men (31%) in the Xtandi group and 178 (38%) in the placebo group had died, and that adding Xtandi to ADT significantly extended the men’s lives by nearly a year compared with ADT alone (67 vs. 56.3 months).
This overall survival benefit reflected a 27% lowered risk of death in the Xtandi group.
Moreover, 33% of Xtandi-treated patients and 65% of those on a placebo (84% when including cross-over patients) started on a new anti-cancer therapy after treatment discontinuation. This treatment began after a median of 66.7 months in the Xtandi group and 19.1 months in the placebo group.
These findings highlighted that the combination therapy significantly lowered the risk of metastasis and death, and delayed the need for any subsequent anti-cancer therapy compared with standard ADT alone.
Xtandi’s safety profile was consistent with that reported in previous analyses and studies, with fatigue and musculoskeletal events (including muscle-related pain and stiffness, muscular weakness, and muscle spasms) most commonly reported side effects.
While a greater proportion of men in the Xtandi group experienced severe to life-threatening and serious adverse events than those on a placebo, these differences were mitigated after adjustment for total patient-years of exposure to treatment.
The most frequently reported adverse events leading to death were cardiovascular events — 2% in the Xtandi group and less than 1% in the placebo group — but most of these men had a significant history of cardiovascular disease, the researchers noted.
“Although none of the cardiovascular deaths were attributed to [Xtandi] by the investigators, physicians should be aware of the increased risk when determining whether a patient with preexisting cardiovascular disease should receive [Xtandi], and patients receiving this treatment should be followed closely,” they wrote.
In a separate Weill Cornell Medicine news story, Sternberg said “these results are extremely important,” and that patients treated with Xtandi “may live longer” without “too much toxicity.”
Trial findings also validated the use of metastasis-free survival as a meaningful clinical outcome and as a potential substitute for overall survival in this patient population.