Treatment with Xtandi (enzalutamide) does not seem to improve overall survival in men with non-metastatic castration-resistant prostate cancer (CRPC), according to the first interim analysis of a Phase 3 clinical trial.
These findings were published in the study, “Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer,” in the New England Journal of Medicine.
Men with non-metastatic CRPC and rapidly rising prostate-specific antigen (PSA) levels — a sign of rapid disease progression — are at a high risk of developing metastasis. Currently, only one recently approved treatment, Erleada (apalutamide), is available to these patients.
Xtandi, an androgen receptor inhibitor, is an approved treatment for metastatic CRPC patients. It was shown to delay disease progression and prolong these patients’ overall survival.
The Phase 3 PROSPER trial (NCT02003924) is evaluating whether adding Xtandi to standard androgen deprivation therapy (ADT) is better than ADT alone in patients with rising PSA levels.
The randomized, double-blind, placebo-controlled trial enrolled 1,401 men with prostate cancer whose disease had progressed — based on rising PSA levels — despite a strong reduction in testosterone levels with ADT, but with no symptoms or other evidence of metastasis.
Participants were randomly assigned to receive either 160 mg of Xtandi (933 patients) or a placebo (468 patients) orally, in addition to standard therapy. The study’s primary objective was metastasis-free survival, the length of time a patient lives without cancer spreading or until death from any cause.
Secondary goals included extension of the time to PSA progression and to the first use of a subsequent anticancer chemotherapy, patients’ overall survival, and safety.
The combination therapy significantly extended the time a patient remained alive and metastasis-free by nearly two years (21.9 months), the time to PSA progression by almost three years (33.3 months), and the time to the first use of chemotherapy by nearly two years (21.9 months), compared to single standard therapy.
Adding Xtandi to ADT reduced the risk of developing metastases or death by 71%, compared with ADT alone.
At the time of the first interim analysis, half of the patients in each group were still alive, and so median overall survival had not been reached. However, the risk of death was found to be 20% lower with Xtandi than with placebo, but the result was not statistically significant.
There were no significant differences in overall survival between the two groups, with 103 deaths (11%) in the Xtandi group and 62 (13%) in the placebo group. However, the researchers noted that more patients receiving the combination therapy died without detectable development of metastasis (32 patients, or 31%) than in the placebo group (four patients, or 6.5%).
In these patients, no trend regarding the cause of death was found, and only two deaths were considered to be related to Xtandi treatment. The researchers noted that these patients were elderly, with a median age of 80 years in the Xtandi group and 81 years in the placebo group, and they had a high burden of other coexisting conditions.
Xtandi’s safety profile was consistent with previous studies, the most common adverse event being fatigue. Xtandi treatment was associated with a higher frequency of severe adverse events (31%) than ADT alone (23%).
Cardiovascular events were observed in 5% of patients in the Xtandi group, and in 3% in the placebo group, and were the main cause of death associated with adverse events during the trial.
“Further safety analysis is ongoing to assess whether a subgroup of patients may be at higher risk for these adverse events,” the researchers wrote.
Subsequent follow-up and additional interim analysis are expected to clarify the benefits of Xtandi in patients’ overall survival in the PROSPER study.