The addition of enzalutamide to abiraterone acetate plus prednisone (AAP) does not improve overall survival of patients with metastatic hormone-sensitive prostate cancer, results from STAMPEDE demonstrated. However, the survival benefit of AAP when added to androgen deprivation therapy was maintained at 7 years.

Recent research suggests that, in men with metastatic, hormone-sensitive prostate cancer (mHSPC), addition of either AAP or enzalutamide to androgen deprivation therapy (ADT) improves outcomes. Combining AAP and enzalutamide has been shown to benefit progression-free survival (PFS), but not OS, in patients with metastatic, castration-resistant prostate cancer (mCRPC). However, the benefit of combining AAP and enzalutamide in mHSPC is unknown. In addition, survival outcomes of mHSPC on ADT plus AAP or AAP/enzalutamide beyond 5 years have not been reported. A comparison of two randomized, phase 3 trials in the multi-arm, multi-stage STAMPEDE protocol can give insight into both questions. Dr. Gerhardt Attard (UCL Cancer Institute London, UK) presented the results at ESMO 2022.

The two trials—with no overlapping controls—randomized 1,003 patients with mHSPC to ADT plus AAP and 916 to ADT plus AAP/enzalutamide. Controls were treated with standard of care (SOC) ADT or ADT plus docetaxel. Treatment continued to progress. The primary outcome of the trials was OS.

Median follow-up times were 95.8 months in the AAP-trial and 71.7 months in the AAP/enzalutamide trial. In both trials, the addition of second-generation hormonal agent(s) improved OS (HR, 0.62 for AAP vs SOC, P<0.0001; HR, 0.65 for APP/enzalutamide vs SOC, P<0.0001). No evidence was seen of a difference in treatment effect (interaction HR, 1.05; P=0.71) between both trials. At 84 months of follow-up, 48% of patients treated with ADT plus AAP were still alive versus 30% of patients treated with ADT alone.

Rates of adverse events were similar in both trials but occurred more commonly in patients treated with AAP/enzalutamide compared with AAP. Grade 3-5 adverse events in the first 5 years were observed in 54.4% of patients treated with AAP and in 67.9% of patients treated with AAP/enzalutamide.

Based on these results, Dr. Attard concluded that “enzalutamide and AAP should not be combined for treatment of patients with mHSPC. Addition of enzalutamide to APP does not improve survival and only increases the incidence of adverse events. In addition, these results show that the survival benefit of AAP, when added to ADT, is maintained at 7 years.”

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