The addition of 2 years of abiraterone acetate plus prednisolone (AAP) to androgen-deprivation therapy improves metastasis-free survival and overall survival compared with androgen-deprivation therapy alone in men with nonmetastatic castration-sensitive prostate cancer, according to a primary analysis of two comparisons from the multiplatform STAMPEDE trial presented during the European Society for Medical Oncology (ESMO) Congress 2021.1 The addition of enzalutamide to AAP and androgen-deprivation therapy was more toxic than adding AAP alone and provided no observable difference in survival benefit compared to AAP alone.
Metastasis-free survival was improved by 47% with the addition of AAP; there were 108 metastasis-free survival events in the AAP arm vs 306 in the androgen-deprivation therapy–alone arm (P < .001). Overall survival was also significantly improved with AAP plus androgen-deprivation therapy, with 147 deaths in the AAP plus androgen-deprivation therapy arm vs 236 deaths with androgen-deprivation therapy alone, representing a 40% improvement (P < .0001).
“The magnitude of overall survival benefit is much greater than previously estimated. We saw no difference in treatment effect by randomization period.”— Gerhardt Attard, MD
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“Two years of AAP-based therapy significantly improves metastasis-free survival and overall survival in men with high-risk nonmetastatic prostate cancer starting androgen-deprivation therapy and should be considered a new standard of care,” stated lead author Gerhardt Attard, MD, of University College London Cancer Institute, United Kingdom. “This will involve more hospital visits during this period to manage administration of the drug, but by reducing subsequent relapse, it may reduce the overall burden for both patients and health services. The analysis of STAMPEDE also showed that adding enzalutamide to AAP increases toxicity but has no discernible effect on efficacy compared to AAP alone.”
Dr. Attard stated: “These headline results are excellent news for patients and physicians and could be rapidly implemented to improve cure rates and the outcomes of men with this disease.” Docetaxel added to androgen-deprivation therapy has been shown to improve survival in metastatic prostate cancer but not in nonmetastatic prostate cancer. The benefit of second-generation hormonal therapy is also clear in metastatic prostate cancer, but in an earlier report of STAMPEDE, it was uncertain in patients with nonmetastatic disease.2 The -STAMPEDE investigators sought to assess whether there is a benefit for AAP in high-risk nonmetastatic prostate cancer.
STAMPEDE was a multiarm, multistage, pragmatic trial that has reported results from several phase III trials built into the platform protocol over the past decade. To assess the addition of AAP or AAP plus enzalutamide to androgen-deprivation therapy, the STAMPEDE investigators have conducted phase III trials in men with aggressive prostate cancer. Given the uncertainty that exists for the benefit of AAP therapy in nonmetastatic patients, this report prespecified patients with nonmetastatic disease from those with metastatic disease. This analysis was powered for the primary endpoint of metastasis-free survival and used meta-analysis methods to pool new data from both trials that randomly assigned men to 2 years of AAP therapy or AAP with enzalutamide. The analysis included patients with node-positive or high-risk, node-negative disease randomly assigned to androgen-deprivation therapy alone vs androgen-deprivation therapy with AAP or androgen-deprivation therapy vs androgen-deprivation therapy with AAP plus enzalutamide.
The analysis included 1,974 randomly assigned patients (primarily with newly diagnosed nonmetastatic disease). They had a median age of 68 years, and a median prostate-specific antigen level of 34 ng/mL; 39% had one positive lymph node. Median follow-up was 72 months.
Other Major Findings
Metastasis-free survival was improved by about 56% with the addition of AAP to androgen-deprivation therapy in both randomization periods. The benefit of AAP was observed in all subgroups, including nodal status, age, World Health Organization performance status, aspirin use at baseline, and radiotherapy to the prostate as part of planned treatment.
Overall survival was also significantly improved by 40% with the addition of AAP (P = .92 × 10−7). The 6-year survival improved from 77% with androgen-deprivation therapy to 86% with AAP plus androgen-deprivation therapy.
“The magnitude of overall survival benefit is much greater than previously estimated. We saw no difference in treatment effect by randomization period,” Dr. Attard reported.
Secondary outcome measures, including prostate cancer–specific survival and progression-free survival, were also significantly improved by AAP. The 6-year prostate cancer–specific survival improved from 85% with androgen-deprivation therapy alone to 93% with AAP plus androgen-deprivation therapy. Progression-free survival improved by 56% with the addition of AAP.
During the first 2 years of treatment, adverse events were increased for both AAP and enzalutamide compared with androgen-deprivation therapy alone. There were four grade 5 events in the AAP-plus-enzalutamide treatment group, three grade 5 events in the AAP arm and none in the androgen-deprivation therapy–alone arms.
Grade 4 events occurred in 12 patients in each of the androgen-deprivation therapy arms, 17 patients in the AAP arm, and 23 patients in the AAP-plus-enzalutamide arm. AAP plus enzalutamide was associated with a higher incidence of grade 3 erectile dysfunction, hypertension, and fatigue, as well as grade 3 or 4 transaminitis, compared with AAP alone.
The analysis had several limitations, including no data on long-term complications or treatment duration beyond 2 years, underrepresentation of relapsed patients, and no evidence of single-agent androgen-receptor antagonist efficacy. “Those trials [of single-agent androgen-receptor antagonists] are ongoing, and we look forward to the results,” Dr. Attard said. He also noted that more information is needed on the optimal length of AAP treatment. “We did not study different durations of treatment, so administering AAP for a shorter time than 2 years may be equivalent, and longer may be even more effective,” he said.
“Tens of thousands of lives have been improved by chemists who developed abiraterone acetate a number of years ago. I believe the story has come full circle.” he told listeners.
DISCLOSURE: Dr. Attard has received consulting fees and travel support from Janssen, Astellas, Pfizer, Sanofi-Aventis, Bayer, Belgene, Essa, and Novartis; speakers fees from Janssen, Astellas, AstraZeneca, Pfizer, and Sanofi-Aventis; and research support from Janssen, AstraZeneca, and Astellas.
1. Attard G, Browne LC, Clarke N, et al: Abiraterone acetate plus prednisolone with or without enzalutamide added to androgen deprivation therapy compared to androgen deprivation therapy alone for men with high-risk non-metastatic prostate cancer: Combined analysis from two comparisons in the STAMPEDE platform protocol. ESMO Congress 2021. Abstract LBA4_PR. Presented September 19, 2021.
2. James ND, de Bono JS, Spears MR, et al: Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med 377:338-351, 2017.
Eleni Efstathiou, MD
Invited discussant Eleni Efstathiou, MD, of Houston Methodist Cancer Center and Athens Medical Center, Greece, said that both the STAMPEDE meta-analysis1 and the PEACE-1 trial2 firmly establish the importance of introducing abiraterone acetate earlier in the course of...