In the phase II TRANSFORMER trial reported in the Journal of Clinical Oncology, Denmeade et al found no difference in progression-free survival with bipolar androgen therapy—defined as rapid cycling between high and low serum testosterone—vs enzalutamide in men with metastatic castration-resistant prostate cancer whose disease progressed after treatment with abiraterone. Results among patients crossing over to the alternative treatment indicated that bipolar androgen therapy may sensitize castration-resistant prostate cancer to subsequent antiandrogen therapy.

In the U.S. multicenter trial, 195 men were randomly assigned between April 2015 and April 2018 to receive bipolar androgen therapy with testosterone cypionate at 400 mg intramuscularly once every 28 days (n = 94) or enzalutamide at 160 mg daily (n = 101). Patients were permitted to cross over to the alternative treatment upon disease progression. The primary endpoint was clinical or radiographic progression-free survival.

Progression-Free Survival

Median follow-up among surviving patients was 31.9 months. Median progression-free survival at primary analysis in November 2018 was 5.7 months (95% confidence interval [CI] = 5.1–7.6 months) in the bipolar androgen therapy group vs 5.7 months (95% CI = 4.0–8.4 months) in the enzalutamide group (hazard ratio [HR] = 1.14, 95% CI = 0.83–1.55, P = .42). With additional follow-up through November 2019, median progression-free survival was 5.7 months in both groups (HR = 1.14, 95% CI = 0.83–1.55, P = .42). Reduction in prostate-specific antigen (PSA) by ≥ 50% (PSA50 response) was observed in 28.2% vs 25.3% of patients. Median overall survival was 32.9 months vs 29.0 months (HR = 0.95, 95% CI = 0.66–1.39, P = .80).

Overall, 37 (39.3%) patients initially on bipolar androgen therapy crossed over to receive enzalutamide and 48 (47.6%) crossed from enzalutamide to bipolar androgen therapy. PSA50 response occurred in 77.8% of patients crossing to enzalutamide and 23.4% of patients crossing to bipolar androgen therapy. PSA progression-free survival with enzalutamide increased from 3.8 months after abiraterone to 10.9 months after bipolar androgen therapy. Median progression-free survival-2 was 28.2 months among patients crossing from bipolar androgen therapy to enzalutamide vs 19.6 months for those crossing from enzalutamide to bipolar androgen therapy (HR = 0.44, 95% CI = 0.22–0.88, P = .02). Median overall survival was 37.1 months for patients crossing from bipolar androgen therapy to enzalutamide vs 30.2 months for those crossing from enzalutamide to bipolar androgen therapy (HR = 0.68, 95% CI = 0.36–1.28, P = .225).

Adverse Events

Grade 3 or 4 adverse events occurred in 28.1% of patients in the bipolar androgen therapy group vs 35.1% of the enzalutamide group; generalized pain (3.4%) and back pain (3.4%) were the most common in the bipolar androgen therapy group, and fatigue (7.2%) and back pain (7.2%) were the most common in the enzalutamide group. Serious adverse events occurred in 19.1% vs 20.6% of patients. Adverse events led to discontinuation of treatment in 9.0% vs 5.2%.

Overall, bipolar androgen therapy was associated with increased frequency of sexual side effects and musculoskeletal complaints, and enzalutamide was associated with increased frequency of fatigue and other constitutional symptoms and gastrointestinal complaints.

The investigators concluded, “This randomized trial establishes meaningful clinical activity and safety of bipolar androgen therapy and supports additional study to determine its optimal clinical integration. Bipolar androgen therapy can sensitize castration-resistant prostate cancer to subsequent antiandrogen therapy. Further study is required to confirm whether sequential therapy with bipolar androgen therapy and enzalutamide can improve survival in men with castration-resistant prostate cancer.”

Samuel R. Denmeade, MD, of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by a grant from the Department of Defense PCa Research Program. For full disclosures of the study authors, visit ascopubs.org.