Bipolar Androgen Therapy Induces PSA Reductions in Metastatic CRPC

The use of bipolar androgen therapy (BAT), involving rapid cycling between high and low serum concentrations, was safe and resulted in responses and resensitization to enzalutamide in men with metastatic castration-resistant prostate cancer (CRPC) who progressed after initial enzalutamide therapy, according to a new study.

“Clinically, metastatic CRPC that has progressed after enzalutamide treatment is minimally responsive to further therapy that inhibits androgen receptor signaling,” wrote study authors led by Benjamin A. Teply, MD, of Johns Hopkins School of Medicine in Baltimore. “Theoretically, rapidly varying the androgen concentrations between the extremes of supraphysiological and near-castrate, a strategy termed BAT, provides insufficient time for CRPC cells to adaptively regulate androgen receptor concentrations,” and thus may promote cancer cell death and prevent resistance.

The new open-label phase II study tested BAT in 30 patients. Treatment consisted of intramuscular testosterone cipionate 400 mg every 28 days until progression, as well as continued luteinizing hormone-releasing hormone agonist therapy. After progression, men were rechallenged with enzalutamide. The results were published in Lancet Oncology.

Patients had an average age of 74 years, and 90% were white; most had a performance status of 0 (73%), and the cohort’s average prostate-specific antigen (PSA) level was 39.8 ng/mL. Patients received a median of 6 treatment cycles, and all received at least one.

Nine of the 30 patients (30%) achieved the primary endpoint of a 50% decline in PSA from baseline (P < .0001). Twenty-one of the patients (70%) completed BAT and were then treated with enzalutamide. On an intention-to-treat analysis, 15 patients (52%) who were rechallenged with enzalutamide achieved a 50% decline in PSA (P < .0001).

Among 12 patients with evaluable lesions, 50% had a partial or complete response during BAT. Among eight who were evaluable following enzalutamide rechallenge, none had a radiographic response.

The most common grade 3/4 adverse event during BAT was hypertension, which was reported in three patients (10%). There were no dose-limiting toxicities, and no patients required dose adjustments during BAT. Three serious adverse events were potentially attributable to testosterone, including one pulmonary embolism, one non–ST segment elevation myocardial infarction, and one urinary obstruction.

“For asymptomatic patients with progression after enzalutamide, BAT induces clinical responses and subsequent resensitization to enzalutamide,” the authors wrote. “Studies in progress, including a randomized trial comparing BAT to enzalutamide in patients progressing on abiraterone, will further define a potential clinical role for BAT in the management of metastatic CRPC, as well as the clinical features of patients with the highest chance for benefit.”