Bipolar Androgen Therapy Effective After Enzalutamide in mCRPC

One-third of asymptomatic men with metastatic castration-resistant prostate cancer who progressed on enzalutamide (Xtandi) achieved a 50% decline in PSA concentration from baseline (PSA50) following bipolar androgen therapy.

Benjamin A. Teply, MD

One-third of asymptomatic men with metastatic castration-resistant prostate cancer (mCRPC) who progressed on enzalutamide (Xtandi) achieved a 50% decline in PSA concentration from baseline (PSA50) following bipolar androgen therapy (BAT).1

The small study also showed that BAT resensitized most patients to enzalutamide (Xtandi) rechallenge.

Thirty men enrolled in this single-center, open-label, multicohort phase II study from August 2014 to May 2016. Twenty-nine completed BAT. Nine patients (30%; 95% CI, 15-49; P <.0001) achieved a PSA50.

Twenty-one patients proceeded to enzalutamide rechallenge, 52% of whom achieved a PSA50 (95% CI, 33-71; P <.0001).

“These data are promising, considering published series have shown evidence of cross-resistance between abiraterone [acetate] and enzalutamide, with objective responses of 0 to 11% and progression-free survival of 3 to 4 months in patients receiving abiraterone or enzalutamide after progressing on the alternate drug,” first author Benjamin A. Teply, MD, department of oncology, Johns Hopkins University School of Medicine, and coinvestigators wrote.

“Furthermore, our results support the hypothesis that an alternative strategy of therapeutically targeting the androgen receptor with BAT in the setting of progression on second-line androgen receptor—signaling inhibitors might be beneficial to patients,” added Teply et al.

Men in the study had progressed on hormonal therapies, and investigators intended to analyze each cohort separately. Evidence of metastatic disease by CT scan or nuclear medicine bone scan was required, but measurable disease by RECIST was not a prerequisite for enrollment.

Participants were required to have radiographic or PSA progression on enzalutamide, and a continuing PSA concentration rise during the 4 week washout from enzalutamide.

BAT consisted of 400 mg of intramuscular testosterone cypionate on day 1 of a 28-day cycle while continuing LHRH agonist therapy. There was no predefined stopping point, and therapy could continue indefinitely. Investigators did not modify testosterone doses.

Patients discontinuing BAT proceeded to a 28-day washout period to allow testosterone concentrations to return to the castrate range. The PSA concentration after washout was considered baseline for purposes of evaluation of enzalutamide response. Treatment proceeded with 160 mg of daily oral enzalutamide with dose adjustments allowed per the prescribing label.

Clinical investigations were done at baseline and every 3 cycles and included complete blood counts, serum hormone concentrations, and metabolic parameters.

Median age was 74 (range, 50-89), 90% of the cohort was white, and all patients had an ECOG performance status of 0 (73%) or 1 (27%). All patients were refractory to previous enzalutamide therapy, and 47% had previously achieved PSA50 with enzalutamide. Median time on enzalutamide was 8 months (range, 1-39).

Median follow-up was 4.9 months (IQR, 2.8-7.6). Twelve patients (40%) had RECIST-evaluable lesions, half of whom had a partial or complete response (95% CI, 21-79). The remaining 18 patients were not RECIST-evaluable due to non-measurable bone-only metastatic disease or lack of follow-up radiographic imaging.

Twenty-eight patients (93%) had PSA progression events on BAT, leading to a median PSA progression-free survival (PFS) of 3.3 months (95% CI, 2.7-5.5). Seventeen patients (57%) had a clinical or radiographic progression event with BAT. The median clinical or radiographic PFS was 8.6 months (95% CI 4.7—not reached).

Fourteen patients with measured testosterone values had castrate testosterone (<50 ng/dL) following the 28-day washout period, and the remainder had near castrate concentrations (median 30 ng/dL, range <20—133 ng/dL). Two-thirds of patients with PSA measured before and after the washout period had continued increases in PSA concentrations.

Median follow-up after enzalutamide rechallenge was 2.7 months (IQR, 2.4-5.5). None of the 8 evaluable patients demonstrated a radiographic response to enzalutamide.

Eleven patients rechallenged with enzalutamide had PSA progression events, and the median PSA PFS was 5.5 months (95% CI, 4.6—not reached). Thirteen of the 21 patients rechallenged with enzalutamide had clinical or radiographic progression events. Median clinical or radiographic PFS was 4.7 months (95% CI, 2.7–not reached).

Four patients remained on enzalutamide at the time of final analysis, all of whom met the coprimary endpoint of PSA50 response to enzalutamide.

The most common grade 3/4 adverse event (AE) was hypertension (10%). There were no dose-limiting toxicities observed and no patients required dose adjustment. Three grade 3/4 AEs—pulmonary embolism, non-ST segment elevation myocardial infarction, and urinary obstruction—were potentially attributable to testosterone.

Two patients discontinued BAT because of AEs, including 1 non—treatment-related patient death due to severe sepsis with multiorgan dysfunction syndrome and 1 myocardial infarction. There were no treatment-related deaths.

“The major focus of the past 25 years has been toward total androgen annihilation,” Christopher P. Evans, MD, department of urology, University of California, Davis, Comprehensive Cancer Center, wrote in an accompanying editorial.2 “The provocative study by Teply and colleagues builds upon years of observations and mechanistic rationale to exploit tumor adaptive resistance to androgen removal. It very possibly is one new move in the endocrine chess match of treatment versus tumor.”


  1. Teply BA, Wang H, Luber B, et al. Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study. Lancet Oncol. 2018;19(1):76-86. doi: 10.1016/S1470-2045(17)30906-3.
  2. Evans CP. Bipolar androgen therapy: an intriguing paradox. Lancet Oncol. 2018;19(1):8-10. doi: 10.1016/S1470-2045(17)30907-5.