A new installment in the Sam Denmeade BAT (Bipolar Androgen Therapy) story.
The concept of BAT is very simple. While androgen deprivation [ADT] is initially successful about 95% of the time, it mostly fails within two years. Would the periodic re-introduction of testosterone [T] disrupt progression to ADT resistance [i.e. CRPC]? Further, might it reverse progression & reset the clock?
BAT is possible in various settings - it could be started at the same time as ADT. In the current study, men with mCRPC (metastatic castration-resistant prostate cancer) who had also progressed on Xtandi (enzalutamide) were enrolled. 30 patients "with no more than two previous second-line hormonal therapies, and a castrate concentration of testosterone ... and did not have high-risk lesions for tumour flare (eg, >5 sites of visceral disease or bone lesions with impending fracture)."
"Nine ... of 30 patients achieved a PSA50 (50% decline in PSA) to BAT."
"29 patients completed BAT and 21 proceeded to enzalutamide rechallenge, of whom 15 ... achieved a PSA50 response."
Management of PCa in this population is challenging, which makes the results even more impressive. A third achieved a 50% drop in PSA on BAT alone. And 5 out of 7 men achieved a 50% drop after Xtandi was resumed.
Currently, BAT is a one-size-fits-all therapy. Men continue on Lupron, say, but receive monthly T injections ("testosterone cipionate 400 mg every 28 days until progression").
The T response is variable. Not all men achieve the target level. In addition, a more significant target might be free T, which varies with SHBG (sex hormone binding globulin) levels. Clearance of T is also variable. It's possible that better results would occur if dosage & frequency were tailored to the patient.
-Patrick
thelancet.com/journals/lano...
Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study
Benjamin A Teply, MD, Hao Wang, PhD, Brandon Luber, MS, Rana Sullivan, RN, Irina Rifkind, RN, Ashley Bruns, RN, Avery Spitz, RN, Morgan DeCarli, BS, Victoria Sinibaldi, CRNP, Caroline F Pratz, CRNP, Changxue Lu, PhD, John L Silberstein, MHS, Jun Luo, PhD, Michael T Schweizer, MD, Prof Charles G Drake, MD, Prof Michael A Carducci, MD, Channing J Paller, MD, Emmanuel S Antonarakis, MD, Prof Mario A Eisenberger, MD, Prof Samuel R Denmeade, MD
Summary
Background
Prostate cancer that progresses after enzalutamide treatment is poorly responsive to further antiandrogen therapy, and paradoxically, rapid cycling between high and low serum testosterone concentrations (bipolar androgen therapy [BAT]) in this setting might induce tumour responses. We aimed to evaluate BAT in patients with metastatic castration-resistant prostate cancer that progressed after enzalutamide.
Methods
We did this single-centre, open-label, phase 2, multicohort study in the USA. We included patients aged 18 years or older who had histologically confirmed and radiographically documented metastatic castration-resistant prostate cancer, with no more than two previous second-line hormonal therapies, and a castrate concentration of testosterone. Patients were asymptomatic, with Eastern Cooperative Oncology Group performance status of 0–2, and did not have high-risk lesions for tumour flare (eg, >5 sites of visceral disease or bone lesions with impending fracture). For the cohort reported here, we required patients to have had progression on enzalutamide with a continued prostate-specific antigen (PSA) rise after enzalutamide treatment discontinuation. Patients received BAT, which consisted of intramuscular testosterone cipionate 400 mg every 28 days until progression and continued luteinising hormone-releasing hormone agonist therapy. Upon progression after BAT, men were rechallenged with oral enzalutamide 160 mg daily. The co-primary endpoints were investigator-assessed 50% decline in PSA concentration from baseline (PSA50) for BAT (for all patients who received at least one dose) and for enzalutamide rechallenge (based on intention-to-treat analysis). These data represent the final analysis for the post-enzalutamide cohort, while two additional cohorts (post-abiraterone and newly castration-resistant prostate cancer) are ongoing. The trial is registered with ClinicalTrials.gov, number NCT02090114.
Findings
Between Aug 28, 2014, and May 18, 2016, we accrued 30 eligible patients and treated them with BAT. Nine (30%; 95% CI 15–49; p<0·0001) of 30 patients achieved a PSA50 to BAT. 29 patients completed BAT and 21 proceeded to enzalutamide rechallenge, of whom 15 (52%; 95% CI 33–71; p<0·0001) achieved a PSA50 response. During BAT, the only grade 3–4 adverse event occurring in more than one patient was hypertension (three [10%] patients). Other grade 3 or worse adverse events occurring during BAT in one [3%] patient each were pulmonary embolism, myocardial infarction, urinary obstruction, gallstone, and sepsis. During enzalutamide retreatment, no grade 3–4 toxicities occurred in more than one patient. No treatment-related deaths were reported during either BAT or enzalutamide retreatment.
Interpretation
BAT is a safe therapy that resulted in responses in asymptomatic men with metastatic castration-resistant prostate cancer and also resensitisation to enzalutamide in most patients undergoing rechallenge. Further studies with BAT are needed to define the potential clinical role for BAT in the management of metastatic castration-resistant prostate cancer and the optimal strategy for sequencing between androgen and antiandrogen therapies in metastatic castration-resistant prostate cancer to maximise therapeutic benefit to patients.
Funding
National Institutes of Health and National Cancer Institute.
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