madman
Super Moderator
Transdermal square-wave testosterone therapy: A pilot trial in metastatic castration-resistant prostate cancer (2023)
Nellowe Candelario, Andrew Nicklawsky, Laura Graham, Elaine T. Lam, Eryn Callihan, Michael Wacker, Thomas W. Flaig, Elizabeth R Kessler; the University of Colorado Cancer Center Anschutz Medical Campus, Aurora, CO
Background
Metastatic castration-resistant prostate cancer (mCRPC) becomes resistant to antiandrogen therapies due to a variety of adaptive mechanisms. Intramuscular bipolar androgen therapy (BAT) which alternates between high and low testosterone (T) levels is therapeutically active in mCRPC and confers sensitivity to second-generation androgen receptor antagonists such as enzalutamide (ENZA). We hypothesized that transdermal T with sustained supraphysiologic T levels would lead to high response rates to ENZA in mCRPC. We also hypothesized Square-wave transdermal T therapy would be a safe alternative to BAT due to the ability to quickly withdraw therapy in the setting of symptoms.
Methods
This was an open-label, single-site, phase 2 feasibility trial in men with asymptomatic mCRPC who had not previously received ENZA. Transdermal T was administered at a dose of 100 mg/day for a minimum of 12 weeks and until disease progression. Therapy was then switched to ENZA 160 mg/day until the next disease progression. Patients who initially responded to T could receive a second course of transdermal T followed by ENZA, remaining on study until progression on both T and ENZA or for the 12-month study duration, whichever was sooner. ADT was continued throughout. The primary endpoint of the study was feasibility. T dose was adjusted to achieve T levels between 900-1500 ng/dL. Secondary endpoints included PSA50 response rate (50% decline in PSA) and safety.
Result
Fifteen patients were enrolled. Ten (66.7%) had Gleason .8 disease. Thirteen (86.7%) patients had bone metastases. The median baseline PSA was 11.73 ng/mL. The primary endpoint of feasibility based on patient recruitment and retention was met. The median testosterone level on T was 901.3 ng/dL (Range: 645.2 to 1171.1). Median time on therapy was 15.9 weeks on T and 25.9 weeks on ENZA. PSA50 was 13.3% on initial T therapy and 66.7% after switching to ENZA. Three (20%) patients did not initiate ENZA after T progression. Two desired to avoid androgen-related side effects and 1 initiated chemotherapy. No Grade 3 or higher adverse events (AEs) occurred on T and the most common AEs were weight gain, rash, and nipple sensitivity.
Conclusions
Square-wave transdermal T alternating with ENZA is feasible and achieves adequate T levels in the treatment of asymptomatic mCRPC. Given the acceptable safety profile and quick reversibility, transdermal T warrants further exploration, and we have expanded enrollment to include higher-risk patient populations.
Nellowe Candelario, Andrew Nicklawsky, Laura Graham, Elaine T. Lam, Eryn Callihan, Michael Wacker, Thomas W. Flaig, Elizabeth R Kessler; the University of Colorado Cancer Center Anschutz Medical Campus, Aurora, CO
Background
Metastatic castration-resistant prostate cancer (mCRPC) becomes resistant to antiandrogen therapies due to a variety of adaptive mechanisms. Intramuscular bipolar androgen therapy (BAT) which alternates between high and low testosterone (T) levels is therapeutically active in mCRPC and confers sensitivity to second-generation androgen receptor antagonists such as enzalutamide (ENZA). We hypothesized that transdermal T with sustained supraphysiologic T levels would lead to high response rates to ENZA in mCRPC. We also hypothesized Square-wave transdermal T therapy would be a safe alternative to BAT due to the ability to quickly withdraw therapy in the setting of symptoms.
Methods
This was an open-label, single-site, phase 2 feasibility trial in men with asymptomatic mCRPC who had not previously received ENZA. Transdermal T was administered at a dose of 100 mg/day for a minimum of 12 weeks and until disease progression. Therapy was then switched to ENZA 160 mg/day until the next disease progression. Patients who initially responded to T could receive a second course of transdermal T followed by ENZA, remaining on study until progression on both T and ENZA or for the 12-month study duration, whichever was sooner. ADT was continued throughout. The primary endpoint of the study was feasibility. T dose was adjusted to achieve T levels between 900-1500 ng/dL. Secondary endpoints included PSA50 response rate (50% decline in PSA) and safety.
Result
Fifteen patients were enrolled. Ten (66.7%) had Gleason .8 disease. Thirteen (86.7%) patients had bone metastases. The median baseline PSA was 11.73 ng/mL. The primary endpoint of feasibility based on patient recruitment and retention was met. The median testosterone level on T was 901.3 ng/dL (Range: 645.2 to 1171.1). Median time on therapy was 15.9 weeks on T and 25.9 weeks on ENZA. PSA50 was 13.3% on initial T therapy and 66.7% after switching to ENZA. Three (20%) patients did not initiate ENZA after T progression. Two desired to avoid androgen-related side effects and 1 initiated chemotherapy. No Grade 3 or higher adverse events (AEs) occurred on T and the most common AEs were weight gain, rash, and nipple sensitivity.
Conclusions
Square-wave transdermal T alternating with ENZA is feasible and achieves adequate T levels in the treatment of asymptomatic mCRPC. Given the acceptable safety profile and quick reversibility, transdermal T warrants further exploration, and we have expanded enrollment to include higher-risk patient populations.
