Top Line: 50+ years ago, oral estrogen was the standard means of medical castration for prostate cancer.
The Study: Afterall, it provides incredibly effective negative feedback to the hypothalamus to shut down testosterone production. Then came LHRH agonists in the 1980s promising to lower associated cardiovascular risk seen when oral estrogens are metabolized in the liver ramping up liver-derived coagulation factors. The problem then is men are dealing with sequelae of tanked testosterone AND estrogen, the latter associated with all the joys of menopause: hot flashes, insomnia, fatigue, brittle bones, metabolic derrangements…must we go on. Enter this pragmatic adaptive phase 2–3 trial combining prospective cohorts from both PATCH and STAMPEDE where 1360 men with localized high-risk prostate cancer were randomized to more modern transdermal estradiol patches versus standard LHRH agonists. At 3 years, the primary endpoint of metastasis-free survival was officially non-inferior with the patch (87%) versus LHRH agonist (86%). Overall survival at 5 years was similarly comparable (81% versus 79%). Testosterone suppression was equivalent over time, with faster initial castration with the patch. Side effect profiles diverged as hoped: the patch produced dramatically fewer hot flashes (44% versus 89%), improved bone health with half the rate of fracture (5% versus 10%), better metabolic parameters (lower fasting glucose and improved lipid panels), and lower reported insomnia and fatigue—but at the cost of significantly more gynecomastia (85% versus 42%). Importantly, earlier concerns about cardiovascular thromboembolic risk with estrogen were not borne out, presumably due to avoidance of first-pass hepatic metabolism with the transdermal route. Unfortunately, the 46 men (8%) who received prophylactic breast irradiation along with the patch saw no decrease in risk of gynecomastia, but it would be nice to learn more details about this.
TBL: In this trial, transdermal estrogen had noninferior outcomes compared to LHRH agonists for locally advanced prostate cancer with less hot flashes but more gynecomastia. | Langley, N Engl J Med 2926
The Study: Afterall, it provides incredibly effective negative feedback to the hypothalamus to shut down testosterone production. Then came LHRH agonists in the 1980s promising to lower associated cardiovascular risk seen when oral estrogens are metabolized in the liver ramping up liver-derived coagulation factors. The problem then is men are dealing with sequelae of tanked testosterone AND estrogen, the latter associated with all the joys of menopause: hot flashes, insomnia, fatigue, brittle bones, metabolic derrangements…must we go on. Enter this pragmatic adaptive phase 2–3 trial combining prospective cohorts from both PATCH and STAMPEDE where 1360 men with localized high-risk prostate cancer were randomized to more modern transdermal estradiol patches versus standard LHRH agonists. At 3 years, the primary endpoint of metastasis-free survival was officially non-inferior with the patch (87%) versus LHRH agonist (86%). Overall survival at 5 years was similarly comparable (81% versus 79%). Testosterone suppression was equivalent over time, with faster initial castration with the patch. Side effect profiles diverged as hoped: the patch produced dramatically fewer hot flashes (44% versus 89%), improved bone health with half the rate of fracture (5% versus 10%), better metabolic parameters (lower fasting glucose and improved lipid panels), and lower reported insomnia and fatigue—but at the cost of significantly more gynecomastia (85% versus 42%). Importantly, earlier concerns about cardiovascular thromboembolic risk with estrogen were not borne out, presumably due to avoidance of first-pass hepatic metabolism with the transdermal route. Unfortunately, the 46 men (8%) who received prophylactic breast irradiation along with the patch saw no decrease in risk of gynecomastia, but it would be nice to learn more details about this.
TBL: In this trial, transdermal estrogen had noninferior outcomes compared to LHRH agonists for locally advanced prostate cancer with less hot flashes but more gynecomastia. | Langley, N Engl J Med 2926