ORLANDO — Estrogen patches produce a similar fall in testosterone and prostate-specific antigen levels when compared with luteinizing hormone-releasing hormone analogues in locally advanced and metastatic prostate cancer, according to interim results from the phase II, multicenter PATCH trial.
Intention-to-treat data from the first 100 patients show that castration was achieved at 4 weeks in 67% of 30 men who started treatment with three patches that were changed twice weekly. This increased to 91% of 33 men who started with four patches changed twice weekly. In comparison, 64% of 33 men who were treated with LHRH analogues achieved castration by that time point.
At 12 weeks, castration rates were 72%, 87%, and 93%, respectively, coauthors Dr. Ruth Langley and Dr. Paul Abel reported in a poster at a symposium on genitourinary cancers. Castration was defined as a testosterone level of 50 ng/dL or less.
PSA responses were observed in all three groups at 6 months. Levels fell from a baseline median of 51 ng/mL in both patch groups to 1.3 ng/mL with four patches changed twice weekly and 3.2 ng/mL with three patches changed twice weekly. They went from a median of 35 ng/mL at baseline to 0.9 ng/mL at 6 months in the control group.
“Providing [that these data] continue to look promising, we are aiming to extend this to a phase III study,” Dr. Langley of the U.K. Medical Research Council Clinical Trials Unit said in an interview.
The hypothesis behind the PATCH (Prostate Adenocarcinoma: Transcutaneous Hormones) trial is that the application of estrogen to the skin will avoid first-pass hepatic metabolism (that is, the hepatic metabolism of a drug when it is absorbed from the gut and delivered to the liver via the portal vein), and therefore will not be associated with the same cardiovascular toxicity previously shown by oral estrogen.
Prolonged use of LHRH analogues has also raised concerns about long-term toxicity, particularly osteoporosis and metabolic syndrome.
Estrogen has been shown in previous studies to protect against bone mineral density loss in women, and pilot data from a study in 20 men with prostate cancer show that transdermal estrogen improved bone density at 1 year (J. Urol. 2004;172:2203-7).
“The mechanism underlying this is not clear, but it has been postulated that androgens are converted by aromatase to estradiol in bone, and thus some of the protective effects of androgens on bone are mediated through local production of estrogen,” Dr. Langley said.
As of mid-February 2009, 172 men had been randomized to three arms: three estrogen patches changed twice weekly for 4 weeks, followed by two patches changed twice weekly for an indefinite time; four patches changed twice weekly for 4 weeks, followed by three patches changed indefinitely; or a control arm of LHRH analogues, as per local practice. The primary end point is cardiovascular mortality and morbidity.
A Gleason score greater than 7 was reported in 44% of control patients and in 49% of patch patients. Their median age was 75 years and 73 years, respectively.
Four patients have stopped using patches because they were falling off, and two stopped by choice.
Noncardiovascular toxicity has been as expected, and includes gynecomastia and some erythema, the authors reported at the meeting, which was sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology. One patient developed erythema nodosum, which started approximately 4 weeks after the patches were placed, and resolved when they were discontinued.
The PATCH trial is sponsored by the Imperial College London and funded by Cancer Research U.K. Dr. Abel, of Imperial College London, disclosed consultancy with Ascend Pharmaceuticals, which makes an estrogen gel.