A Randomised Comparison Evaluating Changes in Bone Mineral Density in Advanced Prostate Cancer: Luteinising Hormone-releasing Hormone Agonists Versus Transdermal Oestradiol

Abstract

BackgroundLuteinising hormone-releasing hormone agonists (LHRHa), used as androgen deprivation therapy (ADT) in prostate cancer (PCa) management, reduce serum oestradiol as well as testosterone, causing bone mineral density (BMD) loss. Transdermal oestradiol is a potential alternative to LHRHa.ObjectiveTo compare BMD change in men receiving either LHRHa or oestradiol patches (OP).Design, setting, and participantsMen with locally advanced or metastatic PCa participating in the randomised UK Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) trial (allocation ratio of 1:2 for LHRHa:OP, 2006–2011; 1:1, thereafter) were recruited into a BMD study (2006–2012). Dual-energy x-ray absorptiometry scans were performed at baseline, 1 yr, and 2 yr.InterventionsLHRHa as per local practice, OP (FemSeven 100 μg/24 h patches).Outcome measurements and statistical analysisThe primary outcome was 1-yr change in lumbar spine (LS) BMD from baseline compared between randomised arms using analysis of covariance.Results and limitationsA total of 74 eligible men (LHRHa 28, OP 46) participated from seven centres. Baseline clinical characteristics and 3-mo castration rates (testosterone ≤1.7 nmol/l, LHRHa 96% [26 of 27], OP 96% [43 of 45]) were similar between arms. Mean 1-yr change in LS BMD was −0.021 g/cm3 for patients randomised to the LHRHa arm (mean percentage change −1.4%) and +0.069 g/cm3 for the OP arm (+6.0%; p < 0.001). Similar patterns were seen in hip and total body measurements. The largest difference between arms was at 2 yr for those remaining on allocated treatment only: LS BMD mean percentage change LHRHa −3.0% and OP +7.9% (p < 0.001).ConclusionsTransdermal oestradiol as a single agent produces castration levels of testosterone while mitigating BMD loss. These early data provide further supporting evidence for the ongoing phase 3 trial.Patient summaryThis study found that prostate cancer patients treated with transdermal oestradiol for hormonal therapy did not experience the loss in bone mineral density seen with luteinising hormone-releasing hormone agonists. Other clinical outcomes for this treatment approach are being evaluated in the ongoing PATCH trial.Trial registrationISRCTN70406718, PATCH trial (ClinicalTrials.gov NCT00303784).

Quality‐of‐life outcomes from the Prostate Adenocarcinoma: TransCutaneous Hormones (PATCH) trial evaluating luteinising hormone‐releasing hormone agonists versus transdermal oestradiol for androgen suppression in advanced prostate cancer

“…fewer hot flushes, less fatigue, improved physical functioning, sexual interest and sexual activity, but at a cost of increased incidences of gynaecomastia. This can be viewed in addition to the beneficial effects on tE2 on bone mineral density previously reported within PATCH , also noting the lack of any excess cardiovascular or thromboembolic effects from tE2 . From our present data, hot flushes appear to potentially account for the increased fatigue and reduced global QoL among patients on LHRHa.…”

“…Agents which can potentially preserve bone health during treatment with LHRHa include bisphosphonates, denosumab or toremifine . Importantly, however, data from PATCH recently showed that patients on tE2 avoid the loss in bone mineral density seen with LHRHa administration . The data presented here suggest tE2 as an alternative to LHRHa might limit the requirement for additional treatments to allay the side‐effects of LHRHa over and above bone health.…”

Estradiol for the mitigation of adverse effects of androgen deprivation therapy

“…For bone, threshold levels of 200 ng/dL (6.9 nmol/L) for testosterone and 10 pg/mL (37 pmol/L) for E 2 were demonstrated, below which the risk of bone loss began to increase (Table 1). In the PATCH bone substudy (Langley et al 2016), despite a 7% better lumbar spine BMD in the E 2 arm compared with LHRHa arm at 12 months, there was no association between serum E 2 level and BMD change at any anatomical site within the E 2 arm. This could be because numbers were small, or because the achieved E 2 levels were well above a threshold above which no further benefit can be obtained.…”

“…In a nested BMD substudy of the PATCH trial, 74 men with locally advanced or metastatic PCa, randomized to ADT with LHRHa or E 2 patches, underwent DXA scans at baseline, 1 year and 2 years (Langley et al 2016). Data were available on 60 men for the primary outcome of 1-year change in lumbar spine BMD.…”

Transdermal oestradiol as a method of androgen suppression for prostate cancer within the STAMPEDE trial platform

“…The initial pilot phase showed transdermal E2 achieved equivalent castration rates to GNRH analogues without the excess cardiovascular morbidity or mortality previously seen with oral oestrogen . Subsequent analyses showed a number of other potential benefits of transdermal E2 compared with GNRH analogues, including improved bone mineral density , more favourable metabolic profiles and better quality of life over 6 months of ADT, although with increased likelihood of gynaecomastia .…”