Efficacy of Endocrine Therapy for the Treatment of Breast Cancer in Men: Results from the MALE Phase 2 Randomized Clinical Trial

Abstract

Importance: The extent of changes in estradiol levels in male patients with hormone receptor-positive breast cancer receiving standard endocrine therapies is unknown. The sexual function and quality of life related to those changes have not been adequately evaluated.

Objective: To assess the changes in estradiol levels in male patients with breast cancer after 3 months of therapy.

Design, setting, and participants: This multicenter, phase 2 randomized clinical trial assessed 56 male patients with hormone receptor-positive breast cancer. Patients were recruited from 24 breast units across Germany between October 2012 and May 2017. The last patient completed 6 months of treatment in December 2017. The analysis data set was locked on August 24, 2018, and analysis was completed on December 19, 2018.

Interventions: Patients were randomized to 1 of 3 arms: tamoxifen alone or tamoxifen plus gonadotropin-releasing hormone analogue (GnRHa) or aromatase inhibitor (AI) plus GnRHa for 6 months.

Main outcomes and measures: The primary end point was the change in estradiol levels from baseline to 3 months. Secondary end points were changes of estradiol levels after 6 months, changes of additional hormonal parameters, adverse effects, sexual function, and quality of life after 3 and 6 months.

Results: In this phase 2 randomized clinical trial, a total of 52 of 56 male patients with a median (range) age of 61.5 (37-83) years started treatment. A total of 3 patients discontinued study treatment prematurely, 1 in each arm. A total of 50 patients were evaluable for the primary end point. After 3 months the patients' median estradiol levels increased by 67% (a change of +17.0 ng/L) with tamoxifen, decreased by 85% (-23.0 ng/L) with tamoxifen plus GnRHa, and decreased by 72% (-18.5 ng/L) with AI plus GnRHa (P < .001). After 6 months, median estradiol levels increased by 41% (a change of +12 ng/L) with tamoxifen, decreased by 61% (-19.5 ng/L) with tamoxifen plus GnRHa, and decreased by 64% (-17.0 ng/L) with AI plus GnRHa (P < .001). Sexual function and quality of life decreased when GnRHa was added but were unchanged with tamoxifen alone.

Conclusions and relevance: This phase 2 randomized clinical trial found that AI or tamoxifen plus GnRHa vs tamoxifen alone led to a sustained decrease of estradiol levels. The decreased hormonal parameters were associated with impaired sexual function and quality of life.

Trial registration: ClinicalTrials.gov Identifier: NCT01638247.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Kamischke reported honoraria from Gedeon Richter; travel support from Gedeon Richter, Merck Serono. Dr Stickeler reported honoraria from Roche, AstraZeneca, Novartis, Pfizer, Eisai, Tesaro, and Merck Sharp & Dohme; compensation for consulting and advisory role from Roche and Tesaro; and travel expenses from Roche and Pfizer. Dr Marmé reported personal fees from Clovis, Pfizer, Novartis, Lilly, Immunomedics, Amgen, Roche, AstraZeneca, GlaxoSmithKline Tesaro, Eisai, and Genomic Health; honoraria and compensation for consulting and advisory role from Roche, AstraZeneca, Pfizer, Tesaro, Novartis, Amgen, PharmaMar, GenomicHealth, CureVac, Clovis Oncology, Merck Sharp & Dohme Oncology, Janssen-Cilag, and Immunomedics ; research funding from Roche/Genentech, Novartis, AstraZeneca, Eisai, Tesaro, Clovis Oncology, Merck Sharp & Dohme Oncology, and Vaccibody; travel expenses from Roche, Novartis, PharmaMar, and AstraZeneca. Dr Reinisch reported personal fees from Roche, AstraZeneca, Merck Sharp & Dohme, and Lilly; personal fees and non-financial support from Novartis and Pfizer; honoraria from Roche, Merck Sharp & Dohme, AstraZeneca, Pfizer, and Somatex; consulting or advisory role with Novartis, Roche, Lilly, PFM; and travel support from Celgene, Lilly, and Novartis. Dr Untch reported personal fees from AbbVie, Amgen, Celgene, Daiichi Sankyo, Eisai, Lilly, Merck Sharp & Dohme, Mundipharma, Myriad Genetics, Novartis, Pfizer, Sanofi Aventis, Roche Pharma, Pierre Fabre, and Clovis, and personal fees and non-financial support from AbbVie, Amgen GmbH, AstraZeneca, Bristol Myers Squibb, Celgene GmbH, Daiichi Sankyo, Eisai GmbH, Lilly Deutschland, Lilly Int, Merck Sharp & Dohme, Mundipharma, Myriad Genetics, Odonate, Pfizer GmbH, PUMA Biotechnology, Roche Pharma AG, Sanofi Aventis Deutschland GmbH, TEVA Pharmaceuticals Industries Ltd, Novartis, Pierre Fabre, and Clovis Oncology. Dr Loibl reported grants and other from Pfizer during the conduct of the study, and grants and other from Roche, AbbVie, Amgen, Celgene, Immunomedics, Novartis, Pfizer, Seattle Genetics, AstraZeneca; personal fees from Chugai, grants from Teva, Vifor, Daiichi Sankyo; other from Seagen, PriME/Medscape, Lilly, Samsung, EirGenix, Bristol Myers Squibb, Puma, Merck Sharp & Dohme; as well as a patent to EP14153692.0 pending. Dr Seiler reports personal fees from Amgen, Hexal, Roche, and Mundipharma; other from Novartis and AstraZeneca. Dr Reimer reported personal fees from Roche, Pfizer, AstraZeneca, Lilly, and Novartis. Dr Möbus reports speaker honoraria from Amgen, AstraZeneca, Celgene, Roche, TEVA, and consultancy honoraria from Roche, Amgen, Tesaro, and Myelo Therapeutics. Dr Janni reports honoraria and compensation for consulting and advisory role, research funding, and travel expenses from Amgen, AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pfizer, and Roche. Dr Schmidt reported personal fees from Amgen, AstraZeneca, Lilly, Novartis, Merck Sharp & Dohme, and Seattle Genetics; grants and personal fees from Pantarhei Bioscience and Pierre Fabre; grants, personal fees, and nonfinancial support from Pfizer and Roche; and other from Sividon, and grants and nonfinancial support from BioNTech outside the submitted work; in addition, Dr Schmidt had patents issued to EP 2951317 B1 and to EP 2390370 B1. No other disclosures were reported.

Figures

Figure 1.. Values of Estradiol, Testosterone, Follicle-Stimulating Hormone, and Luteinizing Hormone at Baseline and After 3 and 6 Months of Therapy Within the MALE Study

FSH indicates follicle-stimulating hormone; GnRHa, gonadotropin-releasing hormone analogue; LH, luteinizing hormone. The 6-month analysis set comprised 46 patients (tamoxifen-treated group, 17 patients; tamoxifen plus GnRHa, 14 patients; exemestane plus GnRHa, 15 patients). The box represents the first quartile, median, and third quartile; the whiskers represent minimal and maximal values within 1.5 of the interquartile range; the small circles are values outside 1.5 of the interquartile range.

Figure 2.. International Index of Erectile Function (IIEF) Score at Baseline and After 3 and 6 Months of Therapy Within the MALE Study

A total of 52 patients were analyzed at baseline and after 3 months; 49 were analyzed after 6 months (due to early discontinuation by 1 patient in each cohort). The box represents the first quartile, median, and third quartile; the whiskers represent minimal and maximal values within 1.5 of the interquartile range; the small circles are values outside 1.5 of the interquartile range.

Figure 3.. Aging Male Symptom (AMS) Score at Baseline and After 3 and 6 Months of Therapy Within the MALE Study

A total of 52 patients were analyzed at baseline and after 3 months; 49 were analyzed after 6 months (due to early discontinuation by 1 patient in each cohort). The box represents the first quartile, median, and third quartile; the whiskers represent minimal and maximal values within 1.5 of the interquartile range; the small circles are values outside 1.5 of the interquartile range.