Incidence, Management, and Prevention of Gynecomastia and Breast Pain in Patients with Prostate Cancer Undergoing Antiandrogen Therapy: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Abstract

Background and objective: In patients with prostate cancer treated with antiandrogen monotherapy, gynecomastia and breast pain are relatively common. In the setting of androgen receptor pathway inhibitors (ARPIs), the incidence of these adverse events (AEs) remains unclear. In addition, the effect of prophylactic treatment on gynecomastia remains uncertain. We aimed to evaluate the incidence of gynecomastia and breast pain in prostate cancer patients treated with ARPIs compared with androgen deprivation therapy (ADT) and the effect of prophylactic treatment for these AEs due to antiandrogen therapy. Methods: In June 2024, we queried four databases—PubMed, Scopus, Web of Science, and Embase—for randomized controlled trials (RCTs) investigating prostate cancer treatments involving antiandrogen therapy. The endpoints of interest were the incidence of these AEs due to ARPIs and the effect of prophylactic treatment for these. Key findings and limitations: Eighteen RCTs, comprising 5036 patients, were included in the systematic review and meta-analysis. ARPIs included enzalutamide, darolutamide, and apalutamide. The results indicated that patients who received ARPI monotherapy had a significantly higher incidence of gynecomastia than those who received ADT monotherapy (risk ratio [RR]: 5.19, 95% confidence interval [CI]: 3.58–7.51, p < 0.001). There was no significant difference in the incidence of gynecomastia between ARPI plus ADT therapy and ADT monotherapy (RR: 1.27, 95% CI: 0.84–1.93, p = 0.2). Prophylactic tamoxifen or radiotherapy reduced significantly the incidence of gynecomastia and breast pain caused by bicalutamide monotherapy. Conclusions and clinical implications: We found that ARPI monotherapy increases the incidence of these AEs significantly compared with ADT. In contrast, ARPI plus ADT therapy did not result in a higher incidence of AEs. The use of either tamoxifen or radiotherapy was effective in reducing the incidence of these AEs due to bicalutamide monotherapy. These prophylactic treatments could reduce the incidence of AEs due to ARPI monotherapy. However, further studies are needed to clarify their efficacy. Patient summary: Although androgen deprivation therapy (ADT) improves overall survival in patients with prostate cancer, it is associated with several complications. Androgen receptor pathway inhibitor (ARPI) monotherapy has emerged as a promising strategy for improving oncological outcomes in these patients. However, ARPI monotherapy increases gynecomastia and breast pain in prostate cancer patients compared with ADT, while ARPI plus ADT did not result in a higher incidence of adverse events.

Keywords

• Antiandrogen therapy
• Androgen deprivation therapy
• Androgen receptor pathway inhibitors
• Breast pain
• Gynecomastia