Testicular function after immune-checkpoint inhibitors treatment.

Abstract

e24096 Background: Immune-checkpoint inhibitors (ICIs) have revolutionized cancer treatment, demonstrating durable survival benefits across a wide range of malignancies, from advanced to early-stage disease. While endocrine toxicities of ICIs are well-known, their impact on male reproductive function remains poorly understood. This prospective study aimed to evaluate the effects of ICIs on testicular function in men with melanoma, and no prior gonadotoxic treatments. Methods: This observational, mixed longitudinal and cross-sectional study enrolled men of reproductive age with melanoma requiring systemic therapy at two Australian centres. Baseline andrological assessments included medical history, physical examination, and sperm cryopreservation. Semen analyses (volume, density, motility, morphology) and reproductive hormone measurements (serum LH, FSH, testosterone, SHBG) were performed at baseline and during follow-up. Patients with prior gonadotoxic treatments such as pelvic radiotherapy were excluded. Changes in reproductive parameters were analysed using mixed-effects models for repeated measures with adjustment for potential confounders. Results: Among 29 men with melanoma (22 stage II/III, 7 stage IV), aged 25 ± 1 years, 26 were included in the analysis after excluding 3 who received gonadotoxic treatments. Treatment regimens included anti-PD1 in 24 patients (nine alone, seven with anti-CTLA4, four with anti-LAG3, and six with BREF/MEK inhibitors). Over a median follow-up of 2.8 years (IQR 1.7, 4.5 years), there was a marginally significant reduction in sperm output (34% reduction from baseline median of 193 to 127 million; p = 0.053) and sperm density (30% reduction from 61 to 43 million/mL; p = 0.075), with no changes in motility or morphology. One 28-year-old patient developed isolated azoospermia (persisting three years post-treatment) accompanied by increased serum FSH, while serum testosterone and LH levels remained stable. No other medications were administered, and no immune-related endocrinopathies were identified. Sensitivity analyses excluding this patient showed no significant reductions in sperm parameters. Conclusions: ICIs, widely used across multiple cancers, have minimal impact on male fertility, with stable testicular endocrine function. The observed mild impact on sperm parameters was primarily driven by a single case of persistent azoospermia ( < 5%). These findings highlight the importance of sperm cryopreservation prior to ICI initiation and the need for systematic reproductive health monitoring during and after treatment. Further larger studies are required to confirm these findings, explore potential mechanisms, and develop protective strategies to preserve fertility in male cancer patients undergoing immunotherapy.