Safety profile of apalutamide in prostate cancer: a pooled analysis of phase III trials and the under-recognized need for real-world thyroid monitoring

Background Apalutamide has established efficacy in non-metastatic castration-resistant prostate cancer (nmCRPC) and metastatic castration-sensitive prostate cancer (mCSPC). While some side effects like rash are widely recognized by clinicians, the precise quantification of overall toxicities and their translation into real-world practice remain poorly defined. We aimed to pool directly randomized evidence to quantify apalutamide-associated risks and evaluate contemporary clinical monitoring behaviors. Methods A systematic literature search of PubMed, Embase, and CENTRAL was conducted through August 2026 to identify phase III randomized controlled trials (RCTs) evaluating apalutamide versus placebo. Pooled relative risks (RRs) and 95% confidence intervals (CIs) for pre-specified adverse events (AEs) were calculated using a DerSimonian–Laird random-effects model. Concurrently, a structured survey was conducted among 39 prostate cancer experts from the Korean Prostate Society to evaluate real-world thyroid monitoring practices. Results Two pivotal phase III RCTs (SPARTAN and TITAN) comprising a combined safety population of 2,251 patients were analyzed. Apalutamide was associated with significantly higher risks of rash (pooled RR: 3.57, 95% CI: 2.68–4.76, p < 0.001) and hypothyroidism (pooled RR: 3.16, 95% CI: 1.97–5.08, p < 0.001). Significant risk elevations were also confirmed for fracture (RR: 1.54), fall (RR: 1.49), fatigue (RR: 1.29), diarrhea (RR: 1.33), and decreased appetite (RR: 1.38). Crucially, despite the robust 3-fold increased risk of hypothyroidism established in the trial data, the real-world survey revealed that 59.0% (n = 23) of experts do not monitor thyroid-stimulating hormone (TSH) levels at all during apalutamide therapy, and only 17.9% (n = 7) perform routine periodic testing. Conclusions This pooled analysis refines the safety profile of apalutamide across approved indications. While well-known risks like rash are clinically acknowledged, a striking discrepancy exists regarding apalutamide-induced thyroid dysfunction. The high rate of omitted TSH surveillance in real-world practice highlights an urgent need for standardized clinical guidelines to incorporate routine thyroid function monitoring in urological oncology care.