Clinical and genomic predictors of sipuleucel-T outcomes in men with metastatic androgen pathway modulator resistant prostate cancer

BACKGROUND Survival outcomes following sipuleucel-T in men with metastatic androgen pathway modulator resistant prostate cancer (mAPMR) are variable. Genomic alterations influencing immune response and tumor proliferation may explain outcome heterogeneity. We sought to identify clinical and genomic correlates of survival following sipuleucel-T. METHODS We conducted a single-center retrospective study of men with mAPMR and accessible tumor genomic data who received sipuleucel-T at the Duke Cancer Institute (2014–2024). The primary objective was to associate clinical factors and somatic genomic alterations with overall survival (OS) using multivariable Cox models. RESULTS Among 429 men treated with sipuleucel-T, 185 (43%) had molecular data (tumor tissue 43%, cfDNA 57%). Median age was 70; most were ECOG 0 (60%) and White (85%) or Black (14%). Frequent alterations included TP53 (48%), AR amplification (27%), PTEN loss (20%), and MYC gain (10%). Median OS and progression-free survival (PFS) were 44 and 3.6 months, respectively. MYC gain was the strongest independent genomic predictor of poorer OS. On multivariable analysis, predictors of poorer OS included ≥ 10 bone metastases (HR 42.4, 95% CI 10.3–175, p < 0.001), MYC gain (HR 7.96, 95% CI 2.88-22.0, p < 0.001), older age (HR 1.05, 95% CI 1.01–1.09, p = 0.017), TMPRSS2 wild type vs. mutation (HR _mutation 0.35, 95% CI 0.16–0.78, p = 0.011), higher alkaline phosphatase (HR 1.11 per 10 IU/L, 95% CI 1.04–1.18, p < 0.001), and higher ANC (HR 1.30, 95% CI 1.06–1.58, p = 0.011). CONCLUSIONS MYC gain is strongly associated with poorer OS following sipuleucel-T. Aggressive tumor biology, immune evasion, and advanced disease state may underlie these inferior outcomes; alternative therapies should be considered in MYC-amplified mAPMR. Multicenter validation is planned to further enhance patient selection for sipuleucel-T.