Clinical and Molecular Profiles of Treatment-Emergent Small Cell Neuroendocrine Prostate Cancers in the Era of Intensified Systemic Therapies.

Variant histologic features can emerge in therapy-resistant prostate cancers, with treatment-emergent small-cell neuroendocrine carcinomas (t-SCNC) the most common. Here we report clinical, histopathological, and genomic features of 126 t-SCNCs and 14 other treatment-emergent variant histologies. This retrospective multi-institutional analysis included cases from six academic cancer centers. Molecular testing was acquired from baseline adenocarcinoma biopsies (n=23) and other variant histology biopsies (n=74), including 21 paired samples. 140 treatment-emergent variant prostate cancers were included. Prior to variant histology detection, 48% received androgen deprivation therapy (ADT) alone, 16% received ADT plus an androgen receptor pathway inhibitor (ARPI), 15% received ADT plus chemotherapy, and 20% received triplet therapy (ADT, an ARPI, and chemotherapy). In t-SCNC, prior chemotherapy (HR=1.75, 95% CI=1.16-2.64, adjusted P=0.002) or ADT plus ARPI (HR=3.04, 95% CI=1.73-5.33, adjusted P=0.009) was associated with a shorter interval from mHSPC diagnosis to t-SCNC detection. TP53 alterations were found in 74% of baseline samples, significantly enriched compared to other cohorts of hormone-sensitive tumors. In paired biopsies, RB1 alterations were markedly increased in t-SCNC vs baseline (76% vs 10%, P<0.001). When considering combined inactivation of key tumor suppressor genes (TSGs: TP53, RB1 and PTEN), 76% had dual loss, while 33% harbored alterations in all three, portending worse outcomes (HR=2.12; 95% CI=1.03-4.37; univariate P=0.041). Prior systemic treatment exposures were associated with timing of t-SCNC detection within this selected cohort. Deleterious TP53 alterations were detected in three quarters of baseline tumors, with additional TSG losses (especially in RB1) emerging in the t-SCNC lesion.