Molecular characterization of <i> <i>CDK12</i> </i> mutation in Chinese CRPC and its impact on first-line endocrine therapy efficacy.

e17048 Background: Prostate cancer (PC) often develops resistance to androgen deprivation therapy (ADT) due to various secondary molecular mechanisms like AR amplification, AR mutation, and aberrations in the PI3K or NF-κB pathways, leading to progression to metastatic castration-resistant prostate cancer (mCRPC). CDK12 -mutated PC is highly aggressive and resistant to ADT, PARP inhibitors, and immunotherapy, although some patients benefit from ADT. This study aims to analyze the molecular mechanisms underlying the sensitivity or resistance of CDK12 -mutated PC to endocrine therapy using next-generation sequencing (NGS). Methods: This retrospective study analyzed CDK12 -mutated PC patients receiving first-line endocrine therapy at the Second Hospital of Tianjin Medical University from January 2018 to January 2024. Common regimens included Bicalutamide + Goserelin, Abiraterone + Goserelin, Flutamide + Goserelin, and Apalutamide + Goserelin. Clinical information, Gleason scores (GS), PSA levels, pathological features, NGS results, and progression-free survival (PFS) were collected. The impact of specific mutations on endocrine therapy efficacy was assessed using univariate and multivariate Cox regression analyses. Results: Forty-three patients, with a mean age of 64.7 years, were included. The majority (81.4%) were ≥60 years old, and 95.4% had GS ≥7. Most patients had PSA levels &gt;20 ng/mL (76.7%). Pathologically, 90.7% had prostate adenocarcinoma. Univariate Cox analysis revealed that PSA (HR 2.4, 95%CI 1-5.6), TP53 (2.9, 1.2-6.6), RB1 (2.9, 1.1-7.68), BRCA2 (4.9,1.8-13), and GS (6.6, 0.89-49) were associated with shorter PFS, while AR amp (0.48, 0.25-0.91) was linked to longer PFS. Multivariate analysis identified BRCA2 (8.9, 0.82-97) and PSA (3.2, 1.2-8.2) as independent predictors of therapy response. Kaplan-Meier analysis showed that patients with TP53 , RB1 , or BRCA2 mutations had worse PFS, while those with AR amp, ERBB3 amp, or GS ≤7 had better PFS. Conclusions: The study identifies molecular characteristics of CDK12 -mutated PC associated with sensitivity or resistance to endocrine therapy. Endocrine-sensitive subtypes are characterized by AR amp, ERBB3 amp, GS ≤7, and PSA ≤20 ng/mL, while endocrine-resistant subtypes include TP53 , BRCA2 , RB1 , GS &gt;7, and PSA &gt;20 ng/mL. These findings emphasize the utility of NGS for improving treatment outcomes and predicting first-line endocrine therapy efficacy in CDK12-mutated PC.