Clinical Outcomes in Cyclin-dependent Kinase 12 Mutant Advanced Prostate Cancer

• Published in: European urology 2020-03, Vol.77 (3), p.333-341
• Main Authors: Reimers, Melissa A., Yip, Steven M., Zhang, Li, Cieslik, Marcin, Dhawan, Mallika, Montgomery, Bruce, Wyatt, Alexander W., Chi, Kim N., Small, Eric J., Chinnaiyan, Arul M., Alva, Ajjai S., Feng, Felix Y., Chou, Jonathan
• Format: Article
• Language: English
• Subjects: Cyclin-dependent kinase 12; Genomics; Next-generation sequencing; Prostate cancer
• ISSN: 0302-2838; 1873-7560
• DOI: 10.1016/j.eururo.2019.09.036

Cyclin-dependent kinase 12 (CDK12) loss occurs in 3–7% of metastatic prostate cancer patients and is characterized by a genomic instability signature, but the clinical implications of CDK12 loss are not well established. To determine the clinical course of patients with CDK12 mutant advanced prostate cancer compared with other genomic subtypes. A retrospective analysis of data from three academic medical centers, including 317 patients with advanced prostate cancer and prior next-generation sequencing from tumor tissue (n = 172) or circulating tumor DNA (n = 145), was performed. Forty-six patients had CDK12 mutations; 34 had biallelic CDK12 loss (79%). Patients were stratified by mutation status (CDK12, homologous recombination deficiency [HRD; BRCA1/2 and ATM], TP53, and other cohort). The Kaplan-Meier method was used to evaluate time to event outcomes: time to development of metastatic disease, time to development of castration resistance, and time to prostate-specific antigen (PSA) progression after first-line androgen receptor pathway inhibitor (ARPI) therapy in a patient subset. The median follow-up was 66.6 mo. Patients with CDK12 mutant prostate cancer exhibited shorter time to metastasis (median = 34.9 mo, p =  0.004) and development of castration-resistant disease (median = 32.7 mo, p