CDK12-altered prostate cancer: Clinical features and therapeutic outcomes to standard systemic therapies, poly (ADP-ribose) polymerase inhibitors, and PD-1 inhibitors

Emmanuel S. Antonarakis*, Pedro Isaacsson Velho, Wei Fu, Hao Wang, Neeraj Agarwal, Victor Sacristan Santos, Benjamin L. Maughan, Roberto Pili, Nabil Adra, Cora N. Sternberg, Panagiotis J. Vlachostergios, Scott T. Tagawa, Alan H. Bryce, Andrea L. McNatty, Zachery R. Reichert, Robert Dreicer, Oliver Sartor, Tamara L. Lotan, Maha Hussain

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

PURPOSE In prostate cancer, inactivating CDK12 mutations lead to gene fusion–induced neoantigens and possibly sensitivity to immunotherapy. We aimed to clinically, pathologically, and molecularly characterize CDK12-aberrant prostate cancers. METHODS We conducted a retrospective multicenter study to identify patients with advanced prostate cancer who harbored somatic loss-of-function CDK12 mutations. We used descriptive statistics to characterize their clinical features and therapeutic outcomes (prostate-specific antigen [PSA] responses, progression-free survival [PFS]) to various systemic therapies, including sensitivity to poly (ADP-ribose) polymerase and PD-1 inhibitors. RESULTS Sixty men with at least monoallelic (51.7% biallelic) CDK12 alterations were identified across nine centers. Median age at diagnosis was 60.5 years; 71.7% and 28.3% were white and nonwhite, respectively; 93.3% had Gleason grade group 4-5; 15.4% had ductal/intraductal histology; 53.3% had metastases at diagnosis; and median PSA was 24.0 ng/mL. Of those who underwent primary androgen deprivation therapy for metastatic hormone-sensitive disease (n = 59), 79.7% had a PSA response, and median PFS was 12.3 months. Of those who received first-line abiraterone and enzalutamide for metastatic castration-resistant prostate cancer (mCRPC; n = 34), 41.2% had a PSA response, and median PFS was 5.3 months. Of those who received a first taxane chemotherapy for mCRPC (n = 22), 31.8% had a PSA response, and median PFS was 3.8 months. Eleven men received a PARP inhibitor (olaparib [n = 10], rucaparib [n = 1]), and none had a PSA response (median PFS, 3.6 months). Nine men received a PD-1 inhibitor as fourth- to sixth-line systemic therapy (pembrolizumab [n = 5], nivolumab [n = 4]); 33.3% had a PSA response, and median PFS was 5.4 months. CONCLUSION CDK12-altered prostate cancer is an aggressive subtype with poor outcomes to hormonal and taxane therapies as well as to PARP inhibitors. A proportion of these patients may respond favorably to PD-1 inhibitors, which implicates CDK12 deficiency in immunotherapy sensitivity.

Original languageEnglish (US)
Pages (from-to)370-381
Number of pages12
JournalJCO Precision Oncology
Volume3
DOIs
StatePublished - 2019

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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