CDK12-altered prostate cancer: Clinical features and therapeutic outcomes to standard systemic therapies, PARP inhibitors, and PD1 inhibitors

Abstract Background Although once considered a homologous recombination DNA repair gene, CDK12 is now thought to have a distinct role in maintaining genomic stability. In prostate cancer, inactivating CDK12 mutations lead to gene fusion-induced neoantigens and possibly sensitivity to PD1 inhibitors. Methods We conducted a retrospective multicenter study to identify advanced prostate cancer patients with loss-of-function CDK12 mutations. We characterized their clinical features and therapeutic outcomes, including sensitivity to PARP and PD1 inhibitors. Results 58 men with at least monoallelic CDK12 alterations were identified from 9 academic centers; 28 (48%) had biallelic inactivation. Tissue for genomics was from primary tumors in 45 cases (77%) and from metastatic sites in 13 cases (23%). All CDK12 mutations were somatic-only. Median age at diagnosis was 60 y (41–78 y), 71%/29% were white/nonwhite, 79% had Gleason sum 9-10, 10% had ductal/intraductal histology, 76% had stage T3/T4 disease, 47% had metastases at diagnosis, and the median PSA was 24 ng/mL. Of those undergoing primary ADT (± Abi, ± Doce) for advanced disease (n = 54), only 85% had a PSA50 response, with median PFS of 11.8 (95% CI 8.3–15.4) mo; OS from ADT initiation was 40.8 (95% CI 18.7–53) mo. Of those receiving first-line Abi/Enza for mCRPC (n = 34), only 47% had a PSA50 response, with median PFS of 4.3 (95% CI 2.6–6.0) mo. Of those receiving a first Taxane agent for mCRPC (n = 20), only 35% had a PSA50 response, with median PFS of 4.0 (95% CI 2.6–5.3) mo. Eleven men received a PARP inhibitor (10 Olaparib, 1 Rucaparib): none had a PSA50 response, and median PFS was 3.6 (95% CI 3.0–4.2) mo. Eight men received a PD1 inhibitor as 4th to 6th-line mCRPC therapy (5 Pembro, 3 Nivo): 38% had a PSA50 response, and median PFS was 6.6 (95% CI 2.3–10.8) mo. Conclusions CDK12-altered prostate cancer is an aggressive subtype presenting at young age, with high Gleason grade, and often with de novo M1 disease at diagnosis. Outcomes to hormonal and taxane therapies are poor, and PARP inhibitors are also ineffective. A proportion of these patients respond favorably to PD1 inhibitors, implicating CDK12 deficiency in immunotherapy responsiveness. Legal entity responsible for the study Emmanuel S. Antonarakis. Funding Has not received any funding. Disclosure E.S. Antonarakis: Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Research grant / Funding (institution): Dendreon; Advisory / Consultancy, Research grant / Funding (institution): Medivation; Advisory / Consultancy: ESSA; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Clovis; Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): Johnson & Johnson; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Eli Lilly; Licensing / Royalties: Qiagen. N. Agarwal: Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Argos; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Clovis; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy, Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy: Foundation One; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Medivation; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Nektar; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): Calithera; Research grant / Funding (institution): Celldex. B.L. Maughan: Advisory / Consultancy: Peloton Therapeutics; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Tempus; Advisory / Consultancy: Bayer; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Janssen; Advisory / Consultancy: Astellas. M. Hussain: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Research grant / Funding (institution): Genentech; Honoraria (self): Sanofi Genzyme; Honoraria (self): Research To Practice; Honoraria (self): Aptitude Health; Honoraria (self): Epics. All other authors have declared no conflicts of interest.