Extreme Responses to a Combination of DNA-Damaging Therapy and Immunotherapy in CDK12-Altered Metastatic Castration-Resistant Prostate Cancer: A Potential Therapeutic Vulnerability

• Pathogenic alterations in CDK12 can be identified in 3% to 7% of patients with metastatic castration-resistant prostate cancer (mCRPC). Inactivation of CDK12 results in perturbation of parts of the homologous recombination repair system, DNA replication control, and chromosome alignment. Ultimately, cells become more sensitive to genomic damage and accumulate a greater load of rearrangement-induced neoantigens. For this reason, CDK12 alterations have been associated with an improved response to immunotherapy. Nevertheless, further data showed only modest responses. Therefore, there is an unmet need of treatments for this subset of patients. It has been hypothesized that treatments that induce DNA double-strand breaks, such as bipolar androgen therapy (BAT) or radium-223, may modify the immune microenvironment, priming an immunological response with the use of subsequent immunotherapy. We describe 2 cases of mCRPC patients who harbored CDK12 genomic alterations, and presented exceptional responses to DNA-damaging therapies (BAT and radium-223) after or in combination with immunotherapy (nivolumab and sipuleucel-T). We postulate that these DNA-damaging therapies (BAT and Radium-223) caused an immunological priming effect, generating a more favorable environment for the action of immunotherapy. These data may stimulate future studies with these combinations in patients with CDK12 inactivation.