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

Non-BRCA DNA Damage Repair Gene Alterations and Response to the PARP Inhibitor Rucaparib in Metastatic Castration-Resistant Prostate Cancer: Analysis From the Phase II TRITON2 Study

“…In TOPARP-B, no radiographic or PSA responses were observed in the 20 patients with a CDK12 alteration (6). Similarly, in a recent retrospective study, none of 11 men with CDK12-altered advanced prostate cancer had a radiographic or PSA response to PARP inhibitor treatment (29). In PROfound, median radiographic PFS in patients with a CDK12 alteration was longer with olaparib than with enzalutamide or abiraterone, although the statistical significance of this finding is unclear (8).…”

Long-Term Disease Control Using Taxane/Platinum-Based Chemotherapy in CDK12-Mutated Advanced Prostate Cancer

“…Early data suggest the possibility of immune-responsiveness to program death ligand inhibition in some patients, possibly because of increased neoantigens [1,[3][4][5]. Our patient was subsequently treated with pembrolizumab but had no response.…”

“…Three retrospective data sets report the outcomes in CDK12 somatic mutation patients [3–5], and one of these [3] made reference to platinum use. Reimers et al [3] retrospectively assessed the outcomes of 46 men with CDK12 ‐variant prostate cancer.…”

PARP inhibitors in prostate cancer: time to narrow patient selection?

“…While these CDK12-altered mCRPC patients do not generally respond to PARPi as outlined above, a subset may have favorable responses to PD-1 inhibitors such as pembrolizumab or nivolumab. The percentage of such patients that derive clinical benefit from a PD-1 inhibitor is somewhere in the 20-40% range [17,18], which is on par with the response rate to immune checkpoint inhibitors in prostate cancer patients with mismatch repair (MMR) deficiency [19,20]. Therefore, both MMR mutations and CDK12 mutations seem to be more predictive of benefit to PD-1 blockade rather than PARP inhibition [21].…”