Certain mutations in genes like CDK12 may cause prostate cancers to be more amenable to immune checkpoint inhibitor treatment. A subtype of metastatic castration-resistant prostate cancer with CDK12 variants has been identified that has high levels of neoantigens recognized by the immune system as foreign, as well as greater T-cell infiltration. These CDK12-variant prostate cancers may have higher response rates to PD-1 inhibitors than other genomic subtypes of prostate cancer. Pending clinical trial results, CDK12-variant prostate cancer may become the second defined tumor subtype able to be treated with PD-1 inhibitors.

1. HOW CYCLIN-DEPENDENT KINASE MAY GUIDE
CHECKPOINTINHIBITOR
USE IN ADVANCED PROSTATE CANCER PC
Certain cancer subtypes, particularly with DNA mismatch
repair mutations (MMR) are more amenable to anti-PD1
treatment. Only 2 to 5% of metastatic PCs have such defects.
Mutations/amplifications of CDK12 - an abundant enzyme
with pleiotropic roles e.g., DNA damage response, splicing,
and cellular differentiation - also contribute to cancer. Unlike
MMR-variants, CDK12-variant cancers are not
genomically unstable.
A CDK-12 variant mCRPC subclass has been identified that
may also benefit from immune checkpoint inhibitor treatment.
TUMOR GENOMIC STATUS MAY INFORM ANTI-PD /PD-L USE
Despite treatment advances and improved survival , PC
remains the 2nd-leading cause of cancer-related death
among American men. Metastatic PC is ultimately fatal
in most men. Hormone therapy is the mainstay of
treatment for systemic disease. Multiple molecular
mechanisms may cause hormone (castration)
resistance and cancer progression.
mCRPCs infrequently responds to immune checkpoint
inhibitors (e.g., anti-PD1), but recent discoveries may
expand the treatment landscape for select patients.
STRATEGY SUITED TO ADVANCED PC SUBCLASS
With the exception of MMR-variants, CDK12-variant
PCs had the highest neoantigen (mutated proteins
expressed on tumor surfaces and recognized by
immune system as 'non-self'), of all the known
molecular PC subtypes.
Similarly, CDK12-variant PCs have higher levels of
expanded T-cell clones and T-cell infiltration versus
other genomic PC subtypes. These tumors also had
increased levels of certain chemokines and receptors.
CDK -VARIANT PCs ENRICHED FOR NEOANTIGENS
Response rates for other cancers are higher with anti-
PD1 use versus advanced PC. The only molecular
determinant of PD-1-sensitivity is MMR-deficiency, but
these tumors are only 2 to 5% of all CRPCs. Thus far,
other molecular determinants for favorable responses
have remained elusive.
Pending clinical trial verification of preclinical data,
CDK12-variant PC may become the 2nd genomically
defined tumor subtype amenable to PD1 treatment.
~5- 5% OF ADVANCED PCs RESPOND TO ANTI-PD USE
CDK12 alterations are observed in many cancers,
including gastrointestinal, bladder, uterine, and ovarian
cancers. Other treatment combinations are feasible,
since CDK12 mediates DNA repair via homologous
recombination plus replication-associated repair e.g.,
adding PD-1 and PARP inhibitors. Maybe treatment with
a CDK12-inhibitor may induce sensitivities in PCs with a
wild-type CDK12 status.
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WHAT THE EXPERTS THINK ABOUT THE FUTURE
Abbreviations: PD-1 = programmed death 1; PARP = poly-ADP-ribose-polymerase;
mCRPC = metastatic castration-resistant prostate cancer
Sources: Antonarakis ES. Cyclin-Dependent Kinase 12, Immunity, and Prostate Cancer. N Engl J Med. 2018;379(11):1087-1089.
McVicar G: Prostate Cancer . Clinical Care Options (2017)