A recent study from the University of Michigan Rogel Cancer Center has uncovered why about one-third of advanced prostate cancer patients do not respond to standard hormone-based therapies.
These findings may open the door to earlier use of chemotherapy and new targeted treatments for patients at highest risk.
Researchers analyzed RNA sequencing data and clinical outcomes from multiple prostate cancer trials. They discovered a distinct genetic signature—dubbed the ARPI extreme non-response program—linked to patients who fail to benefit from androgen receptor pathway inhibitors (ARPIs) like enzalutamide. These patients, termed “extreme non-responders,” often experience rapid disease progression and shorter survival times.
“This subgroup of patients doesn’t get the intended benefit from standard ARPI drugs, which are usually quite effective in many men,” said the study’s authors in a statement. “Identifying them early could allow us to shift treatment strategies sooner.”
The study, published in npj Precision Oncology, found that docetaxel, a chemotherapy drug already approved for prostate cancer, may be effective if used earlier in those with this genetic signature—rather than waiting until other therapies fail.
The team also pinpointed a potential new target: a kinase known as CDK2, which helps regulate the ARPI resistance program. Laboratory tests showed that inhibiting CDK2 reduced tumor growth in cancer samples with the extreme non-responder signature. CDK2 inhibitors are currently being tested in clinical trials for other cancers, but the researchers believe they may hold promise for aggressive prostate cancers as well.
Experts say the findings highlight the importance of tailoring treatment to individual patients. “With more precision, we can guide patients toward therapies that offer the best chance of success—and spare them ineffective treatments,” the researchers noted.
Future work will focus on validating CDK2 inhibitors in clinical settings and developing tests to identify patients with the extreme ARPI non-response signature early in their treatment journey.
Related topics:
