Evaluating immune checkpoint blockade in metastatic castration-resistant prostate cancers with deleterious CDK12 alterations in the phase 2 IMPACT trial Journal Article
| Authors: | Nguyen, C. B.; Reimers, M. A.; Perera, C.; Abida, W.; Chou, J.; Feng, F. Y.; Antonarakis, E. S.; McKay, R. R.; Pachynski, R. K.; Zhang, J.; Reichert, Z. R.; Palmbos, P. L.; Caram, M. E. V.; Vaishampayan, U. N.; Heath, E. I.; Hopkins, A. C.; Cieslik, M. P.; Wu, Y. M.; Robinson, D. R.; Baladandayuthapani, V.; Chinnaiyan, A. M.; Alva, A. S. |
| Article Title: | Evaluating immune checkpoint blockade in metastatic castration-resistant prostate cancers with deleterious CDK12 alterations in the phase 2 IMPACT trial |
| Abstract: | Purpose: CDK12 inactivation in metastatic castration-resistant prostate cancer (mCRPC) may predict immunotherapy responses. This phase 2 trial evaluated the efficacy of immune checkpoint inhibitor (ICI) therapy in patients with CDK12-altered mCRPC. Patients and Methods: Eligible patients had mCRPC with deleterious CDK12 alterations and any prior therapies except ICI. Cohort A received ipilimumab (1 mg/kg) with nivolumab (3 mg/kg) every 3 weeks for up to four cycles, followed by nivolumab 480 mg every 4 weeks. Cohort C received nivolumab alone 480 mg every 4 weeks. Patients with CDK12-altered nonprostate tumors were enrolled in cohort B and not reported. The primary endpoint was a 50% reduction in PSA (PSA50). Key secondary endpoints included PSA progression-free survival, overall survival, objective response rate, and safety. Results: PSA was evaluable in 23 patients in cohort A and 14 in cohort C. Median lines of prior therapy were two in cohorts A and C, including any prior novel hormonal agent (74% and 79%) and chemotherapy (57% and 36%). The PSA50 rate was 9% [95% confidence interval (CI), 1%–28%] in cohort A with two responders; neither had microsatellite instability or a tumor mutational burden >10 mutations/megabase. No PSA50 responses occurred in cohort C. Median PSA progression-free survival was 7.0 months (95% CI, 3.6–11.4) in cohort A and 4.5 months (95% CI, 3.4–13.8) in cohort C. Median overall survival was 9.0 months (95% CI, 6.2–12.3) in cohort A and 13.8 months (95% CI, 3.6–not reached) in cohort C. Conclusions: There was minimal activity with ICI therapy in patients with CDK12-altered mCRPC. © 2024 American Association for Cancer Research. |
| Keywords: | adult; aged; aged, 80 and over; middle aged; overall survival; missense mutation; mutation; prednisone; clinical trial; fatigue; mortality; diarrhea; drug safety; drug withdrawal; hepatitis b; hepatitis c; chemotherapy; nuclear magnetic resonance imaging; antineoplastic agent; anorexia; prostate specific antigen; ipilimumab; metastasis; progression free survival; computer assisted tomography; phase 2 clinical trial; nausea; vomiting; antineoplastic combined chemotherapy protocols; cohort analysis; pathology; transcriptomics; tumor marker; abdominal pain; arthralgia; dizziness; pruritus; prostate-specific antigen; maculopapular rash; blood; immunotherapy; microsatellite instability; neoplasm metastasis; human immunodeficiency virus; drug therapy; cyclin-dependent kinases; cyclin dependent kinase; androgen deprivation therapy; disease exacerbation; castration resistant prostate cancer; progression-free survival; abiraterone; immune checkpoint inhibitor; high throughput sequencing; enzalutamide; nivolumab; very elderly; humans; human; male; article; prostatic neoplasms, castration-resistant; immune checkpoint inhibitors; biomarkers, tumor; cdk12 protein, human; cdk12 alteration |
| Journal Title: | Clinical Cancer Research |
| Volume: | 30 |
| Issue: | 15 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2024-08-01 |
| Start Page: | 3200 |
| End Page: | 3210 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-24-0400 |
| PUBMED: | 38787530 |
| PROVIDER: | scopus |
| PMCID: | PMC11293970 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
