Signal for Immunotherapy Benefit Seen in mCRPC With CDK12 Loss

Ajjai S. Alva, MBBS

Immunotherapy shows potential for treating a subset of patients with metastatic castration-resistant prostate cancer (mCRPC) harboring CDK12 loss, according to early results from the phase 2 IMPACT trial (NCT035710619).¹

Ajjai S. Alva, MBBS, explained in a presentation during the 28th Annual Prostate Cancer Foundation Scientific Retreat that CDK12 is a cell cycle gene that has an important role in RNA polymerase 2 and immunotherapy activity. He added that CDK12 loss is more common in metastatic and more advanced forms of prostate cancer.²

CDK12 inactivation or loss has been suggested to be a distinct molecular subtype of prostate cancers characterized by genomic instability resulting in increased gene fusions. As a result of the gene fusions, the CDK12 prostate cancer subtype shows elevated neoantigen burden. These features suggest a potential increased sensitivity to immunotherapy agents.²

Investigators showed that compared with other molecular subtypes, CDK12- mutant prostate cancer represents an aggressive subtype, with a shorter time to metastasis and shorter time to castration-resistant disease than other tested subtypes.³

Investigators initiated the prospective IMPACT trial to look at the use of immunotherapy in patients with metastatic cancers, including CRPC, and CDK12 mutations.¹ This was the first precision genomic-selected immunotherapy study in mCRPC, according to Alva, a clinical associate professor of medical oncology, and hematology at University of Michigan Health in Ann Arbor.

The trial enrolled patients with CDK12 loss confirmed by next-generation sequencing, and these patients were enrolled into 1 of 3 cohorts. Cohort A consisted of patients with mCRPC who were treated with the combination of nivolumab (Opdivo) 3 mg/kg intravenously (IV) and ipilimumab (Yervoy) 1 mg/kg IV every 3 weeks followed by nivolumab monotherapy at 480 mg IV every 4 weeks for up to 92 additional weeks with restaging every 12 weeks. Cohort B consisted of patients with nonprostate solid tumors who were similarly treated with the combination followed by nivolumab. In cohort C, patients with mCRPC were treated with nivolumab monotherapy at 480 mg IV every 4 weeks for up to 52 weeks.

Alva focused on the patients in cohort A, in which the primary end point was overall response rate (ORR), as measured by prostate-specific antigen (PSA) level decline by 50% from baseline.

For patients treated with at least 1 dose in cohort A (n = 33), the median age was 68 years (range, 51-83). Seventy-three percent of patients were White and 18% were Black. Most patients had an ECOG performance status of 1 (range, 0-2). The most common sites of metastases were the bone and lymph nodes. The Gleason score was 9 for 45% of patients, and baseline PSA levels were high in most patients.

Fifty-two percent of patients underwent prostatectomy and less than half of patients received radiation for curative (30%) or palliative intent (27%). Prior therapies consisted of abiraterone (Zytiga) in 61%, docetaxel in 55%, enzalutamide (Xtandi) in 45%, and bicalutamide in 36%, most commonly.

Among 23 evaluable patients thus far, the ORR was 17.39%, and 21.73% of patients showed PSA declines of 30%. Two additional patients are still on therapy in earlier cycles, and the remainder stopped treatment earlier due to toxicity or withdrawal of consent.

“While these [data] are very comparable to immunotherapy efficacy in other solid tumors, [the efficacy is] perhaps not as high as with combination [immunotherapy] in other cancers—more immune-sensitive cancers, like kidney cancer—it’s certainly higher than in wild type and non-MMRd [mismatch repair deficient] prostate populations,” Alva commented.

He also compared the response rates with that of the CheckMate 650 trial (NCT02985957), which also explored the use of nivolumab plus ipilimumab, although at different dosages in patients with mCRPC. The trial showed a lower response rate with the combination of 25% in patients who had not received prior chemotherapy and 10% in patients who had received chemotherapy.⁴

Alva noted that in the IMPACT trial there was a trend toward hyperprogression in a few of the patients,1 which has not typically been noted in prostate cancer before. “These patients had more than a 10-fold increase in PSA on therapy,” Alva said.

In 25 patients evaluable for safety, grade 1 or 2 adverse events (AEs) were reported that were possibly related to treatment (68% of patients), probably related to treatment (28%), or definitely related to treatment (12%). Grade 3 to 5 AEs were possibly related to treatment in 16% of patients. Serious grade 3 to 5 events were observed in 36% of patients.

The most common treatment-emergent AEs of any grade were fatigue in 14 patients, diarrhea/colitis in 11, and constipation in 10. A few of these events were considered immune-mediated.

Follow-up is ongoing in the study and the data are still incomplete. Alva noted that future research will look at treatment earlier on in the course of disease and in patients with confirmed biallelic loss.

_REFERENCES:

_{1. Alva A. Prospective assessment of immunotherapy in CDK12 loss mCRPC. Presented at 2021 Prostate Cancer Foundation Scientific Retreat; October 28-November 5, 2021; Virtual.}

_{2.Wu YM, Cieślik M, Lonigro RJ, et al. Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer. Cell. 2018;173(7):1770-1782.e14. doi:10.1016/j.cell.2018.04.034}

_{3.Reimers MA, Yip SM, Zhang L, et al. Clinical outcomes in cyclin-dependent kinase 12 mutant advanced prostate cancer. Eur Urol. 2020;77(3):333-341. doi:10.1016/j.eururo.2019.09.036}

_{4.Sharma P, Pachynski RK, Narayan V, et al. Nivolumab plus ipilimumab for metastatic castration-resistant prostate cancer: preliminary analysis of patients in the CheckMate 650 trial. Cancer Cell. 2020;38(4):489-499.e3. doi:10.1016/j.ccell.2020.08.007}