CDK12-Altered Prostate Cancer: Clinical Features and Therapeutic Outcomes to Standard Systemic Therapies, Poly (ADP-Ribose) Polymerase Inhibitors, and PD-1 Inhibitors

Abstract

PURPOSE In prostate cancer, inactivating CDK12 mutations lead to gene fusion–induced neoantigens and possibly sensitivity to immunotherapy. We aimed to clinically, pathologically, and molecularly characterize CDK12-aberrant prostate cancers. METHODS We conducted a retrospective multicenter study to identify patients with advanced prostate cancer who harbored somatic loss-of-function CDK12 mutations. We used descriptive statistics to characterize their clinical features and therapeutic outcomes (prostate-specific antigen [PSA] responses, progression-free survival [PFS]) to various systemic therapies, including sensitivity to poly (ADP-ribose) polymerase and PD-1 inhibitors. RESULTS Sixty men with at least monoallelic (51.7% biallelic) CDK12 alterations were identified across nine centers. Median age at diagnosis was 60.5 years; 71.7% and 28.3% were white and nonwhite, respectively; 93.3% had Gleason grade group 4-5; 15.4% had ductal/intraductal histology; 53.3% had metastases at diagnosis; and median PSA was 24.0 ng/mL. Of those who underwent primary androgen deprivation therapy for metastatic hormone-sensitive disease (n = 59), 79.7% had a PSA response, and median PFS was 12.3 months. Of those who received first-line abiraterone and enzalutamide for metastatic castration-resistant prostate cancer (mCRPC; n = 34), 41.2% had a PSA response, and median PFS was 5.3 months. Of those who received a first taxane chemotherapy for mCRPC (n = 22), 31.8% had a PSA response, and median PFS was 3.8 months. Eleven men received a PARP inhibitor (olaparib [n = 10], rucaparib [n = 1]), and none had a PSA response (median PFS, 3.6 months). Nine men received a PD-1 inhibitor as fourth- to sixth-line systemic therapy (pembrolizumab [n = 5], nivolumab [n = 4]); 33.3% had a PSA response, and median PFS was 5.4 months. CONCLUSION CDK12-altered prostate cancer is an aggressive subtype with poor outcomes to hormonal and taxane therapies as well as to PARP inhibitors. A proportion of these patients may respond favorably to PD-1 inhibitors, which implicates CDK12 deficiency in immunotherapy sensitivity.

Characterizing CDK12-Mutated Prostate Cancers

“…We also show that PCa with CDK12 biallelic alterations associate with higher Gleason scores and shorter survival from diagnosis, although we did not observe any differences in outcome on abiraterone/enzalutamide which has been previously reportedmaybe due to the retrospective nature of our investigation [29,30].…”

“…We also show for the first time that PCa with biallelic CDK12 aberrations are predominantly enriched for CD4 + FOXP3cells with these tumors surprisingly not having [32,33], with some of these cells being reported to express high PD-1 (4PD1hi) and being able to inhibit cytotoxic T cell function in a PD-1/PD-L1 dependent fashion as well as limit immunotherapy antitumor activity [32]. The data herein suggest that CD4 + FOXP3cells, which CDK12-altered PCa seem to be enriched for, might have an immunosuppressive role, associating with worse survival and might be relevant to immunotherapy trials as a biomarker of interest [30,[34][35].…”

“…A subset of mCRPC has deleterious CDK12 aberrations [16,27,28], resulting in characteristic genomic profiles with innumerable focal tandem duplications, gene-fusions, and neoantigens [16,27]. These PCa CDK12 alterations, like MMRd, have been postulated to represent a predictive biomarker of response to immunotherapy [17], making their study of huge interest [29,30]. Our analysis is arguably one of the largest integrated efforts interrogating their genomic, pathologic, and clinical characteristics and also investigating their TIL landscape.…”

Current Status and Future Perspectives of Checkpoint Inhibitor Immunotherapy for Prostate Cancer: A Comprehensive Review

“…A recently conducted multicenter trial in patients with advanced PCa with loss of function CDK12 mutations evaluated the efficacies of the poly (ADP-ribose) polymerase and PD-1 inhibitors. Three of eight (38%) patients with CDK12-mutated mCRPC had a significant PSA decline, with a median PFS of 6.6 months [93]. The ongoing IMPACT (NCT03570619) trial is investigating whether this subtype of mCRPC is more susceptible to a combination of ICIs consisting of ipilimumab and nivolumab followed by nivolumab monotherapy [94].…”

Novel therapies are changing treatment paradigms in metastatic prostate cancer

“…Another retrospective multicenter study identified 60 patients with at least monoallelic CDK12 alterations. In this series, nine patients who had CDK12 alterations were treated with either pembrolizumab or nivolumab, of whom 33.3% (3/9) had a PSA response and a median PFS of 5.4 months [ 87 ]. This suggests CDK12 deficiency contributes to impaired HRR and has been shown to associate with immunotherapy response.…”