Investigative Approaches Seek to Enhance Outcomes for Patients With CDK12-Mutant mCRPC

Eric J. Small, MD

DNA damage homologous recombination repair (HRR) genotypic variants are not created equal. Patients with metastatic castration-resistant prostate cancer (mCRPC), whose disease harbors somatic mutations, including BRCA1, BRCA2, and ATM, have demonstrated response to PARP inhibitors such as olaparib (Lynparza) and rucaparib (Rubraca). However, for the approximately 5% of patients with CDK12 variants, outcomes have been limited.¹

Descriptive analyses have detailed the unique genomic profiles of tumors with CDK12 mutations.^2,3 For example, in an analysis of 4918 mCRPC tumors, 6.4% of samples were positive for CDK12 mutations. When investigators explored the genomic profiles of these tumors and compared them with the tumors of patients without CDK12 wild-type disease, differences were present. Among patients with CDK12 mutations, there were significantly fewer loss-of-function genomic alterations in TMPRSS2:ERG (P < .0001), TP53 (P < .0001), PTEN (P < .0001), ATM (P = .001), PIK3CA (P = .003), RB1 (P = .02), BRCA2 (P < .0001), and APC (P = .002).²

Investigators noted that the lower frequencies of these genomic alterations were associated with homologous recombination defect and the mTOR pathway, signaling that platinum agents, PARP inhibitors, and PIK3CA, AKT, or mTOR inhibitors may have efficacy for these patients.²

Significantly higher frequencies of CCND1 (P < .0001), BRAF (P = .007), and ERBB2 (P < .001) were reported among patients with CDK12 mutations in addition to higher frequency of cell regulatory genes MDM2/4 (P < .0001) and CDK6 (P = .002). Finally, investigators also observed that microsatellite instability–high status was more frequent in patients with CDK12 mutationpositive disease vs those without (6% vs 3%; P = .007). The median tumor mutational burden was the same between the cohorts at 2.5.

Finally, in terms of PD-L1 expression, low-positive expression (1%-49% staining) was more frequent among patients with CDK12 positive disease vs those without (18% vs 9%, respectively; P = .02). This finding signaled those patients with CDK12-positive disease may derive additional benefit from treatment with immune checkpoint inhibitors.²

Further expanding on this analysis, in a panel discussion presentation during the 2022 Genitourinary Cancers Symposium, Eric J. Small, MD, noted the limited efficacy of recently approved agents, including olaparib and rucaparib, for patients with CDK12 mutations.^4,5

Olaparib was approved for patients with HRR gene-mutated mCRPC based on data from the PROfound study (NCT02987543). The study included patients with BRCA1, BRCA2, and ATM mutations with progressive disease following treatment with an androgen-signaling inhibitor. Overall, results showed a significant advantage with olaparib (n = 162) compared with placebo (n = 83) with a radiographic progression-free survival (rPFS) of 7.4 months vs 3.6 months, respectively (HR, 0.35; 95% CI, 0.25-0.47; P < .001), overall survival of 19.4 months vs 14.7 months (HR, 0.69; 95% CI, 0.50-0.97; P = .02), and an overall response rate of 33% vs 2%.^6,7

Although the study was not designed to assess each individual variant type, patients with a CDK12 mutation experienced a narrower advantage with olaparib compared with all patients in cohort A of the study; the HR was 0.74 (95% CI, 0.44-1.33).

Similarly, in the phase 2 TRITON2 study (NCT02952534), which led to the approval of rucaparib,5 patients with BRCA alterations derived significant benefit with the targeted agent in both rPFS and prostate-specific antigen (PSA) responses. However, for patients with a cooccurring CDK12 mutation, no patients demonstrated an objective response to PARP inhibitor therapy.⁸

“CDK12 variants result in interesting observations: genomic instability, focal tandem duplications, and increased predictive neoantigens,” Small said. “This raises the question of the utility of checkpoint inhibitors.” Small, who is codirector of the urologic cancer service and a genitourinary oncologist at the University of California, San Francisco, added that small retrospective studies have shown early signals of efficacy with this approach and that prospective studies are needed to validate their use.

Results of a retrospective analysis by Antonarakis et al showed that among 11 men who had a CDK12 mutation and received a PARP inhibitor, none had a PSA response. However, among 9 men who received a PD-1 inhibitor in the fourth- to sixth-line setting, 33.3% had a PSA response, and median PFS was 5.4 months. Therapies included pembrolizumab (Keytruda; n = 5) and nivolumab (Opdivo; n = 4).⁹

The Future of Loss-Of-Function Mutations

Building on these data, investigators are seeking to harness the synergy of CDK4/6 inhibitors with anti–PD-1/PD-L1 agents for patients harboring the loss of function alterations of CDK12.¹

Investigators in a phase 2 trial (NCT04751929) will evaluate the efficacy of the CDK4/6 inhibitor abemaciclib (Verzenio) and atezolizumab (Tecentriq) in patients with mCRPC who have received at least 1 line of prior therapy with an antiandrogen in the hormone-sensitive or castration-resistant setting.^1,10 Patients must also be ineligible for taxane chemotherapy.

The study will primarily evaluate the dual inhibition among patients with unselected mCRPC. However, an exploratory single stage cohort will evaluate atezolizumab monotherapy and the investigational combination among those with loss of function mutations in CDK12. Estimated enrollment is 54 patients in the randomized portion and 21 patients in the exploratory cohort.

Patients in the primary analysis will be randomly assigned 1:1 to receive either abemaciclib monotherapy taken orally twice daily or intravenous atezolizumab administered on day 1 of a 21-day cycle plus abemaciclib in stage 1 of the trial schema. An interim efficacy analysis will be performed before enrollment continues for stage 2 of the trial. In the exploratory cohort, atezolizumab monotherapy will be administered to 5 patients who will undergo Bayesian toxicity monitoring. An additional 16 patients will be enrolled to receive the combination treatment. An on-treatment biopsy will be taken at 6 weeks and treatment will continue until disease progression or intolerance across the cohorts.

The coprimary end points of the unselected cohort include PFS at 6 months using Prostate Cancer Working Group 3 consensus guidelines and objective response rate. At least 1 of 12 planned patients must meet either end point to initiate stage 2 of the trial. Meaningful clinical activity across the trial will be defined as at least 6 of 17 total patients meeting the PFS end point or at least 5 patients meeting the objective response rate end point. In the selected cohort, an additional primary safety end point is incidence of dose-limiting toxicities in patients receiving the combination regimen. Secondary end points include clinical benefit rate, duration of response, and overall survival in the unselected cohort, and safety in all arms. Exploratory end points following tumor biopsy include comparison of FoxP3/CD8 ratio in patients who receive abemaciclib vs abemaciclib plus atezolizumab. Additional biopsy-directed end points include the association of response and genomic alterations identified from tissue or circulating tumor–derived exosomes.

The trial is open for enrollment.

References

1. Rao A, Kwak L, Reimers MA, et al. A phase II trial of abemaciclib (abema) and atezolizumab (atezo) in unselected and CDK12-loss metastatic castration resistant-prostate cancer (mCRPC). J Clin Oncol. 2022;40(suppl 6):TPS213. doi:10.1200/JCO.2022.40.6_ suppl.TPS213
2. Grivas P, Bratslavky G, Jacob JM, et al. Genomic landscape of CDK12 mutated metastatic castrate resistant prostate cancer. J Clin Oncol. 2021;39(suppl 6):165. doi:10.1200/JCO.2021.39.6_suppl.165
3. Rescigno P, Gurel B, Pereira R, et al. Characterizing CDK12-mutated prostate cancers. Clin Cancer Res. 2021;27(2):566-574. doi:10.1158/1078-0432.CCR-20-2371
4. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer. FDA. Updated May 20, 2020. Accessed August 23, 2022. bit.ly/3pJpJyW
5. FDA grants accelerated approval to rucaparib for BRCA-mutated metastatic castration-resistant prostate cancer. FDA. May 15, 2020. Accessed August 23, 2022. bit.ly/3Cu7sgE
6. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):20912102. doi:10.1056/NEJMoa1911440
7. Hussain M, Mateo J, Fizazi K, et al; PROfound Trial Investigators. Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med. 2020;383(24):2345-2357. doi:10.1056/ NEJMoa2022485
8. Abida W, Patnaik A, Campbell D, et al. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin Oncol. 2020;38(32):3763-3772. doi:10.1200/JCO.20.01035
9. Antonarakis ES, Velho PI, Fu W, et al. CDK12-altered prostate cancer: clinical features and therapeutic outcomes to standard systemic therapies, poly (ADP-Ribose) polymerase inhibitors, and PD-1 inhibitors. JCO Precis Oncol. 2020;4:370-381. doi:10.1200/ po.19.00399
10. Abemaciclib with or without atezolizumab for mCRPC. ClinicalTrials.gov. Updated September 21, 2021. Accessed August 24, 2022. https://clinicaltrials.gov/ct2/show/NCT04751929