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Prostate Cancer Patients With CDK12 Mutations May Respond to Immunotherapy, Study Finds

NEW YORK – CDK12-mutated prostate cancer is an aggressive subtype of the disease that usually yields poor outcomes to hormonal therapy, taxane therapy, and PARP inhibitors.

However, according to a study published this week in the JCO Precision Oncology, a portion of these patients could potentially respond to PD-1 inhibitors.

CDK12 codes for a tumor suppressor protein that plays a role in genomic stability. In prostate cancer, CDK12 mutations occur in 5 percent to 7 percent of patients with metastatic castrate-resistant prostate cancer and are found in 1 percent to 4 percent of other cancer types.

The retrospective study, led by Emmanuel Antonarakis of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, looked at 60 advanced prostate cancer patients who had somatic loss-of-function CDK12 mutations, aiming to assess the clinical features associated with the molecular subtype and to match up their responses to different cancer treatments.

The researchers combed through nine academic medical centers' tumor genomic databases in search of cases with the pathogenic CDK12 mutations and pulled the clinical data of patients whose tumors contained the mutation from corresponding electronic health records. Then, they determined prostate-specific antigen levels associated with treatment response and progression-free survival for each type of therapy patients were on.

Researchers looked to see if other genetic mutations occurred alongside CDK12 mutations and found that CDK12 mutations and mutations in ERG, TP52, PTEN/PIK3CA, and SPOP were mutually exclusive. The researchers characterized this group as a potentially "distinct genomic subclass."

Moreover, there was evidence that CDK12-mutated tumors may be enriched by non-BRCA2/ATM homologous recombination deficiency mutations. In patients with CDK12 alterations, 18.3 percent also harbored a concurrent homologous recombination deficiency mutation such as CHEK2, FANCA, ATR, BARD1, and BRIP1.

In the 59 patients who were given first-line androgen deprivation therapy with or without upfront docetaxel or abiraterone, PSA response rates were 79.7 percent, though around 20.3 percent had primary hormonal resistance to therapy. The median progression-free survival for these patients was 12.3 months.

In the 34 patients who received initial treatment with abiraterone or enzalutamide, 41.2 percent had a PSA response, and the median progression-free survival was 5.3 months.

In the 22 patients who received initial treatment with taxane therapy, 31.8 percent had a PSA response and the median progression-free survival was 3.8 months.

Researchers noted that patients with CDK12 mutations appear to have short responses to primary androgen deprivation therapy and first-line treatment with abiraterone and enzalutamide. "These patients could account for a large proportion of the innate resistance to these hormonal agents, and should prompt interrogation for CDK12 mutations in those without responses to primary or secondary hormonal therapies," the authors wrote. "Collectively, these data suggest that alternative systemic therapies are urgently needed for CDK12-deficient prostate cancers."

The team also looked at the responses of patients who were prescribed off-label therapies such as PARP inhibitors and PD-1 inhibitors. No meaningful clinical activity was observed in patients treated with PARP inhibitors. In the 11 patients who were treated with a PARP inhibitor like olaparib (AstraZeneca's Lynparza) or rucaparib (Clovis Oncology's Rubraca), none had PSA responses, and the median progression-free survival was 3.6 months. All but two patients progressed on the PARP inhibitors at last follow-up.

Nine patients were treated with a PD-1 inhibitor such as pembrolizumab (Merck's Keytruda) or nivolumab (Bristol-Myers Squibb's Opdivo) as a fourth- to sixth-line therapy. Among these patients, 56 percent remained on PD-1 inhibitor therapy for more than six months. Of the nine patients, three achieved a PSA response, and the median progression-free survival was 5.4 months.

All three patients who responded had their response within the first 12 weeks of PD-1 inhibitor treatment. One patient had a complete response, defined by PSA levels less than 0.1 ng/mL. Two of the three responding patients remained progression free for 15.1 months and 7.2 months. Researchers found these responses to be clinically meaningful, especially as these therapies were applied in fourth or later-line treatments.

"These data suggest that CDK12 inactivation might be implicated in immunotherapy sensitivity, as hypothesized on the basis of the large number of gene fusion-induced neoantigens predicted to occur in these cancers," the authors concluded.