CDK12 Defects Are an Indicator for the Effectiveness of PARP Inhibitors in mCRPC

Looking at the use of circulating tumor DNA (ctDNA) tests as a predicative means of testing in patients with metastatic castration-resistant prostate cancer (mCRPC) researchers found a slightly higher alteration frequency of CDK12 in their cohort of patients with mCRPC. According to research published in the official Journal of the National Comprehensive Network, this frequency indicated that patients with a CDK12 mutation had a sensitivity to immune checkpoint inhibitors.

In an analysis of 292 patients with mCRPC from China researchers performed multiple next generation sequencing (NGS) tests on patients who previously exhibited progression-free survival (PFS) on treatment for mCRPC and found that with patients treated with abiraterone (n = 58) who had a CDK12 defect had a significant PFS (P < .001). In comparison, in a group treated with docetaxel (n = 68) researchers did not see significant PFS after a univariate analysis, which highlighted that identifying patients with the CDK12 defect could lead to better results on a therapy like abiraterone. However, looking at somatic alterations of CDK12 researchers found an association with abiraterone and saw that patients with CDK12 defects were associated with a shorter PFS after abiraterone treatment (1.6 vs 10.4 months; P = .001). Moreover, only 1 of 7 patients with CDK12 defects achieved a PSA response.

Looking at the 292 patients with mCRPC somatic and deleterious germline alterations were identified in 201 patients, and of those patients 43.2% of the patients carried alterations of homologous recombination repair (HRR) genes and 6.85% harbored alterations in mismatch repair genes, the researchers wrote. CDK12 was the most altered HRR genes, and 15.4% alterations were exclusively somatic events, whereas alterations in BRCA2 (13%) and ATM (7.5%) were either germline or somatic events.

“Our data support that CDK12 had a predictive role in (patients with) mCRPC’s response to multiple treatments, including abiraterone and docetaxel chemotherapy,” the researchers wrote. “CDK12 defects were associated with worse efficacy after abiraterone treatment, whereas the clinical outcome after docetaxel treatment was similar between patients with and without CDK12 defects.”

Previously, researchers have looked at how CDK12 defects can highlight increased susceptibility to PARP inhibitors, like abiraterone, because CDK12-mutated prostate cancer had different molecular characteristics with aggressive clinical behaviors. This is because CDK12 functions in DNA transcription and RNA splicing, which regulates DDR genes involved in HRR. On the other hand, the researchers found that DDR-associated prostate cancer had impressive responses to platinum-based chemotherapy.

Of 7 patients who experienced a PSA response 6 of them (85.7%) had deleterious alterations in DDR genes and 3 had somatic BRCA2 defects. Of the 8 patients who had no PSA decline, 7 had no detectable alteration of DDR genes and researchers found PFS after platinum-based chemotherapy in patients with DDR defects was significantly longer than in those without a DDR defect.

Of 19 patients sequenced before platinum-based chemotherapy, 3 patients discontinued treatment after 1 cycle of cisplatin or carboplatin chemotherapy because of serious adverse effects. But of 16 patients 8 showed deleterious alterations in DDR genes and PSA changes at 12 weeks. Of the 8 patients with a DDR defect, 7 (87.5%) had a PSA decline, which included 1 patient with a CDK12 defect, and 6 patients (75%) had a PSA decline greater than 50%. In the 8 patients who had no PSA decline, only 1 patient harbored an ERCC3 alteration and the remaining 7 had no detectable alteration of DDR genes.

The median PFS in patients with a DDR gene defect was significantly longer than for those without a DDR gene defect on a platinum-based chemotherapy, 12 vs 2 months, respectively (P = .002). Patients with BRCA2 defects had a median PFS of 12 months (95% CI, 11.0–not available), compared to 13 months in patients with other DDR defects, and 2.0 months in those with no DDR defect (P = .008).

“Our results suggest that not all DDR gene defects are equally predictive of a PARP inhibitor response. Patients with BRCA2 defects experienced superior outcomes compared with those with other DDR defects, which is consistent with previous reports,” the researchers concluded. “This finding suggests that when considering PARP inhibitor treatment in patients with mCRPC, it is necessary to carefully examine the established functional association of changes in DDR genes, especially in genes other than BRCA2.”

_References

_{Dong B, Fan L, Yang B, et al. Use of Circulating Tumor DNA for the Clinical Management of Metastatic Castration-Resistant Prostate Cancer: A Multicenter, Real-World Study. J Natl Compr Canc Netw. 2021 May 14:1-10. doi: 10.6004/jnccn.2020.7663}