Combined PARP, ATR Inhibitors potent against prostate cancer with ATM loss

A fraction of patients with aggressive prostate cancer have ATM-deficient disease, and this subgroup appears to be most sensitive to the combination of oral drugs targeting PARP* and ATR**, according to a study.

“ATM restores replication fork topology and arrests cell cycle progression to permit repair,” the investigators pointed out. “In ATM-deficient cells, this protective mechanism is absent, precipitating DNA damage, mitotic catastrophe, senescence, and/or cell death.” [Cell Death Differ 2008;15:1153-1162]

Reports say that inactivated ATM can be synthetically lethal with ATR. Indeed, the experimental ATR inhibitor BAY1895344 demonstrated antitumour activity against ATM-deficient cancers in a first-in-human clinical trial. [Cancer Res 2020;80:2094-2100; Cancer Discov 2020;doi:10.1158/2159-8290.CD-20-0868]

On the other hand, there are two PARP inhibitors approved by the US Food and Drug Administration (FDA) for the treatment of metastatic castrate resistant prostate cancer (mCRPC), namely olaparib and rucaparib. Yet, studies have provided strong support to their use in BRCA2-mutated diseases only, and there is little for their benefit in ATM-deficient tumors. [Eur Urol 2019;76:452-458; Clin Cancer Res 2020;26:2487-2496]

“Our [examinations] indicate that combined PARP and ATR inhibition merits clinical trial evaluation in ATM-deficient prostate cancer and may be superior to either ATR or PARP inhibition alone, although careful dose- and schedule-finding phase I trials will be needed since both these drug classes cause haematological toxicity,” the investigators said.

In the study, they evaluated ATM status in 631 patients with advanced prostate cancer. They collected a total of 766 biopsy samples and subjected them to immunohistochemistry (IHC) and next-generation sequencing.

Sixty-eight patients (11 percent) were found to have ATM loss via IHC. Most biopsies that lacked ATM protein expression on IHC (46 of 71; 65 percent) had ATM mutations or deletions identified by sequencing. Yet, 23 of 61 patients (34 percent) identified as ATM-negative by IHC lacked a detected ATM gene sequence alteration. [Eur Urol 2020;doi:10.1016/j.eururo.2020.10.029]

ATM loss did not necessarily translate to worse outcome from advanced disease, but it was associated with increased genomic instability (NtAI:number of subchromosomal regions with allelic imbalance extending to the telomere, p=0.005; large-scale transitions, p=0.05).

Using in vitro cell line models with inactivated ATM, edited via the CRISPR gene tool, the investigators confirmed that ATM-loss prostate cancer models were sensitive to ATR inhibition, but had variable sensitivity to the PARP inhibitor.

Meanwhile, the combination of ATR and PARP inhibition yielded superior antitumour activity. These results were validated in a patient-derived model.

“The authors make a case that ATM-inactivated metastatic CRPC is more frequent than previously reported and that protein assays may be appropriate for patient stratification in clinical trials evaluating ATR inhibitors,” noted Dr David Quigley, from the University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, who was not involved in a study. [Cell 2015;161:1215-1228; Eur Urol 2020;doi:10.1016/j.eururo.2020.11.018]

“If protein assays emerge as a more reliable biomarker than targeted sequencing assays, it may be appropriate to re-evaluate the apparent lack of association between ATM alterations and PARP inhibitor efficacy, since the FDA approval is designed around diagnostic sequencing,” Quigley wrote in a linked editorial.

At the end of the day, however, it is not PARP inhibitors as monotherapy but rather their combination with ATR inhibitors that holds promise in the treatment of patients with lethal prostate cancer, he added.