Treatment with poly–(adenosine diphosphate–ribose) polymerase (PARP) inhibitor olaparib was well tolerated and demonstrated limited antitumor activity in patients with advanced, platinum-sensitive pancreatic ductal adenocarcinoma cancer (PDAC) with deoxyribonucleic acid damage repair (DDR) genetic alterations (GAs) other than germline breast cancer (BRCA) variants, according to research published in JAMA Oncology.

The 2 studies, conducted between 2016 and 2018, examined the efficacy of olaparib monotherapy in 46 patients (mean age, 65.5 years) with advanced, previously treated PDAC with “BRCAness” from Israel and the United States. Patients in these studies had previously been treated with at least 1 systemic therapy, and all patients lacked the germline BRCA 1/2 variant. In these studies, BRCAness was defined as previous DDR-GA, familial or personal history of BRCA-associated cancers, or ataxia telangiectasia mutated (ATM) protein loss.

The overall median duration of olaparib treatment was 3.0 months. In terms of safety, the most common toxic effects associated with therapy were grade 1 to 2 fatigue, anorexia, anemia, leukopenia, and nausea. Only 1 patient had a confirmed partial response (3.9 months), while 72% of patients had stable disease (SD). A total of 11 patients (24%) with SD had disease stability for >4 months, and 12 patients (26%) experienced progressive disease.


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The median duration of progression-free survival (PFS) was 3.7 months (95% CI, 2.9-5.7 months), which was significantly longer in patients with DDR-GAs compared with patients enrolled based on only family history (5.7 months; 95% CI, 3.6-8.8 months vs 1.9 months; 95% CI, 1.8-4.7 months, respectively; P =.008). The median PFS was also longer in patients with platinum-sensitive vs platinum-resistant PDAC (4.1 months; 95% CI, 3.6-7.8 months vs 2.2 months; 95% CI, 1.8 months to not reached (NR), respectively; P =.01).

The estimated median overall survival, an additional secondary endpoint, was 9.9 months (95% CI, 7.6-16.1 months) in the study cohort and 13.6 months (95% CI, 9.7 months to NR) in a DDR-GA cohort.

Limitations of these studies included the small overall sample sizes as well as the lack of randomized control arms.

While the findings from these studies “suggest a potential therapeutic opportunity for a subset of patients with PDAC,” the investigators concluded that additional “randomized clinical trials will be required to confirm the benefit of PARP inhibitors in this population.”

Disclosure: This clinical trial was supported by AstraZeneca. Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference:

Javle M, Shacham-Shmueli E, Xiao L, et al. Olaparib monotherapy for previously treated pancreatic cancer with DNA damage repair genetic alterations other than germline BRCA variants: findings from 2 phase 2 nonrandomized clinical trials. JAMA Oncol. Published online March 4, 2021. doi:10.1001/jamaoncol.2021.0006