Combined results of two parallel phase II studies reported in JAMA Oncology by Milind Javle, MD, and colleagues indicated that olaparib may have therapeutic value in previously treated patients with platinum-sensitive pancreatic ductal carcinoma with DNA damage repair (DDR) genetic alterations other than germline BRCA pathogenic variants.
As stated by the investigators, “The subtype of pancreatic ductal adenocarcinoma DDR deficiency from BRCA1/2 variants has a favorable prognosis and is sensitive to platinum analogues and [PARP] inhibition with olaparib. Approximately 10% to 20% of patients with pancreatic ductal adenocarcinoma have DDR genetic alterations other than germline BRCA variants. This population has been termed as having BRCAness.”
Milind Javle, MD
The parallel studies included 46 patients enrolled between November 2016 and October 2018 at The University of Texas MD Anderson Cancer Center and Sheba Medical Center, Tel Hashomer, Israel. Patients had to have received one or more prior systemic therapy for advanced pancreatic ductal adenocarcinoma and had to have no germline BRCA1/2 variants. BRCAness in the studies was defined as previously known DDR genetic alterations, personal or family history of BRCA-associated cancers (without DDR genetic alterations), or ATM protein loss determined by immunohistochemistry.
Patients received olaparib at 300 mg twice daily until disease progression or unacceptable toxicity.
Overall, 24 patients had DDR genetic alterations, 17 had family history of BRCA-associated cancers without DDR genetic alterations, and 5 had ATM loss. DDR genetic alterations included ATM (n = 14), PALB2 (n = 2), ARID1A (n = 3), somatic BRCA (n = 1), PTEN (n = 1), RAD51 (n = 1), CCNE (n = 1), and FANCB (n = 2).
The median treatment duration with olaparib was 3.0 months (interquartile range [IQR] = 1.8–6.4 months). Median follow-up among censored patients was 7.4 months (IQR = 4.4–16.8 months).
Partial response was observed in two patients (4%), with response conformed in one (2%); the responses were observed in one patient with PALB2 and another with a somatic ATM variant. The response duration for the patient with confirmed response was 3.9 months. Stable disease was observed in 33 patents (72%), with a duration lasting longer than 4 months in 11 (24%).
Median progression-free survival among all patients was 3.7 months (95% confidence interval [CI] = 2.9–5.7 months). Median progression-free survival was significantly prolonged among patients with DDR genetic alterations (5.7 months, 95% CI = 3.6–8.8 months) vs those with family history alone (1.9 months, 95% CI = 1.8–4.7 months; P = .008) and significantly prolonged among 34 patients with platinum-sensitive disease (4.1 months, 95% CI = 3.6–7.8 months) vs 10 with platinum-resistant disease (2.2 months, 95% CI = 1.8 months–not reached; P = .01).
Median overall survival among all patients was 9.9 months (95% CI = 7.6–16.1 months).
Patients with DDR genetic alterations had numerically but not significantly prolonged median overall survival (13.6 months, 95% CI = 9.7 months–not reached) vs those with ATM protein loss or family history. Patients with platinum-sensitive disease had prolonged survival vs those with platinum-resistant disease (median = 10.5 vs 5.4 months, P = .03).
The most common adverse events of any grade were fatigue (23 patients, grade 3 in 1), nausea (22 patients, all grade 1–2), anemia (16 patients, grade 3 in 5), and anorexia (11 patients, all grade 1). No grade 4 adverse events were observed. Adverse events led to discontinuation of treatment in one patient.
The investigators concluded, “The definition of the BRCAness phenotype in pancreatic ductal adenocarcinoma may be limited to patients harboring DDR genetic alterations. In these two phase II nonrandomized clinical trials, olaparib was well tolerated and showed limited antitumor activity in patients with advanced, platinum-sensitive pancreatic ductal adenocarcinoma with DDR genetic alterations. These conclusions suggest a potential therapeutic opportunity for a subset of patients with pancreatic ductal adenocarcinoma.”
Talia Golan, MD, of the Oncology Institute, Sheba Medical Center, Tel Hashomer, is the corresponding author for the JAMA Oncology article.
Disclosure: The studies were funded by AstraZeneca. For full disclosures of the study authors, visit jamanetwork.com.