Olaparib Monotherapy for Previously Treated Pancreatic Cancer With DNA Damage Repair Genetic Alterations Other Than Germline <i>BRCA</i> Variants
Authors: Milind Javle, Einat Shacham-Shmueli, Lianchun Xiao, Gauri Varadhachary, Naama Halpern, David Fogelman, Ben Boursi, Syeda Uruba, Ofer Margalit, Robert A. Wolff, Talia Golan
Journal: JAMA Oncology (2021)

<h3>Importance</h3> The subtype of pancreatic ductal adenocarcinoma cancer (PDAC) with DNA damage repair (DDR) deficiency from<i>BRCA1/2</i>variants has a favorable prognosis and is sensitive to platinum analogues and poly–(adenosine diphosphate–ripose) polymerase (PARP) inhibition with olaparib. Approximately 10% to 20% of patients with PDAC have DDR genetic alterations other than germline<i>BRCA</i>variants. This population has been termed as having BRCAness. An opportunity exists to define the clinical phenotype, molecular underpinnings, and effectiveness of PARP inhibitors for this population. <h3>Objective</h3> To examine the therapeutic effectiveness of the PARP inhibitor olaparib for patients with pancreatic cancer with BRCAness. <h3>Design, Setting, and Participants</h3> Two parallel phase 2 nonrandomized clinical trials were conducted from November 11, 2016, to October 2, 2018, among 46 patients in Israel and Texas to determine the effectiveness of olaparib as monotherapy in advanced, previously treated PDAC with BRCAness. Inclusion criteria were treatment with 1 or more prior systemic therapies for advanced PDAC, Eastern Cooperative Oncology Group performance status of 0 to 1, and lack of the germline<i>BRCA1/2</i>variant. BRCAness in these studies was defined as previously known DDR genetic alterations (DDR-GAs), personal or family history of<i>BRCA</i>-associated cancers (without DDR-GAs), or ATM protein loss as determined by immunohistochemistry. <h3>Main Outcomes and Measures</h3> The primary study end point was the objective response rate, and the secondary end points were progression-free survival and overall survival (OS). <h3>Results</h3> Forty-eight patients were enrolled, and 46 (26 women [57%]; mean [SD] age, 65.5 [11.1] years) were evaluable. The median treatment duration with olaparib was 3.0 months (interquartile range, 1.8-6.4 months). A total of 24 patients had the DDR phenotype (DDR-GAs), 17 had a family history of<i>BRCA</i>-associated cancers without DDR-GAs, and 5 had ATM loss as determined by immunohistochemistry. The DDR-GAs included<i>ATM</i>(n = 14),<i>PALB2</i>(n = 2),<i>ARID1A</i>(n = 3),<i>BRCA</i>somatic (n = 1),<i>PTEN</i>(n = 1),<i>RAD51</i>(n = 1),<i>CCNE</i>(n = 1), and<i>FANCB</i>(n = 2). Common toxic effects were grade 1 to 2 anemia, fatigue, anorexia, and nausea. One patient had a confirmed partial response (2%), 33 patients experienced stable disease (72%), of whom 11 (24%) experienced disease stability longer than 4 months and 12 patients had progressive disease (26%). The response duration for the patient with confirmed partial response was 3.9 months. Median progression-free survival was 3.7 months (95% CI, 2.9-5.7) and was significantly higher for patients with DDR-GAs (5.7 months; 95% CI, 3.6-8.8 months;<i>P</i> = .008) and platinum-sensitive PDAC (4.1 months; 95% CI, 3.6-7.8 months;<i>P</i> = .01). The estimated median OS was 9.9 months (95% CI, 7.6-16.1 months) in the study and 13.6 months (95% CI, 9.69 to not reached) in the prespecified DDR-GA cohort. <h3>Conclusions and Relevance</h3> The definition of the BRCAness phenotype in PDAC may be limited to patients harboring DDR-GAs. In these 2 phase 2 nonrandomized clinical trials, olaparib was well tolerated and showed limited antitumor activity in patients with advanced, platinum-sensitive PDAC with DDR-GAs. These conclusions suggest a potential therapeutic opportunity for a subset of patients with PDAC.