Pembrolizumab and olaparib in homologous-recombination-deficient metastatic pancreatic cancer: the phase 2 POLAR trial.
СтатьяКлиническое исследование II фазыМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Park Wungki, O'Connor Catherine A, Chou Joanne F, Hilmi Marc, Tarcan Zeynep, Schwartz Carly, Larsen Mary, Homsi Ramzi, Sivaprakasam Karthigayini, Umeda Shigeaki, Perry Maria A, Varghese Anna M, Yu Kenneth H, Balogun Fiyinfolu, Zervoudakis Alice, Katz Seth S, Kim Tae-Hyung, Zhao Ken, Richards Allison L, Lecomte Nicolas, Martin Muldoon Daniel, Karnoub Elias, Chatila Walid, Yang Jessica, El-Dika Imane, Rao Devika, Joshi Smita, Foote Michael B, Sugarman Ryan, Harding James J, Epstein Andrew S, Kelsen David, Chalassani Sree, Keane Fergus, Schoenfeld Joshua D, Singhal Anupriya, Diguglielmo Erin, Bandlamudi Chaitanya, Song Junmin, Ozkan Hulya Sahin, Hong Junguei, Zhang Haochen, Cardenas Agustin Iii, Lao Maria, Melchor Jerry, Shah Ronak, Kang Wenfei, Mazzoni Francesca, Soares Kevin, Donoghue Mark Ta, Santos Ernesto, Rolston Vineet, Reyngold Marsha, Wei Alice Chia-Chi, Tipping Murray, Basturk Olca, Berger Michael, Kihn Do Richard, Schattner Mark, Jarnagin William R, Riaz Nadeem, Balachandran Vinod, Pe'er Dana, Capanu Marinela, Iacobuzio-Donahue Christine, O'Reilly Eileen M
Аннотация
Homologous recombination deficiency (HRD) arising from BRCA1or BRCA2 or PALB2 mutations confers sensitivity to platinum chemotherapy and PARP inhibition in pancreatic cancer (PC) and may enable prolonged disease control with immune checkpoint blockade (ICB). The phase 2 POLAR trial evaluated maintenance pembrolizumab plus olaparib following platinum-based chemotherapy in biomarker-stratified metastatic PC. Sixty-three participants were enrolled into three cohorts: cohort A (BRCA1/BRCA2-mutated or PALB2-mutated HRD, n = 33), cohort B (non-core HRD, n = 15) and cohort C (platinum sensitive, HRD-wild type, n = 15). Cohort A used a two-stage design with co-primary endpoints of at least 43% Response Evaluation Criteria in Solid Tumors (RECIST) objective response rate (ORR) and at least 77% 6-month progression-free survival (PFS) rate. Among RECIST-evaluable participants in cohort A (n = 20), ORR was 35% (95% confidence interval (CI): 15-59%), whereas 6-month PFS rate in the full cohort (n = 33) was 64% (95% CI: 49-82%), not meeting the primary endpoint. At a median follow-up of 37 months (95% CI: 27-47), median PFS and overall survival (OS) for cohort A were 8.3 (95% CI: 5.3-not reached (NR)) and 28 (95% CI: 12-NR) months, with 2-year and 3-year OS rates of 56% (95% CI: 41-76%) and 44% (95% CI: 28-69%), respectively. In cohorts B and C, ORR was 8% (95% CI: 0-38%) and 14% (95% CI: 2%-43%); median PFS was 4.8 (95% CI: 4.0-12) and 3.3 (95% CI: 1.9-4.8) months; and median OS was 18 (95% CI: 13-NR) and 10 (95% CI: 8.9-24) months, respectively. Preplanned translational analyses showed that circulating tumor DNA response, increased tumor-infiltrating lymphocytes and enrichment of frameshift indel neoantigens were associated with durable clinical benefit. These data suggest that a subset of HRD PC may derive prolonged benefit from PARP-ICB maintenance and support further development of biomarker-guided precision immunotherapy strategies in PC. ClinicalTrials.gov identifier: NCT04666740 .