Phase II trial of niraparib for BRCA-mutated biliary tract, pancreatic and other gastrointestinal cancers: NIR-B
Abstract
Due to the widespread use of cancer genetic testing in gastrointestinal cancer, the BRCA1/2 genetic mutation has been identified in biliary tract cancer as well as pancreatic cancer. Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor, and PARP inhibitors exert their cytotoxicity against cancer cells in the context of homologous recombination deficiency, such as BRCA mutations, via the mechanism of synthetic lethality. The aim of this phase II NIR-B trial is to evaluate the efficacy and safety of niraparib for patients with unresectable advanced or recurrent biliary tract cancer, pancreatic cancer or other gastrointestinal cancers with germline or somatic BRCA1/2 mutations revealed by genetic testing. The primary end point is an investigator-assessed objective response rate in each cohort.
Clinical Trial Registration:jRCT2011200023 (ClinicalTrials.gov)
Plain language summary – A clinical study to confirm the efficacy and safety of niraparib for people with advanced biliary tract, pancreatic and other abdominal cancers with the BRCA genetic mutation: the NIR-B trial.
BRCA gene is involved in repairing DNA injury and plays an important role in cancer growth. Cells with a mutation in the BRCA gene cannot repair DNA using a method called homologous recombination repair. Niraparib is part of a class of drugs called ‘PARP inhibitors’ that inhibit enzymes called ‘PARP’ involved in repairing DNA injury, and has shown efficacy against cancers with BRCA gene mutations. BRCA gene mutations are infrequent but have been found in a variety of cancers. The NIR-B trial is a clinical trial to evaluate the efficacy and safety of niraparib for people with advanced biliary tract, pancreatic and other abdominal cancers with BRCA gene mutations.
Chemotherapy is administered to patients with unresectable advanced or recurrent biliary tract and pancreatic cancer. However, the prognosis is extremely poor, and only a limited number of drugs are available. Thus, there is a great unmet medical need for second- or later-line therapy.
In recent years, biomarker-based therapeutic drug selection has gained importance and it is fragmented by multiple biomarkers (even in cancer types with high morbidity such as colorectal cancer and lung cancer), each of which is becoming a rare fraction. For example, in colorectal cancers, high-frequency microsatellite instability (MSI-H) and HER-2 positivity are rare fractions with only a few percent. In addition, there is a discrepancy between the immunohistochemistry test and polymerase chain reaction (PCR) in the detection of MSI-H, and it has been reported that the attention is needed [1].
In biliary tract cancer and pancreatic cancer, which have relatively low morbidity rates, the types and proportions of therapeutic target molecules have been clarified using comprehensive genomic screening. Regarding biliary tract cancer, previous studies have reported the efficacies of pemigatinib, infigratinib and futibatinib for patients with the FGFR2 fusion gene [2–4], ivosidenib for patients with the IDH1 gene mutation [5] and dabrafenib plus trametinib for patients with the BRAFV600E gene mutation [6]. The efficacy of perutuzumab plus trastuzumab and, more recently, the efficacy of trastuzumab deruxtecan for patients with HER2 overexpression and gene amplification, have also been reported in previous studies [7–9]. The development of molecular-targeted therapy for pancreatic cancer has been challenging. Gemcitabine plus erlotinib therapy does not provide adequate survival benefit in proportion to the increase in adverse events, and it has rarely been used in general practice since the development of FOLFIRINOX therapy and gemcitabine plus nab-paclitaxel therapy [10–12]. In an international multicenter phase III trial (POLO) that compared the efficacy of olaparib, a maintenance PARP inhibitor, with placebo in patients with advanced pancreatic cancer with germline BRCA1/2 mutations who remained on platinum-based first-line therapy for at least 16 weeks with response or stable disease, it was reported that olaparib significantly prolonged progression-free survival (PFS), which was the primary end point [13].
Parallel treatment selection and development trials for various rare fractions require systems for efficient and large-scale screening of target molecules. However, as many targets are present in only a small fraction of patients, a large number of patients need to be screened for enrollment in a single study. To overcome this patient identification barrier, SCRUM-Japan, a nationwide large-scale genomic profiling platform, has been efficiently used to perform umbrella-type and basket-type clinical trials [14]. It was reported in a previous study that genomic profiling platforms such as SCRUM-Japan include patients with biliary tract cancer, pancreatic cancer and other gastrointestinal cancers who have BRCA1/2 mutations [15].
NIR-B trial
This NIR-B trial (registration number: jRCT2011200023) is an investigator-initiated trial with the aim of evaluating the efficacy and safety of niraparib for patients with unresectable advanced or recurrent biliary tract cancer, pancreatic cancer, or other gastrointestinal cancers who were found on genetic testing to have germline or somatic BRCA1/2 mutations. This trial is funded by the Japan Agency for Medical Research and Development and Takeda Pharmaceutical Co. Ltd. This trial was initiated in January 2021, and enrollment of study participants is ongoing.
Background & rationale
Niraparib is an anticancer drug classified as a poly(ADP-ribose) polymerase (PARP) inhibitor. PARP is an enzyme necessary for the repair of single-strand DNA breaks and is responsible for base excision repair (BER), which is a DNA single-strand break-repair mechanism [16,17]. Accumulation of unrepaired DNA single-strand breaks due to PARP inhibition leads to double-strand DNA breaks at sites of replication forks during the DNA replication process. During this process, normal cells can be repaired by homologous recombination repair (HRR) mechanisms to escape cell death. However, in cells in which HRR is dysfunctional, such as cells with pathological mutations in HRR-related genes, double-strand DNA breaks accumulate without repair, eventually leading to cell death. When lacking HRR function, as in BRCA-mutant cells, double-strand DNA breaks will be processed by alternative but error-prone repair pathways, such as nonhomologous end joining repair, which leads to the accumulation of genomic instability and ultimately cancer cell death. Nonhomologous end joining repair is faster than homologous recombination and mainly occurs in the G1 phase [18]. Thus, in cells lacking repair machinery for double-strand DNA breaks such as HRR, genomic integrity preservation is dependent on the mechanism of BER, including PARP, and has been shown to induce synthetic lethality by PARP inhibitors [17,19]. PARP inhibitors such as olaparib and niraparib were developed with a mechanism of action that is based on the presence of mutations in BRCA1/2, which is a HRR-related gene, in patients with ovarian or breast cancer [20–24]. It has been reported that niraparib, unlike olaparib, is selective for PARP1/2, is more cytotoxic (due to its PARP-trapping activity) than olaparib and is effective against olaparib-resistant cell lines [25,26]. In addition, olaparib, rucaparib and niraparib trap PARP approximately 100-fold more efficiently than veliparib, based on its enhanced capability to trap PARP on the DNA and its subsequent higher cytotoxicity. However, this enhanced potency is accompanied by a toxicity profile more similar to that observed with chemotherapeutics [27].
In a large-scale whole-exome and transcriptome analysis of biliary tract cancers in Japan, it was found that HRR-related gene mutations made up 1–4% of BRCA1 gene mutations, 4–7% of BRCA2 gene mutations and 3–7% of ATM gene mutations [28]. Furthermore, a large-scale whole-exome and whole-genome analysis of pancreatic cancer revealed that HRR-related gene mutations made up 8% of BRCA1 gene mutations, 13% of BRCA2 gene mutations, 9% of ATM gene mutations and 6% of PALB2 gene mutations [29]. Regarding gastrointestinal and abdominal malignancies other than biliary tract and pancreatic cancers, it was reported that BRCA1/2 mutations increase the risk of gastric and colorectal cancers [30]. However, there are no collective reports on the prevalence of BRCA1/2 mutations in gastric and colorectal cancers, but very few cases are expected [31].
BRCA1/2 mutation tests have been mainly performed in blood samples for the identification of germline mutations. To date, the need to also identify somatic mutations on formalin-fixed paraffin-embedded samples has emerged. Several technical characteristics differentiate BRCA detection in tissue samples compared with blood, thus the optimization and standardization of molecular analysis is currently important [32].
Guardant360 (Guardant Health, CA, USA) can detect BRCA1/2 mutations and differentiate somatic versus germline variants using a unique algorithm [33,34]. Based on the results of a previous GOZILA study in the SCRUM-Japan project, it was reported that there was a small proportion of cases of BRCA1/2 mutation in biliary tract, pancreatic and other gastrointestinal cancers [15].
Study design
The NIR-B trial is a multicenter, open-label, single-arm, three-cohort, basket-type phase II study (Figure 1). Eligible patients will be enrolled at six trial sites in Japan. Patient screens are performed in the SCRUM-Japan platform, and patients with BRCA1/2 mutation are referred to the trial sites. The first patient was enrolled on 22 March 2021.
The NIR-B trial is a multicenter, open-label, single-arm, three-cohort, basket-type phase II study.
Cohort A: Biliary tract cancer; Cohort B: Pancreatic cancer; Cohort C: Other gastrointestinal cancers.
CGP: Comprehensive genomic profiling; ECOG PS: Eastern Cooperative Oncology Group performance status; GI: Gastrointestinal; PS: Performance status.
Eligibility criteria
The main eligibility criteria are unresectable, advanced or recurrent biliary tract cancer (cohort A), pancreatic cancer (cohort B) and other gastrointestinal cancers (cohort C) with BRCA1/2 gene mutations identified by germline testing or genomic profiling testing using circulating tumor DNA (ctDNA) or tumor tissue refractory or intolerant to previous treatments, and adequate organ function. Germline testing is BRACAnalysis (Myriad Genetics, UT, USA) for pancreatic cancer and BRCA genetic testing performed in genetic practice departments. Genomic profiling testing is multigene panel testing that can be used in Japanese clinical practice or research, Guardant360 and FoundationOne Liquid CDx (Foundation Medicine, MA, USA) for ctDNA, and FoundationOne CDx (Foundation Medicine) and OncoGuide NCC Oncopanel System (Sysmex Corporation, Kobe, Japan) for tumor tissue. The test should be performed at any time before enrollment. A summary of the key inclusion and exclusion criteria are shown in Table 1.
| Inclusion criteria |
|---|
| – Patients with advanced or recurrent solid tumors diagnosed as cancers by histology or cytology and not curatively resectable [Cohort A] Biliary tract cancers with BRCA mutations refractory to or intolerant to one or two regimens of standard-of-care chemotherapy (histology includes adenocarcinoma and adenosquamous carcinoma) [Cohort B] Pancreatic cancer patients with BRCA mutations refractory to or intolerant to one or two regimens of standard-of-care chemotherapy (histology includes adenocarcinoma and adenosquamous carcinoma) [Cohort C] Patients with gastrointestinal cancers other than biliary tract and pancreatic cancer with BRCA mutations refractory to or intolerant to standard chemotherapy (prior treatment is based on the number of standard treatment regimens for each cancer type) – Genetic testing has confirmed the presence of BRCA mutations. Patients will be eligible if any of the following tests have been used to confirm BRCA mutations: [Examination using circulating tumor DNA] Comprehensive genomic profiling with Guardant360 and FoudationOne Liquid CDx [Examination using tumor tissue] Comprehensive genomic profiling using an insured sequencing [Testing using blood genomic DNA] BRACAnalysis™ and BRCA genetic testing conducted by the genetic medicine department (e.g., genetic counseling) – Measurable lesions can be evaluated by computed tomography or magnetic resonance imaging – Age at the time of informed consent is 20 years or older – ECOG performance status is 0 or 1 – The most recent blood test within 14 days of enrollment meets all the following criteria: neutrophil count ≥1500/mm3; hemoglobin ≥9.0 g/dl; platelet count ≥100,000/mm3; total bilirubin ≤1.5 mg/dl; AST ≤100 IU/l; ALT ≤100 IU/l; and creatinine clearance ≥30 ml/min |
| Exclusion criteria |
| – Active double cancer – Prior PARP inhibitor use – Moderate or severe ascites – Carcinomatous meningitis, symptomatic brain metastases or spinal metastases requiring surgical intervention – Systemic steroid therapy over 10 mg/day equivalent to prednisolone or immunosuppressive medication within 14 days before enrollment – Lymphoid malignancy, myelodysplastic syndrome or acute myeloid leukemia – Adverse events considered related to prior treatments that have not recovered to grade 1 or lower |
Study procedure
Patients with body weight ≥77 kg and platelet count ≥150,000/mm3 will be administered 300 mg of niraparib orally once daily. In contrast, patients with body weight <77 kg or platelet count <150,000/mm3 will be administered 200 mg of niraparib orally once daily.
Outcome measures/end points
The primary end points of this trial are: 1) objective response rate (ORR) of patients with BRCA1/2 mutation determined from genetic testing by the investigator or sub-investigator; and 2) ORR of patients with BRCA1/2 mutation determined by the investigator or sub-investigator from ctDNA testing based on a screening study that utilized comprehensive ctDNA sequencing performed prior to the initiation of protocol treatment. The secondary end points include the following: ORR determined by the central review committee, PFS (assessed by the principal investigator or sub-investigator and the central review committee), overall survival, disease control rate, duration of response, time to treatment failure, change in tumor diameter sum and incidence of adverse events. ORR, disease control rate, PFS and overall survival will be analyzed based on the status of germline or somatic BRCA1/2 mutations. Furthermore, pre-treatment tumor tissue and serial ctDNA will be collected and analyzed to investigate resistance mechanisms and to provide a clinically meaningful biomarker that can be used to identify and implement treatment changes.
Planned sample size & statistics
The target sample size in this study is 60 patients, including 25 patients in cohort A, 25 patients in cohort B and ten patients in cohort C. Regarding cohort C, we will enroll up to ten patients beyond feasibility as we anticipate a small sample size of patients with gastrointestinal cancers other than biliary tract and pancreatic cancers who have BRCA1/2 mutations. A threshold ORR of 10% and an expected ORR of 35% will be set for niraparib therapy in each cohort. This study has a 90% experiment-wise power for the primary end point with a one-sided 5% family-wise error rate for the basket-trial design [35]. The NIR-B trial is a Bayesian basket trial design that borrows information across strata based on the similarity between the posterior distributions of the response probability. The calculated sample size was 15 in cohort A, 15 in cohort B and six in cohort C, and it was applied to a population found to have BRCA1/2 mutation using ctDNA testing. Approximately two-thirds of patients considered to have BRCA1/2 mutation based on genetic testing were also considered to have BRCA1/2 mutation based on ctDNA testing. It is expected that some patients will not be eligible for this trial and that some patients will not be treated. The target sample size includes expected drop off cases and this is a single-stage phase II trial.
Ethical considerations
This NIR-B trial is conducted in accordance with the trial protocol approved by the institutional review boards of the participating institutions (Hokkaido University Hospital Institutional Review Board, R2-10; National Cancer Center Institutional Review Board, T4913 and K1028; Kanagawa Cancer Center Institutional Review Board, 396; Institutional Review Board of Osaka University Hospital, 219002-A; National Hospital Organization Kyushu Cancer Center Institutional Review Board, D048). Furthermore, the trial is conducted in compliance with the ethical principles of the Declaration of Helsinki, good clinical practice and applicable regulatory requirements. Written informed consent will be obtained from all the patients before enrollment in this study.
Conclusion
The aim of this trial is to assess the efficacy and safety of niraparib for patients with unresectable advanced or recurrent biliary tract cancer, pancreatic cancer, or other gastrointestinal and abdominal malignancies with BRCA1/2 mutations on genetic panel testing of ctDNA or tumor tissue. If niraparib therapy is confirmed to be beneficial in this trial, then niraparib may be considered a treatment option for unresectable advanced or recurrent biliary tract and pancreatic cancers with BRCA1/2 mutations. Furthermore, the establishment of effective treatment options for biliary tract and pancreatic cancers with BRCA1/2 mutations will pave the way for the development of treatments using rare fractions restricted to patients with certain genetic mutations.
Background
Recent comprehensive genomic profiling testing has revealed therapeutic target molecules.
It has been proven that the BRCA1/2 genetic mutation has been identified in biliary tract and pancreatic cancer.
Niraparib is classified as a poly(ADP-ribose) polymerase (PARP) inhibitor, and PARP inhibitors exert cytotoxicity against cancer cells in the context of homologous recombination deficiency, such as BRCA mutations, by the mechanism of synthetic lethality.
Niraparib has been shown to be selective for PARP1/2 as well as more cytotoxic than other PARP inhibitors owing to its PARP-trapping activity.
NIR-B trial
This NIR-B trial is a multicenter, open-label, single-arm, three-cohort and basket-type phase II study, with the aim to evaluate the efficacy and safety of niraparib for patients with unresectable advanced or recurrent biliary tract cancer, pancreatic cancer and other gastrointestinal cancers with germline or somatic BRCA1/2 mutations observed on genetic testing.
Eligible patients will be enrolled at six trial sites in Japan.
Patients with a body weight ≥77 kg and platelet count ≥150,000/mm3 will be administered 300 mg of niraparib orally once daily, while patients with a body weight <77 kg or platelet count <150,000/mm3 will be administered 200 mg of niraparib orally once daily.
The primary end point is an investigator-assessed objective response rate (ORR) in each cohort with a threshold ORR of 10% and an expected ORR of 35%.
The key secondary end points are progression-free survival, overall survival, disease control rate, duration of response and safety.
Pretreatment tumor tissue and serial circulating tumor DNA will be collected and analyzed to investigate the resistance mechanisms and to provide a clinically meaningful biomarker that can be used to identify and implement treatment changes.
The trial was initiated in January 2021, and enrollment is ongoing.
Author contributions
Y Kawamoto participated in coordinating the study, designing and writing the protocol, data collection and writing this manuscript. C Morizane, Y Komatsu, M Ueno, M Furukawa, T Satoh, M Ikeda, Y Hatanaka, Y Nakamura and T Yoshino acted as the protocol preparation committee and participated in all phases of this study, including designing and writing the protocol, data collection and preparation of this manuscript. S Kondo, S Kobayashi, L Lee, D Sakai and H Imaoka participated in all phases of this study, including data collection. A Miura participated in all phases of this study, including designing and writing the protocol, and data collection. I Yokota was the chief statistician and participated in the statistical setting of the study design and data analysis. All authors reviewed and approved the final manuscript.
Acknowledgments
The authors are grateful to all the patients and their families, as well as the investigators, medical staff and data center staff for their cooperation in the NIR-B trial. They appreciate Dr. S Nakano for their great contributions to the development of the protocol.
Financial disclosure
The NIR-B trial is funded by Japan Agency for Medical Research and Development, and Takeda Pharmaceutical Co., Ltd. In addition, the personnel in charge of this study are subject to the conflict of interest policies of their institutions. Y Kawamoto, S Kondo, S Kobayashi, M Ikeda and Y Nakamura have received grants and honoraria from Takeda Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Competing interests disclosure
The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Ethical disclosure
This NIR-B trial is conducted in accordance with the trial protocol approved by the institutional review boards of the participating institutions (Hokkaido University Hospital Institutional Review Board, R2-10; National Cancer Center Institutional Review Board, T4913 and K1028; Kanagawa Cancer Center Institutional Review Board, 396; Institutional Review Board of Osaka University Hospital, 219002-A; National Hospital Organization Kyushu Cancer Center Institutional Review Board, D048). Further, the trial is conducted in compliance with the ethical principles of the Declaration of Helsinki, good clinical practice, and applicable regulatory requirements. Written informed consent will be obtained from all the patients before enrollment in this study.
Writing disclosure
The authors would like to thank Enago (www.enago.jp) for the English language review.
Previous presentation
Poster presented at American Society of Clinical Oncology Annual Meeting, Chicago, IL, 3–7 June 2022 [36].
Open access
This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. Microsatellite instability testing in colorectal patients with Lynch syndrome: lessons learned from a case report and how to avoid such pitfalls. Per. Med. 19(4), 277–286 (2022).
- 2. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 21(5), 671–684 (2020).
- 3. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J. Clin. Oncol. 36(3), 276–282 (2018).
- 4. Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma. N. Engl. J. Med. 388(3), 228–239 (2023).
- 5. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 21(6), 796–807 (2020).
- 6. Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol. 21(9), 1234–1243 (2020).
- 7. Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 22(9), 1290–1300 (2021).
- 8. Multicenter phase II trial of trastuzumab deruxtecan for HER2-positive unresectable or recurrent biliary tract cancer: HERB trial. Future Oncol. 18(19), 2351–2360 (2022).
- 9. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing unresectable or recurrent biliary tract cancer (BTC): an investigator-initiated multicenter phase 2 study (HERB trial). J. Clin. Oncol. 40(Suppl. 16), 4006 (2022).
- 10. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol. 25(15), 1960–1966 (2007).
- 11. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 364(19), 1817–1825 (2011).
- 12. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 369(18), 1691–1703 (2013).
- 13. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N. Engl. J. Med. 381(4), 317–327 (2019).
- 14. SCRUM-Japan GI-SCREEN and MONSTAR-SCREEN: path to the realization of biomarker-guided precision oncology in advanced solid tumors. Cancer Sci. 112(11), 4425–4432 (2021).
- 15. Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies. Nat. Med. 26(12), 1859–1864 (2020). • Shows the prevalence of BRCA1/2 mutations in biliary tract cancer, pancreatic cancer and other gastrointestinal cancers.
- 16. PARP inhibition: PARP1 and beyond. Nat. Rev. Cancer 10(4), 293–301 (2010).
- 17. . The DNA damage response and cancer therapy. Nature 481(7381), 287–294 (2012). •• Shows the mechanism of action of poly(ADP-ribose) polymerase (PARP) inhibitors.
- 18. BRCA mutations in ovarian and prostate cancer: bench to bedside. Cancers (Basel) 14(16), 3888 (2022).
- 19. . Synthetic lethality – a new direction in cancer-drug development. N. Engl. J. Med. 361(2), 189–191 (2009). •• Shows the mechanism of action of PARP inhibitors.
- 20. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N. Engl. J. Med. 366(15), 1382–1392 (2012).
- 21. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N. Engl. J. Med. 379(26), 2495–2505 (2018).
- 22. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N. Engl. J. Med. 377(6), 523–533 (2017).
- 23. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N. Engl. J. Med. 375(22), 2154–2164 (2016).
- 24. Niraparib in patients with newly diagnosed advanced ovarian cancer. N. Engl. J. Med. 381(25), 2391–2402 (2019).
- 25. Structural basis for potency and promiscuity in poly(ADP-ribose) polymerase (PARP) and tankyrase inhibitors. J. Med. Chem. 60(4), 1262–1271 (2017).
- 26. A comparative pharmacokinetic study of PARP inhibitors demonstrates favorable properties for niraparib efficacy in preclinical tumor models. Oncotarget 9(98), 37080–37096 (2018).
- 27. Recent insights into PARP and immuno-checkpoint inhibitors in epithelial ovarian cancer. Int. J. Environ. Res. Public Health 19(14), 8577 (2022).
- 28. Genomic spectra of biliary tract cancer. Nat. Genet. 47(9), 1003–1010 (2015).
- 29. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518(7540), 495–501 (2015).
- 30. BRCA1 and BRCA2 gene mutations and colorectal cancer risk: systematic review and meta-analysis. J. Natl. Cancer Inst. 110(11), 1178–1189 (2018).
- 31. . Cancer incidence in BRCA1 mutation carriers. J. Natl. Cancer Inst. 94(18), 1358–1365 (2002).
- 32. Implementation of BRCA mutations testing in formalin-fixed paraffin-embedded (FFPE) samples of different cancer types. Pathol. Res. Pract. 243, 154336 (2023).
- 33. Identification of incidental germline mutations in patients with advanced solid tumors who underwent cell-free circulating tumor DNA sequencing. J. Clin. Oncol. 36(35), 3459–3465 (2018).
- 34. A novel approach to differentiation of somatic vs. germline variants in liquid biopsies using a betabinomial model. Cancer Res. 78(Suppl. 13), 4272 (2018).
- 35. A Bayesian basket trial design that borrows information across strata based on the similarity between the posterior distributions of the response probability. Biom. J. 62(2), 330–338 (2020).
- 36. An investigator-initiated phase II trial of a PARP inhibitor niraparib monotherapy for pre-treated patients with BRCA-mutated unresectable/recurrent biliary tract, pancreatic and other gastrointestinal cancers (NIR-B trial). Poster presented at: American Society of Clinical Oncology Annual Meeting. IL, USA, 3–7 June 2022.
