Search

Introduction: Esophageal adenocarcinoma (EAC) remains a devastating disease and second line treatment options in the metastatic space are limited. Homologous recombination (HR) defects have been described in EAC in up to 40% of patients. Poly (ADP-ribose) polymerase (PARP)1 and PARP2 inhibitors have shown efficacy in HR defective prostate and ovarian cancers. Here, we describe the activity of the PARP inhibitor niraparib in metastatic EAC with HR defects. Methods: In this single arm Simon two-stage Phase II study, we assessed the safety and efficacy of niraparib in patients with metastatic EAC previously treated with platinum containing chemotherapy harboring defective HR. Defective HR was defined as deleterious alterations in the following HR genes: BRCA1/2, PALB2, ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, NBN, ARID1A and GEN1. Results: 14 patients were enrolled in this study. The trial was stopped early due to slow accrual. 3 patients did not have post-treatment scans because of rapid clinical decline. The overall response rate (ORR) (95% exact CI) was 0/11 = 0% (0%, 28.49%). The disease control rate (DCR) (95% exact CI) was 2/11 = 18.2% (2.3%, 51.8%). The median PFS was 1.8 months (95% CI = 1.0-3.7). The median OS for evaluable patients was 6.6 months (95% CI =2.7-11.4) and 5.7 months for all patients (95% CI =2.7-10.1). The most common adverse events seen were anemia, fatigue, and thrombocytopenia. Conclusion: In patients with metastatic EAC, single agent niraparib as second line therapy is not an effective option. [ABSTRACT FROM AUTHOR]

Between December 2014 and May 2020, the United States Food and Drug Administration approved 9 indications for poly (ADP-ribose) polymerase (PARP) inhibitor use in ovarian cancer. Between June 2022 and September 2022, all 3 indications for PARP inhibitor treatment of recurrent ovarian cancer were withdrawn. Between November 2022 and September 2023, all 3 indications for PARP inhibitor maintenance therapy in recurrent ovarian cancer were restricted. The 3 indications for PARP inhibitor maintenance therapy in newly diagnosed advanced ovarian cancer are unchanged. This article reviews the timelines and data leading to regulatory changes for PARP inhibitor use in ovarian cancer in the United States. [ABSTRACT FROM AUTHOR]

Background: The NOVA study (NCT01847274) compared niraparib with placebo as a maintenance treatment for patients with recurrent ovarian cancer (OC) but was not powered to detect an overall survival (OS) improvement. Objective: To compare OS in a real-world population of patients with BRCA wild-type (BRCA wt) recurrent OC who received second-line maintenance (2LM) niraparib monotherapy versus active surveillance (AS). Design: A retrospective study using a US-based nationwide deidentified electronic health record-derived database. Methods: Patients diagnosed with epithelial OC (January 1, 2011–May 31, 2021) who completed second-line (2L) therapy (January 1, 2017–March 2, 2022) and were BRCA wt were included. A NOVA study-like subpopulation included patients with an Eastern Cooperative Oncology Group performance status score of 0–1 and platinum-sensitive disease. Patients were assigned to 2LM niraparib or AS cohorts. Follow-up was measured from the index date (2L non-maintenance therapy end) until the first of study end (May 31, 2022), last clinical activity, or death. Median OS (mOS) and hazard ratios were estimated with an emulated trial methodology. Results: The overall population comprised 199 patients in the 2LM niraparib monotherapy cohort and 707 patients in the AS cohort; the NOVA study-like subpopulation included 123 patients in the 2LM niraparib monotherapy cohort and 143 in the AS cohort. Demographic and clinical characteristics were similar in both populations. Overall, adjusted mOS was 24.1 months for the 2LM niraparib monotherapy cohort versus 18.4 months for the AS cohort (hazard ratio, 0.8; 95% confidence interval [CI]: 0.7–0.9). In the NOVA study-like subpopulation, adjusted mOS was 28.1 months for the 2LM niraparib monotherapy cohort versus 21.5 months for the AS cohort (hazard ratio, 0.6; 95% CI: 0.5–0.9). Conclusion: These results provide important real-world OS data for patients with recurrent BRCA wt OC who received niraparib monotherapy compared with patients receiving AS. Plain language summary: Niraparib maintenance treatment versus monitoring for recurrent ovarian cancer without BRCA mutation This study examined the real-life survival of patients with ovarian cancer (OC) who received two lines of chemotherapy for OC, known as recurrent OC. We compared two groups: one patient group received a subsequent oral medication called niraparib (a type of maintenance therapy) to delay recurrence, whereas the other group was monitored by their physicians without receiving any medication (also known as active surveillance). This study analyzed health records from across the United States, focusing on patients who were diagnosed with OC between January 2011 and May 2021. Importantly, these patients completed their second line of therapy between January 2017 and March 2022 and had BRCA wild-type disease (meaning that they did not have a specific gene mutation known as BRCA). Patients then received maintenance therapy with niraparib or active surveillance. To assess how long patients lived, patient records were reviewed until the study ended in May 2022, or for patients who did not have data available through that date, until the date of their last visit or death. The study found a significant difference in how long the two groups of patients survived on average. Those patients who received the medication niraparib survived for 24.1 months, compared with 18.4 months for patients in the group that was monitored by their physicians. These results provide valuable insights into the real-life benefits of using niraparib to treat OC outside of a clinical trial. Importantly, these results support the positive outcomes seen in clinical trials, indicating that this medication is a promising option for patients with recurring OC. [ABSTRACT FROM AUTHOR]

The phase III PRIMA/ENGOT-OV26/GOG-3012 trial met its primary endpoint. Niraparib first-line maintenance significantly prolonged progression-free survival (PFS) among patients with newly diagnosed advanced ovarian cancer that responded to first-line platinum-based chemotherapy, regardless of homologous recombination deficiency (HRD) status. Final overall survival (OS) results are reported. Patients were randomized 2:1 to niraparib or placebo, stratified by response to first-line treatment, receipt of neoadjuvant chemotherapy, and tumor HRD status. After reaching 60% target maturity, OS was evaluated via a stratified log-rank test using randomization stratification factors and summarized using Kaplan–Meier methodology. OS testing was hierarchical [overall population first, then the homologous recombination-deficient (HRd) population]. Other secondary outcomes and long-term safety were assessed; an updated, ad hoc analysis of investigator-assessed PFS was also conducted (cut-off date, 8 April 2024). The median follow-up was 73.9 months. In the overall population, the OS hazard ratio was 1.01 [95% confidence interval (CI) 0.84-1.23; P = 0.8834] for niraparib (n = 487) versus placebo (n = 246). In the HRd (n = 373) and homologous recombination-proficient (n = 249) populations, the OS hazard ratios were 0.95 (95% CI 0.70-1.29) and 0.93 (95% CI 0.69-1.26), respectively. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 11.7% and 15.8% of niraparib patients and 37.8% and 48.4% of placebo patients in the overall and HRd populations, respectively. The 5-year PFS rate numerically favored niraparib in the overall (niraparib, 22%; placebo, 12%) and HRd populations (niraparib, 35%; placebo, 16%). Myelodysplastic syndromes/acute myeloid leukemia incidence was <2.5% (niraparib, 2.3%; placebo, 1.6%). No new safety signals were observed. In patients with newly diagnosed advanced ovarian cancer at high risk of recurrence, there was no difference in OS between treatment arms. In the HRd population, patients alive at 5 years were two times as likely to be progression free with niraparib treatment than placebo. Long-term safety remained consistent with the established niraparib safety profile. • No difference in OS was observed between treatment arms in the overall population or by HRD/ BRCA status. • In the HRd population, patients alive at 5 years were two times as likely to be progression free with niraparib than placebo. • A higher rate of subsequent poly(ADP)-ribose polymerase inhibitor therapy was observed in patients who received a placebo. • Long-term safety findings were consistent with the known safety profile of niraparib; no new safety signals were observed. [ABSTRACT FROM AUTHOR]

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. Executive summary 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. [ABSTRACT FROM AUTHOR]

Patterns of disease recurrence on poly(ADP-ribose) polymerase inhibitor maintenance therapy are unclear and may affect subsequent treatment. This ad hoc subgroup analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study evaluated patterns of initial recurrence in patients with advanced ovarian cancer (AOC). PRIMA included participants at high risk for disease progression. This ad hoc analysis only evaluated participants randomized to niraparib maintenance without evidence of disease at baseline. The number and site(s) of initial recurrent lesions at investigator-assessed progressive disease (PD) were evaluated. Of the 314 niraparib-treated patients analyzed, 190 developed ≥1 new lesion (median number of new lesions, 1.0; interquartile range, 1–2). In total, 93.2% (177/190) of patients developed 1–3 lesions at first disease progression. The most common sites of recurrence were the peritoneum (30.0% [57/190]), lymph nodes (26.3% [50/190]), and liver (20.5% [39/190]). Similar results were observed when patients with PD were stratified by biomarker status, disease stage at diagnosis, and type of debulking surgery. Patients with homologous recombination-proficient tumors, stage III disease, or a history of primary debulking developed a median of 2.0 new lesions at first progression; patients with homologous recombination-deficient tumors, stage IV disease, or a history of interval debulking developed a median of 1.0 new lesion. Many patients with AOC without lesions at first-line maintenance treatment initiation develop oligometastatic disease at first recurrence. Prospective evaluation is required to determine whether these patients have improved outcomes when local therapies are combined with continuous, systemic, targeted maintenance therapy. • In an ad hoc analysis of PRIMA, 93.2% (177/190) of niraparib-treated patients developed 1–3 lesions at first progression. • The most common sites of progression were the peritoneum (30.0%), lymph nodes (26.3%), and liver (20.5%). • Similar results were seen when patients were stratified by biomarker status, disease stage, and type of debulking surgery. • Thorough evaluation can help identify niraparib-treated patients with advanced ovarian cancer who develop oligometastases. • These patients may benefit from integration of local therapy into an ongoing, systemic, targeted maintenance regimen. [ABSTRACT FROM AUTHOR]