Newly diagnosed and relapsed epithelial ovarian cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.

Poly (ADP-ribose) polymerase inhibitors (PARPi) represent a new standard of care in the upfront treatment of advanced epithelial ovarian cancer to the point that the vast majority of patients now receive a PARPi, alone or in combination with the anti-angiogenic bevacizumab, as part of their first-line maintenance therapy. The clinical benefit of PARPi is well established; however, much has changed since their introduction and several relevant questions have been raised and remain unresolved in the post-PARPi era. The decision-making process regarding the most appropriate first-line maintenance therapy could be challenging in clinical practice, especially in the homologous recombination-proficient setting, and several other factors need to be considered apart from the mutational status. Concerns regarding post-PARPi progression treatment have emerged, highlighting an unmet need to define a valid algorithm strategy. PARPi may not only compromise the response to further platinum due to cross-resistance mechanisms but the impact on subsequent non-platinum chemotherapy and surgery also remains unclear. Definitive results on the role of PARPi rechallenge are awaited, especially in the case of oligoprogression managed with locoregional treatment. Moreover, the updated overall survival data from the recurrent setting warrant caution in using PARPi as single agents for unselected patients. Several PARPi combination regimens are emerging for overcoming PARPi resistance and may become our new therapeutic armamentarium. This review discusses a set of clinically relevant issues in the PARPi era and provides a glimpse of future challenges and opportunities in ovarian cancer treatment.

https://ijgc.bmj.com/content/ijgc/33/4/431.full.pdf

Poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer: lessons learned and future directions

Niraparib is a poly (ADP-ribose) polymerase inhibitor that has shown a significant improvement in progression-free survival irrespective of biomarker status in patients with advanced epithelial ovarian cancer. This review focuses on the adverse events associated with niraparib and their management to maintain efficacy of niraparib treatment and improve quality of life for patients. In five trials assessing efficacy of niraparib in patients with advanced epithelial ovarian cancer (PRIMA, NOVA, NORA, QUADRA, and PRIME), treatment-emergent adverse events of any grade were reported in nearly all patients (≥99%) receiving niraparib; the events were grade ≥3 in 51–74% of patients. Across all lines of therapy, treatment-emergent adverse events led to dose interruptions in 62–80% of patients receiving niraparib and dose reductions in 47–71%. Hematologic events were most frequently reported, including thrombocytopenia, anemia, and neutropenia. Common non-hematologic events included gastrointestinal events, which were generally low grade (<5% were grade ≥3). Clinical strategies to manage these and other events, such as fatigue and insomnia, cognitive behavioral therapy and pharmacologic agents, are summarized. Once-daily niraparib dosing may be advantageous for some patients for many reasons, including night-time dosing which may help alleviate gastrointestinal symptoms. An individualized starting dose (determined by baseline body weight and platelet count) of niraparib demonstrated an improved safety profile while maintaining efficacy. Patients receiving the niraparib individualized starting dose had fewer grade ≥3 adverse events, dose interruptions, and dose reductions than patients receiving a fixed starting dose. The safety profile of niraparib across five pivotal studies in advanced epithelial ovarian cancer was consistent across multiple lines of treatment, including as maintenance therapy in first-line and recurrent settings and as treatment in heavily pre-treated patients. Long-term safety data from the NOVA trial confirmed that, with appropriate and early dose modifications, niraparib is well tolerated.

https://ijgc.bmj.com/content/ijgc/early/2023/02/14/ijgc-2022-004079.full.pdf

Safety and management of niraparib monotherapy in ovarian cancer clinical trials

BackgroundNiraparib significantly prolonged progression-free survival versus placebo in patients with platinum-sensitive, recurrent ovarian cancer (PSROC), regardless of germline BRCA mutation (gBRCAm) status, in NORA. This analysis reports final data on overall survival (OS).MethodsThis randomised, double-blind, placebo-controlled, phase 3 trial enrolled patients across 30 centres in China between 26 September 2017 and 2 February 2019 (clinicaltrials.gov, NCT03705156). Eligible patients had histologically confirmed, recurrent, (predominantly) high-grade serous epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma (no histological restrictions for those with gBRCAm) and had received ≥2 prior lines of platinum-based chemotherapy. Patients were randomised (2:1) to receive niraparib or placebo, with stratification by gBRCAm status, time to recurrence following penultimate platinum-based chemotherapy, and response to last platinum-based chemotherapy. Following a protocol amendment, the starting dose was individualised: 200 mg/day for patients with bodyweight <77 kg and/or platelet count <150 × 103/μL at baseline and 300 mg/day otherwise. OS was a secondary endpoint.FindingsTotally, 265 patients were randomised to receive niraparib (n = 177) or placebo (n = 88), and 249 (94.0%) received an individualised starting dose. As of 14 August 2023, median follow-up for OS was 57.9 months (IQR, 54.8–61.6). Median OS (95% CI) with niraparib versus placebo was 51.5 (41.4–58.9) versus 47.6 (33.3–not evaluable [NE]) months, with hazard ratio [HR] of 0.86 (95% CI, 0.60–1.23), in the overall population; 56.0 (36.1–NE) versus 47.6 (31.6–NE) months, with HR of 0.86 (95% CI, 0.46–1.58), in patients with gBRCAm; and 46.5 (41.0–NE) versus 46.9 (31.8–NE) months, with HR of 0.87 (95% CI, 0.56–1.35), in those without. No new safety signals were identified, and myelodysplastic syndromes/acute myeloid leukaemia occurred in three (1.7%) niraparib-treated patients.InterpretationNiraparib maintenance therapy with an individualised starting dose demonstrated a favourable OS trend versus placebo in PSROC patients, regardless of gBRCAm status.FundingZai Lab (Shanghai) Co., Ltd; National Major Scientific and Technological Special Project for "Significant New Drugs Development" in 2018, China [grant number 2018ZX09736019]. 

Niraparib maintenance therapy using an individualised starting dose in patients with platinum-sensitive recurrent ovarian cancer (NORA): final overall survival analysis of a phase 3 randomised, placebo-controlled trial

Poly-ADP-ribose polymerase inhibitors (PARPis) were first approved for the treatment of epithelial ovarian cancer (EOC), where as a maintenance therapy they transformed clinical management of this disease in both patients with and without homologous recombination deficiency. In this review, we provide a historical overview of PARPi use in EOC and discuss recent updates on overall survival data, highlighting their impact on regulatory approvals. We explore their potential as combination regimens with antiangiogenic and cell-cycle checkpoint inhibitors, as well as other small molecule inhibitors, to overcome resistance mechanisms and enhance therapeutic efficacy, providing a future perspective on the use of PARPis in EOC treatment.

PARP inhibitors in ovarian cancer.

VP7-2022: An ad-hoc interim overall survival results of niraparib with individualized starting dose as maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer (NORA): A double-blind, randomized, placebo-controlled, phase III trial

We aimed to investigate the efficacy and safety of S1 plus oxaliplatin in combination with tislelizumab, a novel engineered anti-PD-1 monoclonal antibody, and apatinib, an inhibitor of VEGFR-2, as neoadjuvant therapy for Borrmann IV、large Borrmann III type(tumor size>5cm) and Bulky N positive advanced gastric cancer (GC). 

85P Tislelizumab combined with apatinib and oxaliplatin plus S1 as neoadjuvant therapy for Borrmann IV large Borrmann III type and bulky N positive advanced gastric cancer: A single-arm multicenter trial (TAOS-3B-Trial)

Activity and safety of preclinical and a phase 1 study of purinostat mesylate, a uniquely potent and selective hdac i/iib inhibitor in relapsed or refractory lymphoma

Preclinical and a phase 1 study of purinostat mesylate, a novel hdac i/iib selective inhibitor, for the treatment of relapsed or refractory multiple myeloma

Treatment option is limited for EGFR-mutated NSCLC after failure to EGFR TKIs. This multicenter, open-label, phase II study aims to evaluate the efficacy and safety of TIS plus chemo (cohort 1) or TIS plus chemo and bevacizumab (cohort 2) in EGFR-mutated nsq-NSCLC pts failed to EGFR TKI therapies. Herein, the primary analysis of cohort 1 is reported. 

136P Tislelizumab (TIS) plus chemotherapy (chemo) for EGFR-mutated non-squamous non-small cell lung cancer (nsq-NSCLC) failed to EGFR tyrosine kinase inhibitors (TKIs) therapies: The primary analysis

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