Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial

Mirza, Mansoor Raza; Lundqvist, Elisabeth Åvall; Birrer, Michael J.; Christensen, René dePont; Nyvang, Gitte Bettina; Malander, Susanne; Anttila, Markku; Werner, Theresa L.; Lund, Bente; Lindahl, Gabriel; Hietanen, Sakari; Peen, Ulla; Dimoula, Maria; Roed, Henrik; Knudsen, Anja Ør; Staff, Synnöve; Vistisen, Anders Krog; Bjørge, Line; Mäenpää, Johanna; investigators, Avanova

doi:10.1016/s1470-2045(19)30515-7

Cited by 204 publications

(186 citation statements)

References 28 publications

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“…Finally, AVANOVA (NCT02354131) is a phase II superiority trial, comparing single-agent niraparib 300 mg with combination niraparib-bevacizumab (15 mg/kg once every 3 weeks), until disease progression [92]. Ninety-seven enrolled women with high-grade serous or endometrioid platinum-sensitive EOC were assessed based on myChoice HR-deficient scores.…”

Section: Parp Inhibitors and Antiangiogenic Agentsmentioning

confidence: 99%

Poly (ADP-Ribose) Polymerase Inhibitors: Talazoparib in Ovarian Cancer and Beyond

et al. 2020

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Genetic complexity and DNA damage repair defects are common in different cancer types and can induce tumor-specific vulnerabilities. Poly(ADP-ribose) polymerase (PARP) inhibitors exploit defects in the DNA repair pathway through synthetic lethality and have emerged as promising anticancer therapies, especially in tumors harboring deleterious germline or somatic breast cancer susceptibility gene (BRCA ) mutations. However, the utility of PARP inhibitors could be expanded beyond germline BRCA1/2 mutated cancers by causing DNA damage with cytotoxic agents in the presence of a DNA repair inhibitor. US Food and Drug Administration (FDA)-approved PARP inhibitors include olaparib, rucaparib, and niraparib, while veliparib is in the late stage of clinical development. Talazoparib inhibits PARP catalytic activity, trapping PARP1/2 on damaged DNA, and it has been approved by the US FDA for the treatment of metastatic germline BRCA1/2 mutated breast cancers in October 2018. The talazoparib side effect profile more closely resembles traditional chemotherapeutics rather than other clinically approved PARP inhibitors. In this review, we discuss the scientific evidence that has emerged from both experimental and clinical studies in the development of talazoparib. Future directions will include optimizing combination therapy with chemotherapy, immunotherapies and targeted therapies, and in developing and validating biomarkers for patient selection and stratification, particularly in malignancies with 'BRCAness'. Key PointsPARP inhibitors are a family of enzymes that play a role in DNA repair.

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Section: Parp Inhibitors and Antiangiogenic Agentsmentioning

confidence: 99%

Poly (ADP-Ribose) Polymerase Inhibitors: Talazoparib in Ovarian Cancer and Beyond

et al. 2020

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“…(patients with front-line bevacizumab and/or PARPi also included) assessed niraparib versus niraparib (300 mg, once daily) and bevacizumab (15 mg/kg, every 3 weeks) as a treatment strategy; showing a significant improvement in progression-free survival in the intention-to-treat population (irrespective of HRD), as well as in the pre-specified non-germline BRCAm carrier subgroup, but not in BRCAm carriers. 38 Grade≥3 adverse events were more frequent in the combination arm (65% vs 45%), largely driven by more frequent hypertension; however, dose reductions were similar between arms and discontinuations numerically lower in the combination arm. 38 Preliminary results from two multi-tumor early-phase trials have shown a signal of activity of the combination of PARPi with immunecheckpoint inhibitors, with overall response rates of 25%-72%.…”

Section: Reviewmentioning

confidence: 88%

“…38 Grade≥3 adverse events were more frequent in the combination arm (65% vs 45%), largely driven by more frequent hypertension; however, dose reductions were similar between arms and discontinuations numerically lower in the combination arm. 38 Preliminary results from two multi-tumor early-phase trials have shown a signal of activity of the combination of PARPi with immunecheckpoint inhibitors, with overall response rates of 25%-72%. 39 40 Across both trials, the most common grade ≥3 adverse events in the ovarian cancer cohort were anemia (9%-21%), neutropenia (3%-4%), and laboratory abnormalities (amylase and lipase elevation), suggesting that the combination may be tolerable.…”

Section: Reviewmentioning

confidence: 88%

Manage wisely: poly (ADP-ribose) polymerase inhibitor (PARPi) treatment and adverse events

Madariaga

Bowering

Ahrari

et al. 2020

Int J Gynecol Cancer

100

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Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have transformed the treatment landscape in front-line and recurrent high-grade serous ovarian cancer. Maintenance strategies with PARPi have been assessed in randomized phase III trials in ovarian cancer; switch maintenance in the case of olaparib, niraparib, and rucaparib; and concurrent followed by continuation maintenance with veliparib. These studies have shown progression-free survival advantage with PARPi maintenance, with no major adverse changes in the quality of life; however, overall survival data remain immature to date. PARPi have also been incorporated in clinical practice as a single-agent treatment strategy in high-grade serous ovarian cancer, mainly in women who harbor alterations in the BRCA1/2 genes or have alterations in the homologous recombination deficiency (HRD) pathway. Contemporary studies are looking into potentially synergistic combination strategies with anti-angiogenics and immune checkpoint inhibitors, among others. The expansion of PARPi treatment has not been limited to ovarian cancer; talazoparib is licensed in patients with HER2-negative breast cancer with germline BRCA mutations (BRCAm), and front-line olaparib maintenance in patients with pancreatic cancer with germline BRCAm. Numerous studies assessing PARPi either in monotherapy or in combination with other agents are ongoing in multiple tumors, including prostate, endometrial, brain, and gastric cancers. Many patients are being treated with PARPi, some for prolonged periods of time. As a result, a thorough knowledge of the potential short- and long-term adverse events and their management is warranted to improve patient safety, treatment efficacy, and towards maintaining an appropriate dose intensity.

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“…This improvement was regardless of HRD status or the chemotherapy-free interval, although the addition of bevacizumab appeared to be more beneficial in the subgroup with an interval of between 6 and 12 months as compared with patients with >12 months since the last chemotherapy. An additional exploratory analysis showed that the addition of bevacizumab to niraparib did not improve PFS significantly in BRCA-mutated cancers, whereas the combination was highly beneficial in BRCA-wildtype cases [10].…”

Section: Parpi In Recurrent Ovarian Cancermentioning

confidence: 99%

PARP inhibitors in the treatment of ovarian cancer

Zeimet

Wieser

Knoll

et al. 2020

memo

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The recent exciting findings on the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor (PARPi) maintenance therapy in the first-line and later lines of treatment in ovarian cancer are illustrated. Unprecedented advantages have been shown in first-line therapy not only in BRCA-mutated cancers, but also in tumor exhibiting a homologous recombination repair deficiency (HRD) unrelated to BRCA aberrations. The advantages of PARP maintenance therapy in around 50% of HR-proficient highgrade ovarian cancers are far less clear and, even though of statistical significance, the clinical benefit for the patients may be of borderline significance. The pre-treatment testing of HRD remains a matter of debate especially in the light of the current era of precision medicine. Data on the combination of PARPi with bevacizumab maintenance therapy uncovered additive beneficial therapeutic effects. In recurrent ovarian cancer, results on PARPi maintenance therapy after response to platinum-based reinduction chemotherapy are also excellent. At present, however, PARPi maintenance therapy remains reserved for PARPi-naive patients, since the data on PARPi after PARPi is extremely sparse.

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Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial

Cited by 204 publications

References 28 publications

Poly (ADP-Ribose) Polymerase Inhibitors: Talazoparib in Ovarian Cancer and Beyond

Poly (ADP-Ribose) Polymerase Inhibitors: Talazoparib in Ovarian Cancer and Beyond

Manage wisely: poly (ADP-ribose) polymerase inhibitor (PARPi) treatment and adverse events

PARP inhibitors in the treatment of ovarian cancer

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