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5 september 2019: 

Hier het studierapport gepubliceerd in The Lancet van onderstaande studie: Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial

Kernpunten: 

  • In deze gerandomiseerde fase II-studie werd de combinatie van niraparib plus bevacizumab versus niraparib alleen vergeleken bij 97 patiënten met een recidief van chemo (op platinabasis) gevoelige eierstokkanker. De combinatie van bevacizumab plus niraparib werd geassocieerd met een significante verbetering van de mediane progressievrije overleving in vergelijking met alleen niraparib.
  • De combinatie van niraparib plus bevacizumab is veelbelovend in deze populatie en er is een gerandomiseerde fase III-studie gepland.

Het abstract staat onderaan artikel.

17 juni 2019: Bron: ASCO 2019

Wanneer eierstokkankerpatienten direct de parpremmer niraparib krijgen plus ook bevacizumab - Avastin dus zonder chemo vooraf, of als ze bij chemo intermitterend gegeven (rustpauzes tussen de chemokuren door remissie van 6 tot 12 maanden) in de rustperiode geen chemo maar wel niraparib plus bevacizumab - Avstin krijgen dan levert dat een veel langere ziektevrije tijd op tot er zich een recidief voordoet en ook duurt mediaan de ziektevrije tijd veel langer. 

De odds ratio (OR) voor een objectieve response verbeterde sterk met de combinatiebehandeling  (60% vs 27%, OR 4.23, P = .001), en de ziektecontrole verbeterde ook statistisch signicant. (79% vs 53%, OR 3.36, P = .008).

Patienten die gerandomiseerd waren ingedeeld om of niraparib (Zejula) plus bevacizumab (Avastin) te krijgen hadden een mediane ziekte progressievrije tijd (PFS= van 11.9 maanden versus 5.5 maand voor niraparib alleen. Patienten met eerder een  platinum-vrije interval (PFI) van 6 tot 12 maanden of meer dan 12 maanden toonden een zelfde resultaat van de combinatiebehandeling. 

Deze studie: Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer. A randomized controlled chemotherapy-free study—NSGO-AVANOVA2/ENGOT-OV24.

werd gepresenteerd op ASCO 2019. 

Hier een link naar een verslag van de resultaten op basis van de presentatie: 

Niraparib/Bevacizumab Combo Active in Recurrent Ovarian Cancer

A chemotherapy-free doublet for platinum-sensitive recurrent ovarian cancer (PSROC) more than doubled progression-free survival (PFS) as compared with single-agent PARP inhibitor, a randomized trial showed.

Patients randomized to niraparib (Zejula) plus bevacizumab (Avastin) had a median PFS of 11.9 months versus 5.5 month for niraparib alone. Patients with a prior platinum-free interval (PFI) of 6 to 12 months or more than 12 months derived similar benefit from the combination regimen.

Niraparib and bevacizumab also proved active in patients with or without homologous recombination deficiency (HRD) and those with or without BRCA mutations, as reported at the 2019 ASCO Annual Meeting.1

“[This study] is the first randomized trial to evaluate a chemotherapy-free combination of two established agents approved for use in recurrent ovarian cancer,” said Mansoor R. Mirza, MD, of Copenhagen University Hospital. “Compared with niraparib alone, the combination of niraparib and bevacizumab as definitive treatment for ovarian cancer significantly improved progression-free status regardless of HRD status or chemotherapy-free interval.

“The combination was well tolerated, and most patients remained on treatment until disease progression. No detrimental effect on quality of life was observed with combination therapy.”

A planned randomized phase III trial will compare the combination with standard-of-care therapy for PSROC, he added.

Platinum-based chemotherapy remains standard of care for PSROC but its use is limited by cumulative toxicity. In the phase III NOVA trial, niraparib maintenance following platinum-based chemotherapy significantly improved PFS without adversely affecting sensitivity to subsequent therapy.2 Single-agent niraparib also proved active as definitive treatment for relapsed ovarian cancer.3

Mirza reported findings from the AVANOVA randomized phase II trial to evaluate PARP inhibition and anti-angiogenesis as alternative strategies to platinum-based chemotherapy. The rationale for the combination included observations that tumor hypoxia induced by anti-angiogenic agents enhanced PARP inhibition.

Investigators in the Nordic Society of Gynecologic Oncology enrolled patients with high-grade serous or endometrial PSROC and any number of prior lines of therapy. Patients were randomized to niraparib alone (300 mg once daily) or to the same dose of the PARP inhibitor plus bevacizumab 15 mg/kg every 3 weeks. Treatment continued until disease progression or development of unacceptable toxicity. The primary endpoint was investigator-assessed PFS in the intention-to-treat population.

Data analysis included 97 randomized patients, who had a median age of 66. About 40% of the patients had a PFI of 6 to 12 months and the interval exceeded 12 months in the rest. About 60% tested positive for HRD, and a third had BRCA-mutant disease.

The primary analysis showed a 6.4-month improvement in median PFS with the combination, which represented a 65% reduction in the hazard for disease progression or death (P <.0001). The advantage conferred by the combination was similar for patients with a PFI of 6 to 12 month (11.3 vs 2.2 months, P = .0006) or >12 months (13.1 vs 6.1 months, P = .0062) and patients with HRD-positive tumors (11.9 vs 6.1 months, P = .0019) or HRD-negative tumors (11.3 vs 4.2 months, P = .0129). The combination offered a numerical advantage to patients with BRCA-mutant tumors (14.4 vs 9.0 months, P = .0947) and a statistically significant advantage to patients with BRCA-wild type tumors (11.3 vs 4.2 months, P =.0001).

The odds ratio (OR) for objective response quadrupled with the combination (60% vs 27%, OR 4.23, P = .001), and the odds of achieving disease control more than tripled (79% vs 53%, OR 3.36, P = .008).

Patients randomized to the combination had more adverse events, particularly nausea, vomiting, hypertension (associated with bevacizumab), peripheral neuropathy, and proteinuria. Severity was grade 1/2 in most cases except for a 20% incidence of grade ≥3 hypertension.

An assessment of global health quality and quality of life over time showed no deterioration in either treatment group and no significant differences between the groups.


References

  1. Mirza MR, Avall-Lundqvist E, Birrer MJ, et al. Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer. A randomized controlled chemotherapy-free study—NSGO-AVANOVA2/ENGOT-OV24. J Clin Oncol. 2019;37 (suppl; abstr 5505).
  2. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164.
  3. Moore KN, Secord AA, Geller MA, et al. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019;20(5):636-648. doi: 10.1016/S1470-2045(19)30029-4.

 

The combination of bevacizumab plus niraparib was associated with significant improvement in median progression-free survival compared with niraparib alone.

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

BACKGROUND

Platinum-based chemotherapy is the foundation of treatment for platinum-sensitive recurrent ovarian cancer, but has substantial toxicity. Bevacizumab and maintenance poly(ADP-ribose) polymerase (PARP) inhibitors both significantly improve efficacy versus standard therapy, primarily in terms of progression-free survival, and offer the potential for chemotherapy-free treatment. AVANOVA2 compared niraparib and bevacizumab versus niraparib alone as definitive treatment for platinum-sensitive recurrent ovarian cancer.

METHODS

This open-label, randomised, phase 2, superiority trial in 15 university hospitals in Denmark, Sweden, Finland, Norway, and the USA enrolled women aged 18 years or older with measurable or evaluable high-grade serous or endometrioid platinum-sensitive recurrent ovarian cancer. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2, and had to have previously received platinum-containing therapy for primary disease but ≤1 prior non-platinum-containing regimen for recurrent disease. Previous treatment with bevacizumab or first-line maintenance PARP inhibitors was permitted. Eligible patients were randomly assigned 1:1 (by random permuted blocks with block sizes of two and four, no masking), stratified by homologous recombination deficiency status and chemotherapy-free interval, to receive once-daily oral niraparib 300 mg alone or with intravenous bevacizumab 15 mg/kg once every 3 weeks until disease progression. The primary endpoint was progression-free survival, assessed by the investigators in the intention-to-treat population after events in at least 62 patients. Safety was analysed in all patients who received at least one dose of study drug.

FINDINGS

Between May 23, 2016, and March 6, 2017, 97 patients were enrolled and randomly assigned: 48 to niraparib plus bevacizumab and 49 to single-agent niraparib. Median follow-up was 16·9 months (IQR 15·4-20·9). Niraparib plus bevacizumab significantly improved progression-free survival compared with niraparib alone (median progression-free survival 11·9 months [95% CI 8·5-16·7] vs 5·5 months [3·8-6·3], respectively; adjusted hazard ratio 0·35 [95% CI 0·21-0·57], p<0·0001). Grade 3 or worse adverse events occurred in 31 (65%) of 48 patients who received niraparib plus bevacizumab and 22 (45%) of 49 who received single-agent niraparib. The most common grade 3 or worse adverse events in both groups were anaemia (7 [15%] of 48 vs 9 [18%] of 49) and thrombocytopenia (5 [10%] vs 6 [12%]), and hypertension in the combination group (10 [21%] vs 0). Niraparib plus bevacizumab was associated with increased incidences of any-grade proteinuria (10 [21%] of 48 patients vs 0) and hypertension (27 [56%] of 48 vs 11 [22%] of 49) compared with niraparib alone. No treatment-related deaths occurred.

INTERPRETATION

The efficacy observed with this chemotherapy-free combination of approved agents in women with platinum-sensitive recurrent ovarian cancer warrants further evaluation. A randomised phase 3 trial investigating niraparib plus bevacizumab versus chemotherapy plus bevacizumab in platinum-sensitive recurrent ovarian cancer is planned.


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