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Raadpleeg ook onze literatuurlijsten van arts-bioloog drs. Engelbert Valstar
1 november 2018: Zie ook dit artikel:
https://kanker-actueel.nl/olaparib-als-onderhoudsbehandeling-voor-brca-12-uitgezaaide-platinum-gevoelige-eierstokkanker-geeft-70-procent-minder-kans-op-overlijden-in-vergelijking-met-placebo.html
1 augustus 2018: Bron: The Lancet
Uit twee onafhankelijk van elkaar uitgevoerde studies blijken zowel olaparib en niraparib, twee zogeheten parpremmers, indien gegeven als onderhoudsbehandeling aan patiënten met gevorderde eierstokkanker die nog steeds gevoelig zijn voor op platinum gebaseerde chemo, de kwaliteit van leven niet aan te tasten. In tegendeel de kwaliteit van leven verbeterde parallel aan de verbetering van de overall overleving.
Beide studies waren placebo gecontroleerde gerandomiseerde studies en werden de effecten van toegevoegde parpremmers olaparib en niraparib op de kwaliteit van leven dus vergeleken met een placebo. Beide studies zijn gepubliceerd in The Lancet
Uit de SOLO2/ENGOT Ov-21 studie met olaparib:
Deze analyse van de SOLO2 / ENGOT Ov-21 studie rapporteert de kwaliteit van leven bij eierstokkankerpatiënten met op platina gebaseerde chemo gevoelig recidief van gevorderde eierstokkanker die olaparib kregen versus placebo-onderhoud. Overall overlevingstijd zonder significante symptomen van toxiciteit en op kwaliteit van leven gecorrigeerde progressievrije overleving waren significant langer met olaparib versus placebo.
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Deze analyse van het SOLO2 / ENGOT Ov-21-onderzoek toont de kwaliteit van leven bij patiënten met platinagevoelige recidiverende eierstokkanker die olaparib kregen als onderhoudsbehandeling versus placebo. Overall overlevingstijd zonder significante symptomen van toxiciteit en op kwaliteit van leven gecorrigeerde progressievrije overlevingstijd waren significant langer met olaparib in vergelijking met een placebo.
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Olaparib werd niet geassocieerd met enig nadelig effect op de kwaliteit van leven, terwijl het de progressievrije overleving verbetert.
Uit de ENGOT-OV16/NOVA studie met niraparib:
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Deze subgroepanalyse van de ENGOT-OV16 / NOVA-studie analyseerde de kwaliteit van leven bij patiënten met recidiverende eierstokkanker die goed reageerden op hun laatste op platina gebaseerde chemotherapie en die gerandomiseerd ingedeeld waren in een groep voor niraparib versus placebo als onderhoudstherapie. In de niraparib-groep verbeterden alle symptomen, met uitzondering van misselijkheid, in de loop van de tijd of bleven stabiel ten opzichte van placebo.
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Niraparib had geen negatief effect op de kwaliteit van leven, terwijl het resulteerde in een verbeterde progressievrije overleving.
Astrazeneca gaf een persbericht uit over de studie met olaparib (klik op de titel voor het persbericht):
Over the past few years, a new class of drugs known as “PARP” inhibitors has begun to change how ovarian cancer is treated. Data released by AstraZeneca and partner Merck this morning, from a Phase 3 study of the drug olaparib (Lynparza), could continue the trend.
AstraZeneca (NYSE: AZN) and Merck (NYSE: MRK) said that olaparib succeeded in a study known as “SOLO-1.” The drug helped stop cancer from spreading longer than a placebo when used as a maintenance therapy for advanced ovarian cancer patients who had responded to chemotherapy. These patients all have a mutated BRCA gene, a known driver of ovarian cancers. About 15 percent of ovarian cancer diagnoses are tied to a BRCA mutation, according to the Dana-Farber Cancer Institute.
The two companies didn’t disclose the details of the study, so it’s unclear how significant the drug’s benefit was. They also said, without specifics, that the drug’s side effects were “consistent with previous trials.” AstraZeneca and Merck will dish details at a future medical meeting and begin discussions with regulators in the U.S. and Europe about possible approval.
Olaparib blocks an enzyme, PARP, that tumors use to repair DNA damage. After some initial clinical setbacks, three PARP blockers have won FDA approval since 2014: olaparib, Tesaro’s (NASDAQ: TSRO) niraparib (Zejula) and Clovis Oncology’s (NASDAQ: CLVS) rucaparib (Rubraca). Olaparib was first, approved for patients with certain forms of ovarian cancer and defective BRCA genes who have failed multiple chemo regimens. Rucaparib followed with a similar approval, while Tesaro’s was the first of the class to win approval for ovarian cancer patients but not require a companion diagnostic test for the BRCA mutation. (Olaparib and rucaparib have since followed, and olaparib has been approved for breast cancer patients with BRCA mutations as well.)
Hier de twee abstracten met referentielijst:
women who receive niraparib as maintenance treatment for recurrent ovarian cancer after responding to platinum treatment are able to maintain QOL during their treatment when compared with placebo.
Quality of life in patients with recurrent ovarian cancer treated with niraparib versus placebo (ENGOT-OV16/NOVA): results from a double-blind, phase 3, randomised controlled trial
Summary
Background
Quality of life (QOL) has become an important complementary endpoint in cancer clinical studies alongside more traditional assessments (eg, tumour response, progression-free survival, overall survival). Niraparib maintenance treatment has been shown to significantly improve progression-free survival in patients with recurrent ovarian cancer. We aimed to assess whether the benefits of extending progression-free survival are offset by treatment-associated toxic effects that affect QOL.
Methods
The ENGOT-OV16/NOVA trial was a multicentre, double-blind, phase 3, randomised controlled trial done in 107 study sites in the USA, Canada, Europe, and Israel. Patients with recurrent ovarian cancer who were in response to their last platinum-based chemotherapy were randomly assigned (2:1) to receive either niraparib (300 mg once daily) as a maintenance treatment or placebo. Randomisation was stratified based on time to progression after the penultimate platinum-based regimen, previous use of bevacizumab, and best response (complete or partial) to the last platinum-based regimen with permuted-block randomisation (six in each block) using an interactive web response system. The trial enrolled two independent cohorts on the basis of germline
BRCA (g
BRCA) mutation status (determined by BRAC
Analysis Testing, Myriad Genetics, Salt Lake City, UT, USA). The primary endpoint of the trial was progression-free survival, and has already been reported. In this study, we assessed patient-reported outcomes (PROs) in the intention-to-treat population using the Functional Assessment of Cancer Therapy–Ovarian Symptoms Index (FOSI) and European QOL five-dimension five-level questionnaire (EQ-5D-5L). We collected PROs from trial entry every 8 weeks for the first 14 cycles and every 12 weeks thereafter. If a patient discontinued, we collected PROs at discontinuation and during a postprogression visit 8 weeks (plus or minus 2 weeks) later. We assessed the effect of haematological toxic effects on QOL with disutility analyses of the most common grade 3–4 adverse events (thrombocytopenia, anaemia, and neutropenia) using a mixed model with histology, region, previous treatment, age, planned treatment, and baseline score as covariates. This study is registered with
ClinicalTrials.gov, number
NCT01847274.
Findings
Between Aug 28, 2013, and June 1, 2015, 553 patients were enrolled and randomly assigned to receive niraparib (n=138 in the g BRCAmut cohort, n=234 in the non-g BRCAmut cohort) or placebo (n=65 in the g BRCAmut cohort, n=116 in the non-g BRCAmut cohort). The mean FOSI score at baseline was similar between the two groups (range between 25·0–25·6 in the two groups). Overall QOL scores remained stable during the treatment and preprogression period in the niraparib group; no significant differences were observed between the niraparib and placebo group, and preprogression EQ-5D-5L scores were similar between the two groups in both cohorts (0·838 [0·0097] in the niraparib group vs 0·834 [0·0173] in the placebo group in the g BRCAmut cohort; and 0·833 [0·0077] in the niraparib group vs 0·815 [0·0122] in the placebo group in the non-g BRCAmut cohort). The most common adverse events reported at screening (baseline) were lack of energy (425 [79%]; 97 [18%] reporting severe lack of energy), pain (236 [44%]), and nausea (118 [22%]). All symptoms, except nausea, either remained stable or improved over time in the niraparib group. The most common grade 3 or 4 toxicities observed in the niraparib group were haematological in nature: thrombocytopenia (124 [34%] of 367 patients), anaemia (93 [25%]), and neutropenia (72 [20%]); disutility analyses showed no significant QOL impairment associated with these toxic effects.
Interpretation
These PRO data suggest that women who receive niraparib as maintenance treatment for recurrent ovarian cancer after responding to platinum treatment are able to maintain QOL during their treatment when compared with placebo.
Funding
TESARO.
References
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Article Info
Copyright
© 2018 Elsevier Ltd. All rights reserved.
Olaparib was not associated with any detrimental effect on quality of life, while improving progression-free survival.
Health-related quality of life and patient-centred outcomes with olaparib maintenance after chemotherapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT Ov-21): a placebo-controlled, phase 3 randomised trial
Summary
Background
In the phase 3 SOLO2 trial (ENGOT Ov-21), maintenance therapy with olaparib tablets significantly prolonged progression-free survival (primary endpoint) compared with placebo in patients with a germline BRCA1 or BRCA2 ( BRCA1/2) mutation and platinum-sensitive, relapsed ovarian cancer who had received two or more lines of previous chemotherapy. The most common subjective adverse effects included fatigue, nausea, and vomiting, which were typically low grade and self-limiting. Our a-priori hypothesis was that maintenance olaparib would not negatively affect health-related quality of life (HRQOL) and additionally that the prolongation of progression-free survival with olaparib would be underpinned by additional patient-centred benefits.
Methods
In SOLO2, 196 patients were randomly assigned to olaparib tablets (300 mg twice daily) and 99 to placebo. Randomisation was stratified by response to previous chemotherapy (complete
vs partial) and length of platinum-free interval (>6–12
vs >12 months). The prespecified primary HRQOL analysis evaluated the change from baseline in the Trial Outcome Index (TOI) score during the first 12 months of the study. To be assessable, patients had to have an evaluable score at baseline and at least one evaluable follow-up form. Secondary planned quality-of-life (QOL) analyses included the duration of good quality of life (defined as time without significant symptoms of toxicity and quality-adjusted progression-free survival ). Efficacy and QOL outcomes were analysed in all randomly assigned patients (the full analysis set), and safety outcomes were analysed in all randomly assigned patients who received at least one dose of study drug. This ongoing study is registered with
ClinicalTrials.gov, number
NCT01874353, and is closed to new participants.
Findings
The adjusted average mean change from baseline over the first 12 months in TOI was −2·90 (95% CI −4·13 to −1·67) with olaparib and −2·87 (–4·64 to −1·10) with placebo (estimated difference −0·03; 95% CI −2·19 to 2·13; p=0·98). Mean QAPFS (13·96 [SD 10·96] vs 7·28 [5·22] months; difference 6·68, 95% CI 4·98–8·54) and mean duration of TWiST (15·03 [SD 12·79] vs 7·70 [6·42] months; difference 7·33, 95% CI 4·70–8·96) were significantly longer with olaparib than with placebo.
Interpretation
Olaparib maintenance therapy did not have a significant detrimental effect on HRQOL compared with placebo. There were clinically meaningful patient-centred benefits in both TWiST and QAPFS despite the adverse effects associated with olaparib. These patient-centred endpoints support the improvement in progression-free survival, the primary endpoint in SOLO2, and should be included in future trials of maintenance therapies.
Funding
AstraZeneca.
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Article Info
Copyright
© 2018 Elsevier Ltd. All rights reserved.
eierstokkanker, olaparib, niraparib, kwaliteit van leven, overall overleving, parpremmers, mutaties, BRCA 1, BRCA 2
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