PAOLA-1: olaparib added to bevacizumab maintenance in newly diagnosed ovarian cancer, with benefit confined to HRD-positive tumours
Adding the PARP inhibitor olaparib to bevacizumab after first-line chemotherapy for advanced ovarian cancer roughly doubled the time without progression in women whose tumours had defective DNA repair, but did nothing for those without it.
Double-blind, placebo-controlled phase 3 trial of 806 patients with newly diagnosed advanced high-grade ovarian cancer who had responded to platinum-taxane chemotherapy with bevacizumab, randomised 2:1 to two years of olaparib or placebo added to bevacizumab maintenance. Primary endpoint was investigator-assessed PFS.
Median PFS was 22.1 vs 16.6 months overall (HR 0.59), but 37.2 vs 17.7 months (HR 0.33) in homologous-recombination-deficient (HRD) tumours and no different in HRD-negative tumours (HR 1.00). The 2023 OS analysis showed a survival benefit in HRD-positive disease (5-year OS 65.5% vs 48.4%, HR 0.62). It established HRD testing as a decision tool and olaparib plus bevacizumab as a first-line maintenance standard for HRD-positive ovarian cancer.
- Overall population: median PFS 22.1 vs 16.6 months; HR 0.59 (95% CI 0.49-0.72).
- HRD-positive (including BRCA-mutated): median PFS 37.2 vs 17.7 months; HR 0.33.
- HRD-positive without BRCA mutation: median PFS 28.1 vs 16.6 months; HR 0.43.
- HRD-negative or unknown: no benefit (HR about 1.0).
- Overall survival (Annals of Oncology 2023): HRD-positive 5-year OS 65.5% vs 48.4%, HR 0.62; no OS benefit in the ITT population (HR 0.92).
Women with newly diagnosed advanced ovarian cancer should have their tumour tested for BRCA mutations and homologous recombination deficiency, because those who are HRD-positive gain years of additional disease control and better survival from adding olaparib to bevacizumab maintenance. Those who are HRD-negative gain nothing from olaparib in this combination and should not be exposed to its toxicity and cost. HRD testing has become a routine part of ovarian cancer care as a result.
- HRD assays (Myriad myChoice and alternatives) have imperfect concordance and a substantial proportion of tests are inconclusive.
- All patients received bevacizumab, so the trial cannot say whether olaparib alone would be as good in HRD-positive non-BRCA tumours (PRIMA suggests niraparib alone works).
- No ITT overall survival benefit; the HRD-positive OS result is from a prespecified subgroup.
- Two years of olaparib plus bevacizumab is expensive and adds anaemia, fatigue and nausea.
Pages like this
not linked directly; found by shared links- Key paperSOLO-1: two years of olaparib maintenance after first-line chemotherapy for BRCA-mutated ovarian cancer
Shares Giovanni Scambia, Homologous recombination deficiency (HRD), Synthetic lethality, Germline vs somatic mutations.
- IdeaA functional test for homologous recombination deficiency validated across laboratories
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- Key paperOlympiA: a year of olaparib after surgery for BRCA-mutated, high-risk early breast cancer
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- PersonAlan Ashworth
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- Key paperKEYNOTE-A18: pembrolizumab with chemoradiotherapy for locally advanced cervical cancer
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- InstitutionNewcastle Cancer Centre / Northern Centre for Cancer Care
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- PersonChristopher Lord
Shares Synthetic lethality, Synthetic lethality approaches, PARP inhibitors, PARP.