Lynparza-Avastin First-Line Maintenance Therapy Delays Cancer Progression in Advanced OC, Phase 3 Study Shows

Lynparza-Avastin First-Line Maintenance Therapy Delays Cancer Progression in Advanced OC, Phase 3 Study Shows
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Adding Lynparza (olaparib) to Avastin (bevacizumab) as a first-line maintenance treatment significantly delayed disease progression in women with advanced ovarian cancer — regardless of BRCA mutation status — interim data from a Phase 3 study show.

This maintenance therapy was given after partial or complete response to first-line platinum-based chemotherapy.

The benefits were, however, even more pronounced in women with mutations in the BRCA genes, and others involved in homologous recombination (HR) DNA repair, these early results show.

The results were presented at the European Society for Medical Oncology (ESMO) Congress 2019 that recently took place in Barcelona, Spain. The oral presentation was titled, “Phase III PAOLA-1/ENGOT-ov25 trial: Olaparib plus bevacizumab (bev) as maintenance therapy in patients (pts) with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy (PCh) plus bev.

Lynparza, a PARP inhibitor developed by AstraZeneca and Merck (known as MSD outside the U.S. and Canada), acts by blocking the activity of the PARP enzyme — a DNA damage sensor. That leads to the accumulation of DNA damage and ultimately the death of cancer cells.

This therapy is particularly effective in cancer cells with defects in other DNA repair pathways — such as those with mutations in HR genes, including the BRCA1 and BRCA2 genes. Those cells rely on PARP to survive and proliferate.

This year, Lynparza was approved in the U.S., the European Union, and Japan as a first-line maintenance therapy for women with BRCA-mutated advanced ovarian cancer who responded to standard platinum-based chemotherapy. It also is approved for the treatment of some recurrent or relapsed advanced ovarian cancers, dependent or not of BRCA-mutation status.

The current standard of care for most women with newly diagnosed advanced ovarian cancer is surgery and platinum-based chemotherapy combined with Avastin, followed by Avastin alone as maintenance therapy.

The international, randomized, PAOLA-1 Phase 3 trial (NCT02477644) was designed to evaluate whether adding Lynparza to Avastin first-line maintenance therapy induces greater benefits than Avastin alone in advanced ovarian cancer patients who showed partial or complete responses to platinum-based chemotherapy plus Avastin.

PAOLA-1 included 806 women, with or without BRCA mutations, who were randomly assigned to receive Lynparza (537 patients) or a placebo (269 patients) in addition to Avastin as maintenance therapy. Lynparza and placebo were given orally at 300 mg twice daily for up to 24 months, and Avastin was delivered directly into the bloodstream at 15 mg/kg every three weeks for 15 months.

The study’s main goal is to assess participants’ progression-free survival (PFS), or the time a patient lives without disease progression or death. Secondary assessments include overall survival, safety, and tolerability.

In this interim analysis, women receiving Lynparza had been followed-up for a median of 24 months, and those in the placebo group for a median of 22.7 months.

The results showed that women on Lynparza lived significantly longer without disease progression (22.1 months) than those given a placebo (16.6 months). Overall, the data represents a 41% reduction in the women’s risk of disease progression or death.

“This study reports the greatest [reduced risk] and longest progression free survival we have ever seen,” Isabelle Ray-Coquard, principal investigator of the PAOLA-1 trial and president of the GINECO group, a study sponsor, said in a press release.

In patients with a mutation in the BRCA genes (237 patients), adding Lynparza to Avastin maintenance therapy extended their median progression-free survival even further, from 21.7 months to 37.2 months. Those with mutations in HR genes other than BRCA (152 patients) also saw their PFS increase from 16.6 months to 28.1 months with Lynparza.

Lynparza reduced the risk of disease progression or death by 69% in women with BRCA mutations, by 67% in those with HR mutations, and by 57% in those with HR mutations other than in the BRCA genes.

These findings highlighted that Lynparza-Avastin maintenance therapy was particularly beneficial in participants with HR mutations, regardless of them being in the BRCA genes or not — though these mutations were associated with the best response.

“Patient selection was not restricted by surgical outcome or BRCA mutation status, so participants represent the general population of women with advanced ovarian cancer,” Ray-Coquard said.

Importantly, Lynparza did not increase the frequency of adverse effects, compared with placebo, she noted.

Although treatment interruptions, dose reductions, and discontinuations occurred more often with Lynparza than with placebo, the researchers reported no clinically meaningful differences in health-related quality of life between the two groups.

“The main goal in ovarian cancer is to avoid relapse after first-line therapy because otherwise the probability of cure is quite low,”said Ana Oaknin, MD, head of the gynecologic tumors unit at the Vall d´Hebron University Hospital, in Barcelona.

The Lynparza-Avastin combo as first-line maintenance therapy “should become a new standard of care for patients with advanced ovarian cancer,” she said.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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Inês holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Ciências e Tecnologias and Instituto Gulbenkian de Ciência. Inês currently works as a Managing Science Editor, striving to deliver the latest scientific advances to patient communities in a clear and accurate manner.
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Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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