ESMO 2019 – new data could unlock bigger market for PARP inhibitors

AstraZeneca and GlaxoSmithKline could both benefit from new data that should widen the market for PARP inhibitors as first-line maintenance for ovarian cancer.

AZ’s Lynparza (olaparib) and GSK’s Zejula (niraparib) veliparib showed that they could extend the time women with advanced ovarian cancer live without their disease worsening, regardless of whether their tumours tested positive for the BRCA biomarker, at the ESMO congress in Barcelona.

Meanwhile, AbbVie’s experimental PARP inhibitor veliparib showed that it could improve progression-free survival (PFS) when given alongside chemotherapy as first-line therapy and for maintenance thereafter.

At the moment Lynparza is approved as a monotherapy for this indication in BRCA-positive patients only, while Zejula has yet to be approved as a first-line maintenance therapy in ovarian cancer and veliparib has yet to be approved in any indication.

AZ and partner Merck & Co/MSD showed in the PAOLA-1 trial that adding Lynparza to treatment with Roche’s Avastin (bevacizumab) – a go-to therapy for first-line maintenance after chemo – cut the risk of disease progression or death by 41%.

PFS was 22.1 months with Lynparza plus Avastin versus 16.6 months with Roche’s drug and placebo, and almost half (46%) of women showed no disease progression for at least two years, compared to 28% of the control group.

A subgroup of newly-diagnosed patients with BRCA mutations or another biomarker called homologous recombination (HR) deficiency did even better, showing no disease progression for more than three years (37 months).

AZ is eager to put the new data in front of regulators and extend its lead in first-line maintenance with the new Avastin combination, which could inject additional momentum for the drug. Lynparza is already on course to be a blockbuster with sales of $520 million in the first half of the year, almost double its top-line in the same period of 2018.

GSK is pressing AZ hard with its PRIMA trial, which assessed whether Zejula monotherapy could prevent ovarian cancer recurring in both BRCA-positive and BRCA-negative women who had been treated with just one round of platinum-based chemotherapy.

Zejula on its own reduced PFS by 38% compared to placebo, with a 60% improvement in the BRCA-positive group and a 50% gain in women with HR deficiency, and managed a trend towards improved overall survival at this interim analysis stage.

GSK’s therapy also reduced PFS by 32% in HR-proficient patients, a group which represents approximately half of all ovarian cancer patients.

The data suggest GSK should be able to secure approval as an ‘all-comer’ first-line maintenance therapy after chemo for advanced ovarian cancer, which potentially would give it a niche versus Lynparza’s use as monotherapy for BRCA-positive patients and in combination with Avastin in all-comers.

GSK – which paid $5.1 billion for Zejula’s developer Tesaro – says it is preparing to file for approval in the new indication by the end of the year, adding to Zejula’s current use in second-line ovarian cancer treatment.

While Lynparza and Zejula will certainly tussle for market share, the question at the moment is what role – if any – AbbVie’s veliparib will play after serial failures in earlier studies.

Hopes of a fourth-to-market PARP inhibitor position were dashed in 2017 when veliparib failed studies in lung and breast cancer, while at ASCO this year a mid-stage trial of the drug as a neoadjuvant therapy for rectal adenocarcinoma also disappointed.

At ESMO, AbbVie presented results from the VELIA trial showing that adding veliparib to first-line chemo with carboplatin and paclitaxel followed by maintenance treatment improved PFS to a median of 23.5 months from 17.3 months, a 32% reduction, regardless of biomarker status.

In BRCA-positive patients the median PFS was 34.7 months, compared to 22 months for the control group. There was no significant benefit for women who received veliparib first-line with placebo maintenance.

Crucially, the trial also lacked an arm looking chemo-only first-line followed by veliparib maintenance, which makes it unclear if addition of veliparib to chemo is necessary to provide the observed benefit.

That means that if AbbVie files for approval based on this study it will be promoting a brand new, first-line use for a PARP inhibitor in ovarian cancer without a comparison to Lynparza and Zejula as post-chemo maintenance, and with data that shows the addition of the PARP to chemo increases side effects.

There were increased rates of anaemia and thrombocytopenia when veliparib was combined with chemo, as well as more reports of nausea and fatigue.

AbbVie is however due to report additional data as an add-on to chemotherapy in BRCA-positive breast cancer later today, which could have a bearing on veliparib’s future filing potential.