Astrazeneca has established itself as the king of the Parp inhibitors, and it will not want to relinquish its crown. Another win for its market-leading drug Lynparza, this time in first-line ovarian cancer maintenance treatment, should help the company’s cause.
Success in the investigator-sponsored Paola-1 trial is important because it found a benefit with Lynparza regardless of patients’ BRCA mutation status – the drug is already approved for first-line maintenance, but only in the 20% of patients with BRCA mutations, based on data from the Solo-1 study (Esmo 2018 – Lynparza delivers a huge result in first-line ovarian cancer, October 21, 2018).
All the companies have said so far is that the Prima and Paola-1 trials met the primary endpoint, which in both cases was progression-free survival. Full results will be needed to determine whether there is a clear winner, and the upcoming Esmo meeting looks like a possible venue, raising the prospect of a battle of the UK Parp inhibitor players.
Differences between the trials will make it hard to stack up the results against each other, notwithstanding the usual caution that should be applied when making cross-trial comparisons.
The biggest difference is that Paola-1 tested Lynparza plus Roche’s Avastin versus Avastin alone, while Prima evaluated Zejula versus placebo.
|Zejula||Glaxosmithkline||Prima||1L ovarian cancer maintenance, vs placebo, HRD-positive then all comers||NCT02655016|
|Lynparza||Astrazeneca/Merck & Co||Paola-1||1L ovarian cancer maintenance, +/- Avastin, all comers||NCT02477644|
Astra’s vice-president of oncology, Greg Rossi, told Vantage that there were two main reasons for using an Avastin backbone in the Paola-1 trial: first, that the Roche drug is the standard of care in many markets, especially in Europe; and second, that combining it with a Parp inhibitor might lead to a synergistic effect, particularly in non-BRCA patients.
However, on Glaxo’s second-quarter earnings call its chief scientific officer, Hal Barron, questioned the rationale of adding toxicity and cost with Avastin, and noted that Avastin was only used in around 25% of first-line ovarian maintenance patients – presumably this is in the US where Avastin is less well established.
This might hamstring Lynparza’s expansion in the world’s biggest drug market, assuming the Paola-1 data lead to a new label. And questions around the product’s benefit as a monotherapy in all comers do not look set to be answered soon, as there are no studies ongoing here.
Driven by BRCA?
A separate consideration prompted by both the Paola-1 and Prima data will be how much of the benefit was driven by BRCA-positive patients, who are known to be highly responsive to Parp inhibitors.
A different but related variation could also be important, namely a broken DNA repair mechanism called homologous recombination deficiency (HRD). This can be caused by mutations in the BRCA gene, but also by other factors; HRD is seen in around half of ovarian cancer patients, who are also more susceptible to Parp inhibition than the general population.
Interestingly, while the primary analysis of the Paola-1 trial involved all comers, the primary analysis of the Prima trial was carried out in HRD patients. As this returned a positive result, the analysis was extended to all patients.
Glaxo execs were asked on the company’s second-quarter call whether the group would be breaking down the results in HRD-positive and negative patients as part of its next Prima data drop but Mr Barron declined to comment, saying it was too early to give details.
Astra is also looking at various subgroup analyses, including stratifying patients by BRCA and HRD status, Mr Rossi said. It is unclear when these data will become available.
A lot depends on where and when the Paola-1 data are presented, with Mr Rossi admitting that timelines are tight for “certain upcoming meetings” – no doubt referring to Esmo, which will take place in Barcelona at the tail end of September.
Astra is seeing "nice adoption" of Lynparza in first-line ovarian cancer maintenance, particularly in the US, Mr Rossi told Vantage, without giving more details. The drug is on track to maintain its status as the biggest Parp inhibitor, according to EvaluatePharma, but the extent of the challenge from Glaxo could soon become apparent.
|The Parp inhibitor outlook|
|Lynparza||Astrazeneca/Merck & Co||647||1,441||2,169||2,763|