Astrazeneca, freshly tooled-up with a new partner in Merck & Co, is a formidable force in the Parp inhibitor space with Lynparza. This is true in ovarian cancer at least, where impending data from a first-line maintenance study, Solo-1, could consolidate its position further and move the Parp inhibitors into a curative setting.
However, Astra and Merck’s first mover advantage could be muted because Solo-1, which started in 2013, was designed before it was fully appreciated that these agents might have utility beyond patients carrying a BRCA mutation. Solo-1 only recruited patients harbouring this gene while Tesaro's first-line study, Prima, of its rival agent Zejula accepted all comers. Prima should yield results towards the end of 2019.
The arrival of Lynparza in late 2014, followed by similar agents from Clovis Oncology and Tesaro, marked the first major breakthrough in the treatment of ovarian cancer in more than a decade.
Specifically, the Parps are being used to treat high-grade serous ovarian cancer, which accounts for around 70% of this tumour type. It is thought that around half of these patients have homologous recombination deficiency (HRD) – faulty DNA repair mechanism. A mutation in the BRCA gene is responsible in around 15-20% of HRD cases, and it is these cases that are very effectively targeted by Parp inhibitors.
However, studies have shown that patients with other types of HRD also benefit from Parp inhibitors, albeit to a lesser extent. Even more surprising was the improvement seen in patients with apparently functioning repair pathways, and although the benefit was smaller again the finding led to the all-comers labels in second-line maintenance or recurrent disease.
In this second-line maintenance setting, where Lynparza and Zejula are already approved and Rubraca should be shortly, patients have received first-line platinum chemotherapy but disease has recurred. Patients are then treated a second time with platinum chemo before being given a Parp inhibitor as maintenance therapy.
In the first-line maintenance setting Parps would be given after the first round of platinum chemo.
As an aside it is interesting to note that Tesaro is the only player with a marketed drug to have explicitly used measures of a patient’s response to platinum chemotherapy to guide enrolment in its clinical programmes. The Nova and Prima trials of Zejula both restricted recruitment to subjects who had very strong responses to initial chemotherapy, and researchers believe that platinum sensitivity itself is a biomarker for response to Parp inhibitors.
|Outlook for Parp inhibitors – the sellside view|
|Zejula||Tesaro||-||109||895||1,597||Approved in US and EU for recurrent ovarian cancer|
|Lynparza||Astrazeneca||5||297||1,038||1,529||Approved in US and EU for 3rd-line and recurrent ovarian cancer, and salvage setting in BRCA-mutant breast cancer|
|Rubraca||Clovis||-||56||647||1,135||Approved in US in 3rd-line setting in BRCA-mutant ovarian cancer|
|Total Parp market, incl. others||5||461||2,848||4,906|
|Note: Rubraca and Zejula forecasts likely to come down post Q4 numbers. Source: EvaluatePharma.|
The big question for Astra and Merck – assuming that Solo-1 is positive – is whether regulators will again extrapolate any win to the broad patient population despite the trial’s focus on those with BRCA mutations.
Lynparza’s second-line application was backed up by supporting all-comers data from a phase II trial, Study 19. And, side by side, the three marketed Parp inhibitors are considered to offer broadly comparable efficacy.
While there are reasons to believe that regulators might adopt a wide interpretation of Lynparza’s benefit in the first-line setting too, the fact that these patients can potentially be cured makes this a very different case from the recurrent-disease setting.
As such, safety will be crucial in the final Solo-1 data, which are due in the next couple of months.
Solo-1 recruited 450 advanced ovarian cancer patients with a BRCA mutation, who had responded to first-line platinum chemotherapy. Lynparza or placebo was then dosed as a maintenance therapy.
Although at this stage doctors are gunning for a cure the vast majority of patients will relapse – advanced patients have a 70-90% chance of the cancer returning, according to the NCI. Solo-1 has progression-free survival as its primary endpoint, with overall survival and quality of life key secondary measures.
Patients with advanced disease who respond to initial platinum therapy can live for 20-30 months before recurrence, notes Dr Yvette Drew, senior lecturer and honorary consultant in medical oncology at Newcastle University. While she hopes that Solo-1 will show a benefit, she says this is not inevitable.
“The issue is that people who have BRCA mutations and HRD actually respond very well to chemo. So in the first-line setting it will be interesting to know whether they respond so well you might not see the benefit of Parp inhibition for some time,” she tells EP Vantage.
Still, aside from the Solo-1 and Prima there are several first-line studies ongoing, and Dr Drew expects that the Parp inhibitors will eventually play a significant role here.
“If you extrapolate that people usually respond better earlier, they are almost certainly going to show a benefit” in first-line maintenance, says Dr Drew, who has been involved in late-stage trials of Rubraca and early development of Lynparza and Zejula.
Commercially speaking, getting the first win in this front-line position is important because there is little evidence to support retreatment with a Parp inhibitor once a patient relapses. This would limit the opportunity for agents with later-stage labels – although the extent of the impact that Astra and Merck could have here will depend on whether Lynparza gets an all-comers label.
Tesaro could feasibly achieve this in 2020, though Clovis is substantially behind here. And veliparib is a wild card – the Abbvie Parp has failed in two phase III trials in other tumour types.
Of course, because Parps are considered broadly similar on efficacy grounds off-label use could occur – though all agents could benefit from this. Only one will get a boost from the marketing muscle of two pharma giants, however.
Concerns about how much of the ovarian market Tesaro and Clovis are capable of capturing are largely responsible for the diminishing market valuations of these companies. Other tumour types and combination strategies are still on the table, of course, but in ovarian cancer it looks like these are destined to play catch-up.
|Moving Parps earlier – first-line phase III trials to watch|
|Drug||Company||Study||Important dates||Patient pool (all advanced, FIGO stage III-IV)||Trial ID|
|Lynparza||Astra/Merck||Solo-1||Top-line results due H1 2018||BRCA mutation post 1st-line chemo||NCT01844986|
|Zejula||Tesaro||Prima||Top-line results due end 2019||All-comers with extreme platinum sensitivity; post 1st-line chemo||NCT02655016|
|Veliparib||Abbvie||Viela||Completion due early 2019*||All-comers; first-line chemo +/- veliparib followed by placebo or veliparib as maintenance||NCT02470585|
|Lynparza||Astra/Merck||Paolo-1||Completion due 2022*||All-comers post 1st-line chemo + Avastin (investigator-sponsored)||NCT02477644|
|Rubraca||Clovis||Athena||Due to start H1 2018 in collab with BMS||All-comers post 1st line chemo; +/- Opdivo||TBC|
|Note: FIGO=Federation of Gynecology and Obstetrics. *Primary completion data according to clinicaltrials.gov. Source: clinicaltrials.gov, company websites.|