Lynparza nod confirms a leg up for Glaxo

As the battle between Parp inhibitors for front-line ovarian cancer intensifies, biomarker testing and Avastin biosimilars will play a role.

Policy and regulation

An all-comers label for Lynparza in front-line ovarian cancer was always unlikely, given the results of the Paola-1 study presented at Esmo last year, and so it came to pass last week. The FDA restricted approval to homologous recombination deficiency (HRD)-positive patients; this still represents something of a broadening of the Parp inhibitor’s label, which currently specifies use only in those carrying a BRCA mutation.

This new indication also specifies that the Astrazeneca/Merck & Co drug must be used with Roche’s Avastin in HRD-positive patients, the combination that was examined in Paola-1. This undoubtedly confirms an advantage for Glaxosmithkline, whose Zejula was granted an all-comers, single-agent label in this exact setting last week, although certain complexities make future rivalry far from straightforward.

Substantial differences in the trials that won these label expansions make figuring this situation out particularly difficult. Front-line maintenance, the indication concerned here, covers women who responded to first-line platinum chemotherapy – which remains standard of care – and who can in some cases be cured with a subsequent maintenance treatment.

In those with BRCA-positive disease Lynparza established itself as the go-to maintenance therapy in the Solo-1 study, and the Paola-1 and Prima trials – Zejula’s equivalent phase III test – were run to figure out whether a broader set of patients might benefit from Parp inhibition used in this way.

The answer was yes, although patients with some form of HRD respond much more strongly, as a cross-trial comparison shows.

Front-line ovarian cancer maintenance: cross-trial comparison of median PFS (months)
 

Paola-1

(Avastin plus Lynparza vs Avastin)

Prima

(Zejula vs placebo)

Solo-1

(Lynparza vs placebo)

All-comers

22.1 vs 16.6

(HR 0.59)

13.8 vs 8.2

(HR 0.62) 

n/a
BRCA1/2

37.2 vs 21.7

(HR 0.31)

22.1 vs 10.9

(HR 0.40)

NR vs 13.8

(HR 0.30)

Any HRD 

37.2 vs 17.7

(HR 0.33)

21.9 vs 10.4

(HR 0.43)

n/a
HRD-positive (non-BRCA)

28.1 vs 16.6

(HR 0.43)

19.6 vs 8.2

(HR 0.50)

n/a

HRD-negative/unknown 

16.9 vs 16.0

(HR 0.92)

n/a n/a
HRD-proficient (negative) n/a

8.1 vs 5.4

(HR 0.68)

n/a
HRD unknown  n/a HR 0.85 n/a
Source: Esmo 2019 releases, NEJM & drug labels. 

A hazard ratio of 0.92 in the HRD-negative group in Paola-1 shows why the FDA declined to give the combination an all-comers label. An important point here, however, is that this includes patients whose biomarker status was unknown. In Prima these subjects were split out from the HRD-negative group, one of many caveats when trying to compare results from these studies. 

But the relative approvals means that, for patients with low tumour mutation burden, the choice for physicians becomes Avastin monotherapy or Zejula. This is not a clear-cut decision, however. As SVB Leerink analysts point out, the 16-month PFS achieved by Avastin monotherapy in Paola-1 was double that of Zejula in Prima, the caveats of cross-trial comparison notwithstanding.

Further complicating the issue is the fact that HRD testing, which requires a tumour biopsy, is not well entrenched. This is more complex than identifying a BRCA mutation, which can be done with a simple blood test, and is a widely used diagnostic for ovarian cancer.

And this lack of access to HRD testing could benefit Zejula, particularly when considering that Avastin’s usefulness in ovarian cancer has long been debated; the extent to which the antibody is used in the disease varies widely, geographically.

The arrival of Avastin biosimilars and, presumably, minimal marketing support by Roche must also be considered. It is therefore easy to see how a big push by Glaxosmithkline could generate a healthy uptick in usage in BRCA-negative patients.

Astrazeneca and Merck & Co will not be standing by, of course; the partners can make convincing arguments about superior survival numbers in several of the cohorts detailed above. But for the first time a highly motivated rival has arrived, and one with very straightforward message. Zejula can be used in all patients, regardless of whether a biomarker test is carried out. 

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