Lynparza’s prostate cancer surprise

An unexpectedly broad prostate cancer label gives the Parp inhibitor a strong advantage over Clovis’s rival Rubraca.

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The Profound study presented at last year’s Esmo conference confirmed Lynparza’s potential in prostate cancer, but today’s formal approval in this setting is nevertheless surprising. This is because of the breadth of the label, which allows treatment in second-line patients with any HRR mutation.

It is true that Profound showed the Astrazeneca/Merck & Co drug to elicit a huge progression-free survival advantage in HRR-positive patients, but this was strongly driven by Brca1/2 mutations. In certain other types of HRR mutation, such as ATM, a benefit is hard to discern, yet Lynparza can now be given to these patients.

In the battle of Parp inhibitors this gives Lynparza a dual advantage over Clovis’s Rubraca. Not only can Lynparza be used earlier – five days ago the US FDA approved Rubraca on the basis of its third-line Triton study – the Clovis drug is restricted to Brca-mutated tumours.

Primary endpoint and beyond

Profound’s primary endpoint was PFS in patients with Brca1/2 or ATM mutations – specific subtypes of HRR – and this was met by a wide margin (66% reduction in risk of progression, p<0.0001). The trial enrolled second-line subjects who had failed Xtandi or Zytiga, and the comparator was Zytiga or Xtandi.

But Profound also enrolled a wider group of patients with any HRR mutation, and in all HRR mutants combined Lynparza also reduced risk of progression – by 51%. The problem is that, all the while, it was largely the benefit in Brca mutants that was driving the overall result.

Specifically in those with a single ATM mutation, for instance, median PFS was increased by a negligible 0.7 months, and the hazard ratio was 1.04, meaning that patients on Lynparza were statistically more likely to progress than control. And overall survival numerically favoured control in ATM-mutants, though the survival curves crossed over.

An Astra spokesperson had earlier told Evaluate Vantage that the company filed for a broad HRR-mutant label to bring Lynparza to as many patients as possible.

Interestingly, full publication of the Profound result in the NEJM showed that patients with Brca1-mutated cancers also seemed to derive a marginal PFS benefit. On the other hand, in those with a CDK12 mutation the effect was striking.

The CDK12 gene does not, strictly speaking, function in the HRR pathway, but its mutation does affect other HRR genes. CDK12 mutation is included under the broad HRR setting in Lynparza’s new prostate cancer label.

Subgroup analysis in Lynparza's 2nd-line prostate cancer study Profound
HRR-mutant group mPFS vs control (months) Hazard ratio for progression or death Comment
All HRR mutants* 5.8 vs 3.5 0.49 Strongly statistically significant (p<0.0001)
Brca1/2 or ATM 7.4 vs 3.6 0.34** Strongly statistically significant (p<0.0001)
Brca1/2 9.8 vs 3.0 0.22 Strong driver of PFS in HRR mutants
Brca2 10.8 vs 3.5 (not available) Strong driver of PFS in HRR mutants
CDK12 5.1 vs 2.2 0.74 PFS benefit appears strong
HRR other than Brca1/2 or ATM 4.8 vs 3.3 0.88 Benefit looks marginal
ATM 5.4 vs 4.7 1.04 Hazard ratio favours control
Brca1 2.1 vs 1.8 (not available) Numerical benefit looks marginal
*Approved use; **Profound's primary endpoint. Source: NEJM & Astrazeneca.

If the approval has given Lynparza an advantage over Rubraca – and Clovis’s second-line prostate cancer trial, Triton3, will not read out until 2022 – then its next attempted prostate cancer land grab will be the front-line setting.

Here, Lynparza’s Propel study could yield data next year, testing a Zytiga combo versus Zytiga alone. The crucial point: Propel enrols all-comers, and its primary PFS endpoint applies to this intent-to-treat population, though a subgroup analysis will also look specifically at HRR mutants.

The all-comers approach, the spokesperson said, was the result of a phase II trial that showed a Lynparza/Zytiga combo extending PFS in taxane-progressed prostate cancer patients regardless of their HRR status.

Either way, after earlier this month losing ground to Glaxosmithkline’s Zejula in first-line ovarian cancer maintenance, Lynparza has found a way to save face.

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