Ariel3 puts Rubraca on Parp with Zejula


Clovis’s gain is Tesaro’s loss. Results from the Ariel3 trial of the former’s Parp inhibitor Rubraca suggest that it has a similar performance to Tesaro’s Zejula in the ovarian cancer maintenance setting (see table below).

As well as threatening Zejula’s market share, the data appear to make a long-awaited takeout of Tesaro less likely – Clovis’s market cap is a more digestible $2.7bn versus Tesaro’s $7.8bn. Clovis’s stock was up as much as 46% this morning, while Tesaro sank 6%.

Ariel goes swimmingly

Rubraca is currently approved in third-line ovarian cancer patients with germline and somatic BRCA mutations, but the Ariel3 results should put it on an even footing with Zejula, which is so far the only Parp inhibitor to gain approval in the maintenance setting, and regardless of mutation status (Tesaro wins one battle, but Parp war awaits, March 28, 2017). 

Ariel3 found a benefit in all three groups of patients analysed: first, BRCA-mutants, then all patients with the homologous recombination deficiency (HRD) signature, and finally all-comers.

Although the usual caution about across-trial comparisons applies, the Rubraca data appear to be on par with those from the Nova study of Zejula and the Solo-2 trial of another Parp inhibitor, Astrazeneca’s Lynparza, both also in the maintenance setting.

Across-trial comparison of Parps in maintenance ovarial cancer treatment
Zejula in Nova Lynparza in Solo-2 Rubraca in Ariel3
BRCA mutant*
Enrolment 203 295 196
mPFS (mth) 21.0 vs 5.5 19.1 vs 5.5 16.6 vs 5.4
Hazard ratio 0.26 0.30 0.23
p value <0.0001 <0.0001 <0.0001
Enrolment 162 NA 354
mPFS (mth) 12.9 vs 3.8 NA 13.6 vs 5.4
Hazard ratio 0.38 NA 0.32
p value <0.001 NA <0.0001
BRCA wild type or all-comers
Enrolment 350** NA 564***
mPFS (mth) 9.3 vs 3.9 NA 10.8 vs 5.4
Hazard ratio 0.45 NA 0.36
p value <0.0001 NA <0.0001
Note: Primary analyses were by central review in Nova, and by investigator assessment in Solo-2 and Ariel3. *Nova and Solo-2 looked specifically at gBRCAmut patients, whereas Ariel3 was in somatic and germline mutations. **BRCA wild-type. ***All-comers.

Notably, Rubraca showed a similar performance when disease progression was assessed by the investigator – the primary endpoint – and by blinded, independent central review, a secondary endpoint. The trial also showed a benefit in exploratory analyses of patients specifically with no BRCA mutation.

Safety looks consistent with Rubraca’s label, with the most common adverse event being anaemia. Like the other approved Parp inhibitors, the product carries a warning for myelodysplastic syndrome/acute myeloid leukaemia, but this was seen in less than 1% of patients in Ariel3.

Clovis hopes to present full data from Ariel3 at the Esmo meeting in September. The company plans to file a supplemental new drug application with the FDA in the next four months and is anticipating a review time of around six months, said chief executive Pat Mahaffy.

Three challengers

Rubraca is not the only challenger Tesaro faces: Astrazeneca’s Lynparza is also gunning for a maintenance indication, albeit in the smaller group of germline BRCA (gBRCA) mutant patients (Lynparza matches Tesaro’s superstar status, March 15, 2017). Lynparza, the first Parp inhibitor to gain approval, is available for fourth-line treatment of gBRCA-mutated ovarian cancer.

At present Clovis's strength appears to be Rubraca's effect in HRD-positive and BRCA wild-type patients. However, with Tesaro already boasting an all-comers label this might not amount to a huge advantage.

Moreover, with growing evidence that the Parp inhibitors are similar, along with a post-hoc analysis of the phase II Study 19, Astra might also get a broader maintenance label in all-comers, Leerink analysts noted; the company is expecting a decision in the third quarter.

It is increasingly looking like a three-way battle in the Parp inhibitor space, and perhaps Ariel3's most important role is to have highlighted the valuation disparity between Clovis and Tesaro. No doubt all three players will be looking for any way to set their products apart from their rivals.

When asked on an analyst call today how Rubraca could be differentiated on efficacy and safety, Clovis's chief executive, Pat Mahaffy, said: “All I can say with confidence is that no one has shown better results than we have done today.”

To contact the writer of this story email Madeleine Armstrong or Jacob Plieth in London at, or follow @ByMadeleineA or @JacobPlieth on Twitter

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