Pfizer cranks up Parp breast cancer battle

The Parp inhibitors are already fighting a pitched battle in ovarian cancer, but the contest is now moving to a new frontier – breast cancer.

Data presented with Pfizer’s contender, talazoparib, suggest that – as in ovarian cancer – efficacy in this new indication might be similar across the Parps. Being first to market might therefore be the key to success, and Astrazeneca has a head start with Lynparza, which it filed in breast cancer in October (see tables below).

While the data from the Embraca trial of talazoparib, presented at the San Antonio Breast Cancer Symposium in Texas on Friday, were welcomed by the sellside, others were more sceptical. Neither Pfizer’s agent nor Lynparza have managed to show a benefit on overall survival, instead only managing to demonstrate an improvement on the surrogate endpoint of progression-free survival versus chemotherapy.

Cross-trial comparison of talazoparib vs Lynparza in breast cancer
Embraca study of talazoparib (NCT01945775)
Talazoparib Chemo
Median PFS, months 8.6 5.6
Hazard ratio 0.54
P value p<0.0001
Median OS, months 22.3 19.5
Hazard ratio 0.76
P value p=0.105
Olympiad study of Lynparza (NCT02000622)
Lynparza Chemo
Median PFS, months 7 4.2
Hazard ratio 0.58
P value p=0.0009
Median OS, months 19.3 19.6
Hazard ratio 0.9
P value p=0.57
Source: SABCS presentation, company press releases.

In neither trial does OS data appear to be fully mature.

Still, Bishal Gyawali of King’s College London has questioned whether the Parps represent a meaningful step forward for breast cancer patients. In an editorial discussing the Olympiad data, published two days before the Embraca results were released, he noted that the lack of OS benefit came despite the use of a “weak” comparator, and postulated that the ideal control would have been carboplatin, which has shown similar efficacy to Lynparza. 

Instead, both trials included physician’s choice of chemotherapy as a control, but this was limited to capecitabine, eribulin or vinorelbine – or also gemcitabine in Embraca.

Including carboplatin could have given Astra and Pfizer difficult questions to answer if their Parps had come up short, not least over the cost of their therapies.

As Dr Gyawali put it: “For a 2.8 months benefit in PFS without benefit in OS observed in an unblind trial against a weak comparator, are we ready as a society to pay $100,000 per patient?”

White space

Still, the available data could be enough for both Lynparza and talazoparib to gain approval in breast cancer. An FDA decision on Lynparza is expected in the first quarter of 2018. If approved, it will be the first Parp inhibitor to get the go-ahead outside ovarian cancer, a disorder for which Lynparza, Tesaro’s Zejula and Clovis Oncology’s Rubraca are already available.

Breast cancer could represent an attractive white space, particularly for the early entrants. Others have already tried and failed here, including Tesaro, which had to scrap its open-label Bravo study of Zejula in a similar population in March after control patients, who wanted to receive a Parp inhibitor, dropped out in high numbers.

Meanwhile, a study of Abbvie’s veliparib in triple-negative breast cancer (TNBC) fell flat in April (Abbvie's Parp runs out of puff, April 20, 2017). 

Selected Parp trials in breast cancer
Project Company Trial name Setting  ID Data
Lynparza  Astrazeneca Olympiad Metastatic, germline BRCA mutations, no more than 2 prior chemo regimens NCT02000622 Positive
Dora With/without Imfinzi as maintenance in metastatic TNBC  NCT03167619 Oct 2019
Talazoparib Pfizer Embraca Metastatic, germline BRCA mutations, no more than 3 prior chemo regimens NCT01945775 Positive
Javelin Parp Medley Metastatic solid tumors inc TNBC and HR+ breast cancer NCT03330405 Mar 2020
Rubraca Clovis BRE09-146** TNBC or BRCA-positive, prior chemo NCT01074970 Oct 2017
Ruby** Metastatic, somatic BRCA mutations, at least 1 prior chemo regimen NCT02505048 Dec 2017
Zejula  Tesaro Bravo Metastatic, germline BRCA mutations, no more than 2 prior chemo regimens NCT01905592  Abandoned
Tesaro Topacio* With Keytruda in metastatic TNBC or recurrent ovarian cancer NCT02657889  Mar 2018
Veliparib Abbvie - Early stage TNBC NCT02032277 Failed
Brocade-3 HER2-negative, BRCA-associated breast cancer NCT02163694 May 2018
*In collaboration with Merck & Co; **Investigator-sponsored trials.

Both of these companies are pressing on in breast cancer. But Abbvie’s Brocade-3 trial could, like Bravo, be hit by Lynparza and talazoparib’s success, if patients would rather not risk being randomised to placebo.

Meanwhile, positive preliminary results from Tesaro’s Topacio study, which is evaluating Zejula plus Merck & Co’s Keytruda, suggest that the way forward for Parps in TNBC might be in combination with a checkpoint inhibitor.

Others are already looking at this approach, with the Dora trial of Lynparza plus Imfinzi due to complete in 2019. Clovis Oncology is also said to be planning a study for early 2018 with its Parp, Rubraca, in combination with Bristol-Myers Squibb’s Opdivo in TNBC.

Meanwhile, Pfizer is testing its PD-L1 inhibitor Bavencio alongside talazoparib in the Javelin Parp Medley trial which, as well as TNBC and HER2-positive breast cancer, includes various other solid tumours.

Breast cancer is expected to make up a relatively small proportion of the Parp inhibitor sales at present, and Lynparza and talazoparib could soon have the market sewn up.

The next battleground for the Parps appears to be prostate cancer, where Clovis is due to report data next year. If the agents also perform similarly in this indication, expanding into new markets might become all about getting there first.

The Parp inhibitor landscape 
Product Company 2022e total sales ($m) 2022e breast cancer sales ($m)
Zejula Tesaro 1,671 496
Lynparza Astrazeneca 1,271 169
Rubraca Clovis Oncology 1,146 Not available
Talazoparib Pfizer 514 Not available
Veliparib Abbvie 150 93
Source: EvaluatePharma.

To contact the writer of this story email Madeleine Armstrong in London at [email protected] or follow @ByMadeleineA on Twitter

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