Esmo 2018 – Encouraging early prostate data fail to lift Clovis

Response rates in BRCA-positive patients hint at Parp inhibitors’ potential in prostate cancer, but Clovis reins in hopes for a different genetic marker.

The first substantial look at data on Parp inhibitors in BRCA-positive prostate cancer make for encouraging reading, and bode well for Clovis Oncology’s chances of becoming the first to market in this potentially lucrative new indication for the class. 

The company unveiled a 44% response rate in 25 patients harbouring a BRCA mutation from the Triton 2 study of Rubraca today – it previously said 25% would be enough to warrant seeking accelerated approval. But its chief executive, Patrick Mahaffy, told Vantage that he doubted that the trial would yield a similarly strong signal in another sizeable group of patients, those with an ATM alteration, an opportunity that at 13% is about the same size as BRCA-positives, though there might be overlap. 

“For this study I think it’s unlikely that we will see a meaningful difference [in ATM patients],” he said today in an interview at the Esmo conference in Munich. “We do see some stable disease and minor tumour shrinkage, but we are not yet seeing a response.”

Mr Mahaffy insisted he had not totally ruled out a future for Parp inhibitors in this subset, and believes that an ongoing phase III trial, Triton 3, could tell a different story. That uses progression-free survival as the primary endpoint, rather than objective response rate; as he describes, patients with stable disease might count as a win on a PFS endpoint, despite clearly failing as far as the definition of a response goes. 

“We remain committed to showing whether or not that ATM population might show a progression-free survival advantage compared to chemotherapy, because of this long-term stable disease that we see,” he said. 

Further data in ATM patients will be released tomorrow morning, and so far Clovis has only said that reductions in target lesion diameters and PSA measurements have been seen in patients with an ATM alteration. But the message seems to be to not expect anything groundbreaking; Mr Mahaffy said the consensus among physicians was that responses were not seen in ATM patients. 

First to market?

The ATM alteration opportunity must therefore be viewed as a very long shot. A reining in of expectations here could explain why Clovis shares fell 12% after initially climbing 5%. Comparisons with an early Lynparza study in a similar population that generated a 88% response rate in 16 BRCA positive patients probably also did not help. 

Clovis is quite rightly keen to focus attention on the BRCA results, which were stronger than many investors had expected. Whether this translates into durable responses remains to be seen; median duration of response has yet to be reached, and this remains an important test. Six months would probably need to be shown to warrant filing, analysts believe. 

In another encouraging signal, a 51% confirmed PSA response rate was seen in 45 patients, which Mr Mahaffy believes would be important for clinicians and patients, should Rubraca reach the market in this use. 

If all goes well, that could happen in 2020; Clovis believes that it will have data of sufficient maturity to file for accelerated approval before the end of next year. 

Triton 3 should yield results in 2020-21; this is a slightly earlier, pre-chemo setting than Triton 2, and pits Rubraca against physicians' choice of Xtandi, Zytiga or docetaxel. 

Clovis will be watching Astrazeneca and Merck & Co’s progress with the Profound trial very closely. This study is similar to Triton 3, but excludes the docetaxel option. According to clinical trials.gov Profound reads out in early 2020, meaning that any first-to-market advantage that Rubraca manages to win could be short-lived. 

Parps in prostate cancer 
Triton 2 Rubraca  NCT02952534
Triton 3 Rubraca  NCT02975934
Profound  Lynparza NCT02987543

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