Asco-GU – Talzenna remains a wait-and-see story in prostate cancer

Has Pfizer’s Parp inhibitor Talzenna come through on its promise to show a first-line prostate cancer benefit in all-comers? Presenting late-breaking data at Asco-GU last night the NCI’s Dr Neeraj Agrawal declared that the findings of the Talapro-2 trial backed Talzenna plus Xtandi’s use “regardless of HRR gene alteration status”.

Not so fast. Parp inhibitors have a track record of showing illusory all-comers benefits, and separate data on Lynparza have shown why overall survival matters – data that, crucially, Talapro-2 has yet to yield up. In a takedown of Talapro-2 Dr Elena Castro, of Virgen de la Victoria University Hospital, rubbished Dr Agrawal’s all-comers claim.

Dr Castro, the discussant at yesterday’s Asco-GU session, said: “I think HRR status matters.” She highlighted the falloff in PFS benefit in Talapro-2 when looking only at patients known to be HRR (homologous recombination repair) proficient, and criticised Dr Agrawal for not providing an overall response rate analysis cut by HRR status.

Pfizer had toplined Talzenna-2, a first-line study comparing Talzenna plus Xtandi versus Xtandi, last October, and yesterday said it had filed the data with the FDA. It now falls to the US regulator, due to decide on the filing this year, to decide how broad a label Talzenna should receive.

Lynparza’s canary in the coalmine

As a fourth-to-market Parp inhibitor, a long way behind Astrazeneca/Merck & Co’s Lynparza, Talzenna has it all to do.

Talapro-2 showed that the addition of Talzenna to Xtandi cut risk of progression by 27% (p<0.001). This effect was driven by HRR-deficient patients (hazard ratio 0.46), but was still evident in those whose HRR status was confirmed as proficient (hazard ratio 0.66), said Dr Agrawal.

However supportive this looks, it is important that the effect in HRR-proficient disease is smaller, and it was notable that Dr Agrawal only presented positive overall response rate data in all-comers, not in HRR-proficient patients. There is a real risk that once overall survival data mature these will back only the HRR-deficient subgroup.

This is precisely what has happened in Lynparza’s Propel trial, from which OS data were updated at Asco-GU yesterday. These results were nominally positive for Lynparza plus Zytiga versus Zytiga only in HRR-deficient patients, while in the HRR-proficient subgroup there was clearly no benefit, with the hazard ratio confidence interval’s upper bound above 1.00.

For another salutary lesson, look no further than the separate indication of ovarian cancer. Here Parp inhibitors have come under regulatory scrutiny specifically over whether they offer a benefit in patients whose tumours do not have HRR deficiency (of which Brca mutation is a key example).

While the ovarian cancer maintenance setting saw Lynparza, GSK/J&J’s Zejula and Clovis’s Rubraca secure all-comers labels initially, these were largely based on PFS data. The Nova trial then showed gBrca-negative patients doing worse on Zejula than on control, and in November GSK restricted Zejula’s second-line maintenance label to Brca-positive patients.

Shortly afterwards the FDA asked Clovis to make a similar restriction with Rubraca. Wolfe Research analysts – who suggest that Zejula’s first-line maintenance use setting might be at similar risk – say Clovis complied with this request in December. Rubraca’s prescribing information is currently unavailable, and Clovis is in chapter 11 bankruptcy proceedings.

Only PFS

The ovarian cancer scrutiny is relevant because of the glaring fact that all first-line prostate cancer trials with Parp inhibitors, including Talapro-2, have shown strong backing only in terms of PFS.

And there are already signs of regulatory caution in prostate cancer. Astra/Merck filed Lynparza for an all-comers population based on the Propel trial, but in December the FDA delayed its action date by three months. The lack of an OS benefit in HRR-proficient patients in Propel that Asco-GU has revealed gives a strong hint as to why the FDA is stalling.

It seems increasingly likely that Parp inhibitors in front-line prostate cancer will be restricted to HRR-deficient patients. Of the other two drugs, Zejula is awaiting approval only in the EU so far, and only in HRR-deficient disease. Rubraca’s Caspar study has an all-comers design, and reads out this year.

Dr Castro concluded her discussion by saying that the benefit of Parp combinations in trials such as Talapro-2 needed to be understood better. “The balance between the potential benefit and the side effects depends on HRR status,” she told Asco-GU. “A benefit in PFS does not always translate into a benefit in overall survival.”