In recent development updates Roche has increasingly touted its small-molecule Akt inhibitor ipatasertib as an underappreciated oncology asset. On the basis of the first pivotal study to yield results, however, it is uncertain how big a product ipatasertib could become.
Sellside consensus from EvaluatePharma shows 2026 revenues of $1.3bn, and Roche was aiming to file the project this year for prostate cancer and two breast cancer settings. It is the prostate cancer study Ipatential-150 that read out today, and while a partial success is being claimed this might lack relevance in the real world.
The issue turns on diagnosing patients for the presence of genetic PTEN alterations, because Ipatential-150 has shown ipatasertib to have a benefit in PTEN-altered subjects but not in all-comers. The crux of the matter is that prostate cancer patients are not routinely screened for PTEN mutations, and it does not appear that this is about to change.
A hedged bet
Ipatential-150 had tested ipatasertib on top of a standard of care, Johnson & Johnson’s Zytiga, in first-line castrate-resistant prostate cancer subjects, versus Zytiga control. The primary efficacy measure was progression-free survival, tested in PTEN-altered subjects and in the all-comers population.
The study had been run on the basis of the result of the earlier phase I/II GO27983 trial in the second-line setting. This, according to data presented at the 2018 Esmo-GU symposium, showed ipatasertib plus Zytiga conferring a large PFS benefit versus Zytiga in PTEN-altered subjects, but none in the non-PTEN-altered population.
Mechanistically this is logical: the PTEN tumour suppressor is the major brake on the PI3K/Akt survival pathway that drives some cancers. Since it is PI3K/Akt that ipatasertib inhibits it stands to reason that the project should be active in subjects where a lack of the PTEN brake has activated this pathway.
Roche says PTEN alterations are present in 40-60% of castrate-resistant prostate cancers, but in designing Ipatential-150 it seems to have been hedging its bets. In addition to testing its hypothesis in PTEN-altered subjects, it was hoping that the benefit might be large enough to drive a PFS result in all-comers too.
This has proved not to be the case: Ipatential-150 has read out positively for PFS only in the PTEN-altered population. True, the extent of the benefit, plus any numerically positive result in all-comers, as well as the secondary overall survival endpoint, have yet to be revealed, and could rescue this study.
Without further backing, however, Roche will be left trying to change standard of care to make PTEN testing mandatory in first-line prostate cancer, to determine whether ipatasertib should be added to Zyitiga or not. As doctors are happy to prescribe Zytiga or Xtandi – without any need for testing – this case could be hard to make.
|Roche's pivotal programme for ipatasertib|
|Ipatential-150||1L mCRPC||+Zytiga vs Zytiga||PFS in PTEN-altered & all-comers|
|Ipatunity-130||1L TNBC & HR+ Her2- breast cancer (both PTEN-altered)||+paclitaxel vs paclitaxel||PFS|
|Ipatunity-150||1L HR+ Her2- breast cancer||+fulvestrant+Ibrance vs fulvestrant+Ibrance||PFS in PTEN-altered & all-comers|
|Ipatunity-170||1L TNBC||+Tecentriq+paclitaxel vs Tecentriq+paclitaxel vs paclitaxel, PD-L1+ & PD-L1-||PFS & OS|
|Source: Roche presentation & clinicaltrials.gov.|
In addition to prostate cancer, Roche’s ipatasertib 2020 filing plan includes first or second-line triple-negative breast cancer, and front-line HR-positive Her2-negative breast cancer. Ipatunity-130, a pivotal trial in these settings, reads out this year, and it will be noted that this recruited only PTEN-altered patients.
Unless further studies back a benefit in all-comers the Swiss firm will have to make the case for PTEN testing in breast cancer, too. Otherwise ipatasertib will end up a curate’s egg whose positive aspects fail to redeem its shortcomings.