Does clinical benefit of ipatasertib outweigh risk for adverse events?

Roche/Genentech’s investigational drug ipatasertib has demonstrated a small but statistically significant benefit in the treatment of men with metastatic, castration-resistant prostate cancer (mCRPC) who had tumors exhibiting loss of the phosphatase and tensin (PTEN) homolog: a 2-month improvement in median radiographic progression-free survival (rPFS).

Ipatasertib is an oral drug that is still in development but is designed to target and bind to all three forms of protein kinase B (PKB), which is also known as AKT. AKT is a protein kinase that can play a key role in numerous cellular processes, including glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration. AKT blocks the PI3K/AKT signaling pathway.

According to a report this morning on the FirstWordPharma web site, a presentation by de Bono et al., given yesterday, at the European Society for Medical Oncology (ESMO) virtual congress, provided detailed information about the results of the randomized, double-blind Phase III IPATential150 trial, which had enrolled a total of 1,101 patients with asymptomatic or mildly symptomatic mCRPC, who had received no prior treatment after their progression to castration resistance. These patients were then randomized to treatment with either

  • Abiraterone acetate + predisone or prednisolone + ipataserib or
  • Abiraterone acetate + predisone or prednisolone + a placebo

The study was designed to measure two different primary endpoints:

  • rPFS in the entire intent-to-treat set of 1,101 patients
  • rPFS in the subset of patients with tumors demonstrating loss of the phosphatase and tensin  (PTEN) homolog

We already knew, from a media release issued by Roche on June 19 this year, that the trial had met only one of the two co-primary endpoints, but we didn’t know the details. As of 09:00 a.m Eastern time this morning, there is no further media release on the Roche corporate web site.

According to the presentation by de Bono, as reported by FirstWordPharma, after an average (median) follow-up of 19 months:

  • The rPFS in all patients treated with ipatasertib was 19.2 months as compared to 16.6 months for the men treated with a placebo; this difference of 2.6 months was not statistically significant.
  • The rPFS in patients with tumors exhibiting loss of the PTEN homolog  and treated with ipatasertib was 18.5 months as compared to 16.5 months for similar patients treated with a placebo; this difference of 2.0 months was statistically significant.
  • Serious adverse events (AEs) occurred in 40 percent of patients treated with ipatasertib, as compared to 23 percent treated with a placebo.
  • Adverse events leading to treatment discontinuations occurred in 21 percent of patients treated with ipatasertib, as compared to 5 percent treated with a placebo.
  • Data associated with secondary endpoints for the IPATential 150 trial showed that the overall response rates (ORRs) were
    • 61 percent among all intent-to-treat patients receiving ipatasertib, as compared to 44 percent among patients receiving a placebo
    • 61 percent among patients with tumors exhibiting loss of the PTEN homolog  and treated with ipatasertib, as compared to 39 percent for similar patients treated with a placebo

The question that will have to be addressed by regulatory authorities (like the US Food and Drug Administration) in considering the possible approval of ipatasertib for the treatment of men with PTEN loss and mCRPC will be whether the 2-month survival benefit outweighs the 40 percent risk for serious adverse events. And even if regulatory authorities were to decide that that was the case, and give their approval for use of the drug in such a set of patients, it would still need to be carefully re-considered for each individual patient because some patients will inevitably be at greater risk for the adverse events than others, and they may, therefore, have a much small chance of gaining any clinical benefit from such treatment.

7 Responses

  1. PTEN is known as the inhibitor of the PI3K/AKT/mTOR pathway, which, when upregulated, is proliferative for prostate cancer and is associated with resistance to ADT. Pharmaceutical companies have long been looking for effective inhibitors, as PTEN loss is fairly common in a variety of cancers. Prostate cancer patients with known loss of PTEN might want to look into drugs like metformin and supplements like IP6, which act on both ends of this pathway. Also check out this informative link.

  2. Forgive my ignorance … or more precisely, my memory loss since I took plenty of stats courses +/- 50 years ago, but what makes the very similar improvement statistically significant in the ipatasertib PTEN sample — is it related to sample size?

    Secondly, while we know the rPFS is only 2.6/2.5 months, was the range disclosed?

  3. Dear Rick:

    (1) I don’t have any data to be able to support this statement, but yes, it is almost certainly the sample size (but I don’t know what that was).

    (2) I think you’ll have to wait for the formal publication of the results of this trial for the range (unless you want to e-mail Dr. de Bono at the Royal Marsden Hospital in the UK).

    Please note that the only information currently available was the quoted report, which is pretty sparse.

  4. Tx as ever, Mike.

  5. Rick:

    I think the variance in the PTEN-loss subgroups had to be much narrower than in the population as a whole. That’s the only way that the subgroup difference could be statistically significant while the population was not.

  6. @Rick:

    One possibility is that the statement got it backwards. In other words, the PTEN loss segment of the sample is much smaller than the overall sample as a whole. So a 2.0 month difference in the PTEN loss sample is *not* significant since the n is too small, but the 2.6 month difference in the overall sample *is* significant because the n is larger, and also the effect size is bigger. My guess is someone was just moving to quickly in editing the statement and reversed the two points.

  7. Dear Anonymous:

    Since Roche/Genentech had already announced the same result in June this year (see the media release referred to above) but without the scientific data, I think we can be quite certain that this is the correct result. A post on the MedPage Today site this morning also gives the same result with a little more detail (i.e., the hazard ratios and the fact that the PTEN-loss subgroup included 521 patients).

    A report on the Cancer Network web site posted some time yesterday again gives the same result, and again with slightly more detail.

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