Ipatasertib plus abiraterone improves radiographic PFS in prostate cancer with PTEN loss
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The addition of ipatasertib to abiraterone enhanced antitumor activity and improved radiographic PFS as first-line therapy for metastatic castration-resistant prostate cancer, according to data presented at ESMO Virtual Congress 2020.
Researchers observed these benefits in the randomized phase 3 IPATential150 study among men whose tumors had PTEN loss.
“Metastatic castration-resistant prostate cancer [mCRPC] is a heterogeneous disease, with approximately half of these tumors having lost the AKT phosphatase PTEN, hyperactivating oncogenic PI3K/AKT signaling,” Johann S. de Bono, MD, Regius professor of cancer research, head of the division of clinical studies and professor in experimental cancer medicine at Institute of Cancer Research and Royal Marsden Hospital in London, said during the presentation. “PTEN loss in this disease is associated with a worse prognosis and reduced benefit from androgen receptor blockade.”
A phase 2 study showed dual androgen receptor and PI3K/AKT inhibition with abiraterone and prednisone in combination with ipatasertib (Genentech/Roche), a small-molecule inhibitor of all three AKT isoforms, demonstrated superior radiographic PFS compared with androgen receptor inhibition alone among men with mCRPC. It also showed a greater effect on men with PTEN-loss tumors.
De Bono and colleagues tested the effectiveness and safety of the combination among 1,101 men with previously untreated mCRPC. They randomly assigned the men to 400 mg daily ipatasertib (n = 547; median age, 69 years; 68.7% white) or placebo (n = 554; median age, 70 years; 69.7% white) with 1,000 mg daily abiraterone and 5 mg twice-daily prednisone.
Investigator-assessed radiographic PFS according to Prostate Cancer Working Group 3 criteria among men with PTEN-loss tumors (loss of 50% or greater) by immunohistochemistry and among the overall intent-to-treat population served as the study’s co-primary endpoints.
PSA progression, PSA response rate and confirmed overall response rate, as well as radiographic PFS among men with PTEN loss by next-generation sequencing, served as secondary endpoints.
Median follow-up was 19 months.
Results showed longer median radiographic PFS with the ipatasertib vs. placebo combination among men with PTEN loss by immunohistochemistry (18.5 months vs. 16.5 months; HR = 0.77; 95% CI, 0.61-0.98). The difference among the entire intent-to-treat population did not reach statistical significance as defined by researchers (19.2 months vs. 16.6 months; HR = 0.84; 95% CI, 0.71-0.99).
Results showed superior ORRs with ipatasertib among men with PTEN loss (61% vs. 39%) and all men in the intent-to-treat population (61% vs. 44%). Median duration of response was longer with ipatasertib among men with PTEN loss (17.7 months vs. 13.9 months) but not among the intent-to-treat population (15.9 months vs. 16.2 months).
PSA response rates were higher with ipatasertib in both groups (PTEN loss, 84% vs. 72%; intent-to-treat, 81% vs. 76%).
Median time to PSA progression favored ipatasertib among men with PTEN loss (12.6 months vs. 7.6 months; HR = 0.69; 95% CI, 0.55-0.87) and among the intent-to-treat population (12.9 months vs. 8.4 months; HR = 0.73; 95% CI, 0.62-0.85).
Among men with PTEN loss defined by next-generation sequencing, median radiographic PFS was 19.1 months vs. 14.2 months (HR = 0.65; 95% CI, 045-0.95).
Serious adverse events occurred among 39.6% of men in the ipatasertib group and 22.7% of men in the placebo group. Adverse events leading to discontinuation of treatment occurred in 21.1% of men on ipatasertib and 5.1% of men on placebo.
“In this primary endpoint analysis, ipatasertib in combination with abiraterone as a first-line treatment for mCRPC resulted in significantly superior radiographic PFS and antitumor activity compared with placebo in patients with PTEN loss,” de Bono said. “Improvement of radiographic PFS in the intent-to-treat population was not statistically significant.”
Perspective
Back to TopVaibhav G. Patel, MD
PTEN loss is a major driver of prostate cancer progression. In advanced stages and mCRPC, it’s present in 40% to 60% of patients and portends a poor prognosis.
PTEN works by activating the PI3K/AKT pathway, which is one of the pathways leading to tumorigenesis. Typically, PTEN loss leads to an increase in activation of AKT, so the rationale of this study makes sense.
In the past, PI3K inhibitors and AKT inhibitors have demonstrated limited efficacy as single agents. This combination of drugs is interesting because the PI3K/AKT pathway and the androgen receptor (AR) signaling pathway seem to have a lot of crosstalk. When one gets activated, the other gets downregulated, and vice versa. Blocking just one of the mechanisms, such as through use of AR signaling inhibitors alone, may not be as effective. So, this strategy of targeting both pathways at the same time is a good way to answer important questions that we still have.
A few questions we wanted to answer in this large, randomized study of the combination were:
- Is this purely selected for a PTEN population, or does it work for just an unselected population?
- Is this combination safe to use from a toxicity standpoint, and is it effective?
Overall, the results are very promising and could change the way we treat patients with mCRPC, particularly those who have PTEN loss. The data are not fully mature for OS, but the radiographic PFS is significant for patients who have PTEN loss.
In the overall unselected population, we didn’t have significance with radiographic PFS, but it was still improved in the combination group. So, I think this is one of the first studies that showed the combination works and is tolerated well. However, we must wait for the survival data to answer all these questions.
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De Bono J, et al. Abstract LBA4. Presented at: European Society for Medical Oncology Virtual Congress 2020; Sept. 19-21, 2020.
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