Combining ipatasertib with abiraterone may benefit some mCRPC patients
medwireNews: Dual pathway inhibition with the AKT inhibitor ipatasertib plus the androgen receptor inhibitor abiraterone may benefit certain patients with treatment-naïve, metastatic castration-resistant prostate cancer (mCRPC), phase 3 IPATential150 trial data suggest.
Presenting author Johann de Bono (The Institute of Cancer Research, London, UK) told delegates of the ESMO Virtual Conference 2020 that although the combination did not significantly improve radiographic progression-free survival (PFS) in the intention-to-treat (ITT) population, the “poor-prognosis subset” of patients with PTEN-loss as assessed by immunohistochemistry did derive significant benefit from the addition of ipatasertib to abiraterone.
Indeed, the co-primary endpoint of radiographic PFS in the PTEN-loss group was significantly prolonged for the 260 patients who were randomly assigned to receive ipatasertib 400 mg/day alongside abiraterone 1000 mg/day plus prednisone 5 mg twice daily relative to their 261 counterparts who instead received placebo and abiraterone plus prednisone, at a median of 18.5 and 16.5 months, respectively. This gave a hazard ratio (HR) of 0.77 in favor of the combination, and the corresponding 1-year radiographic PFS rates were 64.4% and 63.3%.
By contrast, in the ITT population, although the median radiographic PFS duration was longer and the 1-year rate was higher for the 547 men who received ipatasertib than the 554 participants who received placebo, at 19.2 versus 16.6 months, and 65.3% versus 63.0%, respectively, the between-group difference did not meet the prespecified cutoff for statistical significance.
The addition of ipatasertib to abiraterone did, however, significantly prolong the time to prostate-specific antigen (PSA) progression relative to abiraterone alone in both the PTEN-loss and ITT populations, at a median of 12.6 versus 7.6 months (HR=0.69) and 12.9 versus 8.4 months (HR=0.73), respectively.
PSA response rates were also significantly higher with ipatasertib versus placebo in the PTEN-loss population, at 84% versus 72%, and the ITT population, at 81% versus 76%.
And ipatasertib plus abiraterone was associated with a higher objective response rate than abiraterone alone in both the PTEN-loss (61 vs 39%) and ITT (61 vs 44%) cohorts; the median duration of response was also longer with the combination in patients with PTEN-loss (17.7 vs 13.9 months).
de Bono noted that “increased toxicity was observed with the addition of ipatasertib to abiraterone,” with 70.1% of patients experiencing a grade 3–5 adverse event (AE) and 4.4% experiencing a grade 5 AE, compared with 39.0% and 3.7%, respectively, of those who received abiraterone alone.
He added that a “high proportion” of patients required ipatasertib dose alterations. Indeed, AEs led to 39.9% of ipatasertib-treated patients requiring a dose reduction and 21.1% discontinuing ipatasertib versus 6.2% and 5.1% of patients reducing the dose of or discontinuing placebo. But the presenter explained that “[d]rug discontinuations may be avoided by instituting prophylactic loperamide and antihistamine for managing diarrhoea and cutaneous adverse events, respectively.”
Discussing these findings, Henrik Grönberg (Karolinska Institutet, Stockholm, Sweden) said that “most likely NGS [next-generation sequencing] is a better way to define PTEN-loss,” than immunohistochemistry. And although NGS data on PTEN-loss were only available for 208 patients, radiographic PFS was also significantly longer with ipatasertib than placebo in this subgroup (median, 19.1 vs 14.2 months).
Grönberg added that this trial provides “very promising data on AKT inhibition in prostate cancer, particularly in the NGS-defined group of PTEN-loss.”
But he emphasized that “we need to see more mature data from this very important trial.”
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