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Addition of ipatasertib, an AKT inhibitor, to the antiandrogen abiraterone, in the first-line treatment of men with metastatic castration-resistant prostate cancer (mCRPC) characterized by PTEN loss was associated with a 23% reduction in the risk of radiologic disease progression or death, according to results of a phase 3 clinical trial presented at the European Society of Medical Oncology (ESMO) Virtual Congress 2020.
The rationale for combination therapy with an AKT inhibitor and abiraterone is based on observations that aberrant activation of both the PI3K–AKT–mTOR pathway and androgen receptor (AR) signaling are common in the setting of mCRPC. Furthermore, loss of PTEN, a tumor suppressor that regulates the PI3K–AKT–mTOR pathway, has been associated with a worse prognosis for patients with mCRPC, and AR blockade is associated with PI3K/AKT signaling activation resulting in reduced benefit from abiraterone.
This study (IPATential150; ClinicalTrials.gov Identifier: NCT03072238) was a double-blind, placebo-controlled phase 3 trial in which patients were randomized in a 1:1 ratio to receive ipatasertib plus abiraterone in combination with prednisone or placebo plus abiraterone in combination with prednisone.
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The coprimary study endpoints were radiologic progression-free survival (PFS) as defined by the Prostate Cancer Working Group 3 (PCWG3) criteria in the subgroup with loss of PTEN expression in at least 50% of tumor cells as measured by immunohistochemistry (IHC), and radiologic PFS by PCWG3 criteria in the intent-to-treat population.
Secondary study endpoints included prostate-specific antigen (PSA) progression, PSA response rate, and objective response rate (ORR) in both the subgroup with disease characterized by PTEN loss by IHC and the ITT population. In addition, radiologic PFS by PCWG3 criteria in patients with PTEN loss as assessed by next-generation sequencing (NGS) was also a secondary study endpoint.
Of the 1101 patients who underwent study randomization, 547 patients were assigned to the ipatasertib-containing arm and 554 were assigned to the placebo-containing arm. A key patient stratification factor was tumor PTEN loss by IHC. Hence, of the 521 patients with disease characterized by PTEN loss by IHC, 261 patients were treated with ipatasertib plus abiraterone and 260 patients received placebo plus abiraterone.
At baseline, the median patient age was approximately 70 years, approximately 18% of patients in both arms of the study had received prior treatment with a taxane, and metastatic disease in the bone was present in more than 80% of patients.
At a median follow-up of 19 months, median radiologic PFS in the subgroup with PTEN loss was 18.5 months with ipatasertinib and 16.5 months with placebo (hazard ratio [HR], 0.77; 95% CI, 0.61-0.98; P =.0335), a statistically significant finding. Furthermore, this radiologic PFS benefit was seen across prespecified patient subgroups, including in study participants who had or had not received prior taxane therapy.
In the ITT population, median radiologic PFS was 19.2 months and 16.6 months with and without ipatasertinib, respectively (HR, .84; 95% CI, 0.71-0.99; P =.0431). However, this latter P value did not meet prespecified criteria for statistical significance.
Combination therapy was significantly favored over abiraterone alone in both the subgroup defined by PTEN loss by IHC and the ITT population with respect to the secondary study endpoints of ORR, PSA response rate, and time to PSA progression.
In particular, in the subgroup defined by PTEN loss by IHC, the complete response rate increased from 6% in the placebo plus abiraterone arm to 19% in the combination therapy arm; in the ITT population, the corresponding change was from 9% to 18%.
In the cohort of patients with PTEN loss as assessed by NGS, median radiologic PFS was 19.1 months for the ipatasertib-containing arm and 14.2 months for the placebo-containing arm (HR, 0.65; 95% CI, 0.45-0.95; P =.0206).
Data on OS were not mature at the time of this analysis.
Regarding safety, the frequency of grade 3/4 adverse events (AEs) was higher in the ipatasertinib-containing arm (70.1%) compared with the placebo-containing arm (39%) of the ITT population, with substantially higher rates of grade 3/4 skin rash, diarrhea, hyperglycemia, and transaminase elevation in the former group.
Of note, the frequency of AEs leading to discontinuation of treatment was 5.1% and 21.1% for those receiving treatment with and without ipatasertib, respectively.
With respect to this finding, Johann de Bono, MB, PhD, professor in experimental cancer medicine at The Institute of Cancer Research and Royal Marsden, United Kingdom, and the presenting author, commented that prophylactic measures with antidiarrheal medications and antihistamines may reduce the need for treatment discontinuation or dose reductions for patients receiving ipataserib in combination with abiraterone.
In his closing remarks, Dr de Bono noted that “overall, combined AR and AKT blockade with ipatasertib plus abiraterone improved clinical outcomes over AR blockade with abiraterone alone for PTEN-loss metastatic CRPC, a poor prognosis subset.”
Disclosures: Research funding for this study was provided by F. Hoffman La Roche Ltd. Some of the presenters reported financial relationships with the pharmaceutical industry. For a full list of disclosures, please refer to the original abstract.
Read more of Cancer Therapy Advisor‘s coverage of the ESMO Virtual Congress 2020 by visiting the conference page.
Reference
de Bono JS. IPATential150: Phase III study of ipatasertib (ipat) plus abiraterone (abi) vs placebo (pbo) plus abi in metastatic castration-resistant prostate cancer (mCRPC). Presented at: European Society of Medical Oncology (ESMO) Virtual Congress 2020; September 19-21, 2020. Abstract LBA4.
