Ipatasertib is a novel oral anti-cancer agent, under investigation in prostate and breast cancers. It is an orally administered agent designed to target three isoforms of AKT (protein kinase B), in order to block the PI3 Kinase/AKT signaling pathway. This pathway is known to contribute to prostate cancer carcinogenesis and also potentially in the resistance to anti-androgen therapies.
In an oral presentation at the Second Presidential Symposium at this year’s European Society of Medical Oncology (ESMO) 2020 Virtual Annual Meeting, Dr. Johann De Bono presented initial results of the IPATential150 trial. This phase III, double-blind, placebo-controlled, randomized controlled trial assessed ipatasertib in combination with abiraterone acetate and steroid (prednisone/prednisolone) as compared to placebo plus abiraterone acetate and prednisone.
Eligible patients had asymptomatic or mildly symptomatic metastatic castration-resistant prostate without previous treatment in this disease space.
Patients were randomized in a 1:1 fashion to receive ipatasertib (400mg PO daily) in combination with abiraterone acetate (1000mg PO daily) and prednisone (5mg PO BID) or placebo plus abiraterone acetate and prednisone. Randomization was stratified according to PTEN-loss by immunohistochemical assay, receipt of prior docetaxel in the castration-sensitive disease space, progression by PSA alone, presence of visceral metastases, and geographic region.
The co-primary outcomes were investigator-assessed radiographic progression-free survival (rPFS) using PCWG3 criteria among patients with PTEN-loss tumors (defined according to immunohistochemical assay demonstrating PTEN-loss in ≥ 50% of tumor cells) and rPFS among the entire intention-to-treat study population. Key secondary outcomes include PSA progression, PSA response rate, confirmed objective response rate, and rPFS in patients with PTEN-loss tumors as diagnosed by next-generation sequencing.
As with many recent trials, this study utilized a sequential testing strategy with a hierarchical approach, as outlined below.
A total of 1101 patients were randomized with 547 receiving ipatasertib, abiraterone acetate, and prednisone and 554 receiving placebo, abiraterone acetate, and prednisone. Overall median follow-up was 19 months, with sufficient analysis for rPFS but not OS at this point.
Patient demographics were well balanced and representative of patients in this disease space.
Among patients with PTEN-loss according to immunohistochemical assay, median radiographic progression-free survival was longer among those receiving ipatasertib, abiraterone acetate, and prednisone (18.5 months, 95% confidence interval 16.3 months to 22.1 months) than those receiving placebo, abiraterone acetate, and prednisone (16.5 months, 95% confidence interval 13.9 to 17.0) with a relative improvement of 23% (hazard ratio 0.77, 95% confidence interval 0.61 to 0.98, p=0.0335).
Among patients with PTEN-loss, the benefit of the combined approach was relatively consistent across key subgroups. Interestingly, the apparent benefit was diminished among those who had received docetaxel in the castration-sensitive disease space.
Assessing secondary outcomes such as objective response rate, duration of response, PSA response rate, and time to PSA progression favoured the combined approach with ipatasertib, abiraterone acetate, and prednisone in both the PTEN-loss cohort and the entire intention-to-treat population. With respect to time to pain progression and time to initiation of cytotoxic chemotherapy, there was suggestion of a benefit, however, too few events were observed to allow for demonstration of statistically significant differences.
The authors also examined PTEN-loss defined by next-generation sequencing, rather than immunohistochemical assay. This demonstrated results comparable to the IHC-based analysis.
To date, overall survival data remains immature and conclusions cannot be drawn.
The authors also assessed toxicity in this phase III trial. While any grade adverse events were common in both arms, they were somewhat more common in patients receiving the combination approach. More notably, adverse events leading to treatment discontinuation, dose reduction, or dose interruption were markedly more common in those receiving ipatasertib, abiraterone acetate, and prednisone.
Diarrhea and skin rash were the predominant severe toxicities among those receiving ipatasertib, abiraterone acetate, and prednisone.
In conclusion, Dr. De Bono highlighted that this combination of ipatasertib, abiraterone acetate, and prednisone improves rPFS and other markers of anti-tumor activity in patients with previously untreated mCRPC, particularly among the poor-prognostic subgroup with PTEN-loss.
Presented by: Johann de Bono, MB ChB FRCP MSc Ph.D. FMedSci. Regius Professor of Cancer Research, Professor, Experimental Cancer Medicine, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust.
Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter at the 2020 European Society for Medical Oncology Virtual Congress (#ESMO20), September 19th-September 21st, 2020.
Read the Invited Discussant Presentation on this Topic: ESMO Virtual Congress 2020: Invited Discussant: (LBA4) IPATential150 and (610O) PROfound
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