Inhibition of the androgen receptor pathway (AR) with novel hormonal therapies such as abiraterone acetate has greatly improved outcomes for patients with metastatic castration-resistant prostate cancer in recent years. However, through numerous mechanisms, tumors ultimately develop resistance within a few years, leading to disease progression and death.
One such mechanism of resistance to AR inhibition is feedback activation of the PI3K/Akt pathway, which occurs when AR is inhibited, promoting prostate cancer cell survival.1 Additionally, functional loss of the PTEN tumor suppressor, due to deletion, mutation, or structural variation, is present in 40% to 60% of patients with metastatic castration-resistant prostate cancer and activates PI3K and Akt signaling, resulting in tumorigenesis and reduced effectiveness of AR inhibition.1,2 Thus, dual inhibition of the AR and PI3K/Akt pathways is a potential way to improve outcomes for patients with metastatic castration-resistant prostate cancer.
Hannah Dzimitrowicz, MD
Andrew J. Armstrong, MD, ScM, FACP
Prior trials of mTOR inhibitors or PI3K inhibitors alone have failed to show a clinical benefit in this setting. However, a phase II trial of combined AR and Akt inhibition in 253 men with metastatic castration-resistant prostate cancer found improved progression-free survival, which was largely restricted to the PTEN-loss subgroup (n = 71, hazard ratio [HR] = 0.39, 95% confidence interval [CI] = 0.22–0.70), as compared with men without PTEN loss (HR = 0.84, 95% CI = 0.51–1.37).3
Closer Look at IPATentia150 Trial
Capitalizing on these observations, the multi-institutional phase III IPATential150 study—reported in The Lancet by Sweeney et al and summarized in this issue of The ASCO Post—evaluated dual pathway inhibition with abiraterone acetate in combination with ipatasertib, a selective ATP-competitive small-molecular inhibitor of Akt, or placebo in patients with previously untreated metastatic castration-resistant prostate cancer. The co-primary endpoints were radiographic progression-free survival in the intention-to-treat population (n = 1,101) and in patients with PTEN loss by immunohistochemistry (IHC subgroup, n = 521).4
Radiographic progression-free survival did not significantly differ between treatment cohorts for the intention-to-treat population (P = .043; not significant at α = .01), suggesting that combined AR and Akt inhibition may be ineffective in unselected men with metastatic castration-resistant prostate cancer, similar to the prior phase II study. In the population of patients with PTEN loss by IHC, radiographic progression-free survival was significantly increased with the addition of ipatasertib, from 16.5 months to 18.5 months (HR = 0.77, 95% CI = 0.61–0.98, P = .034; significant at α = .04). In addition, the objective radiographic response rate rose from 44% with abiraterone alone to 61% with combined therapy in this PTEN-loss-by-IHC population.
“The IPATential150 study is the first phase III study demonstrating clinically meaningful activity with dual AR and Akt pathway inhibition.”— Hannah Dzimitrowicz, MD, and Andrew J. Armstrong, MD, ScM, FACP
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Of note, overall survival is a secondary endpoint in this study, with data thus far immature. Although radiographic progression-free survival is a commonly used endpoint in trials of metastatic castration-resistant prostate cancer, it has not been established as a valid surrogate endpoint for overall survival in this population. Thus, caution is needed in interpreting these results prior to the availability of overall survival data.5
Radiographic Progression-Free Survival: Clinical Implications
A range of agents including cabozantinib, bevacizumab, tasquinimod, sunitinib, and aflibercept have statistically improved radiographic progression-free survival modestly by a few months without significantly improving overall survival The association between radiographic progression-free survival and overall survival in phase III trials remains modest. However, most effective agents that have improved overall survival in men with metastatic castration-resistant prostate cancer have also improved radiographic progression-free survival, such as taxanes, AR inhibitors, and lutetium Lu-177–PSMA-617; however, exceptions clearly exist, as radium-223 and sipuleucel-T have improved survival without delaying disease progression in this setting. Thus, improvement in radiographic progression-free survival, as defined by Prostate Cancer Working Group 2/3 criteria, can be associated with improved survival, but it may not always translate into this benefit due to the mechanism of action of the therapy, life-threatening toxicities, or post-progression events and survival.
The 2-month improvement in radiographic progression-free survival seen in patients with PTEN loss is tempered by adverse events. Grade ≥ 3 adverse events occurred in 70% of patients receiving ipatasertib compared with 39% in the control group, most commonly rash (16%), aminotransferase elevation (16%), hyperglycemia (14%), and diarrhea (10%), including two deaths from complications related to hyperglycemia and chemical pneumonitis.4 The PI3K/Akt pathway is involved in insulin signaling, and thus severe hyperglycemia is an expected on-target toxicity but one that can lead to occasional life-threatening complications.
Selecting Patients Most Likely to Benefit
Given the lack of a significant benefit seen in the overall population and the 2-month radiographic progression-free survival benefit seen in the PTEN-loss-by-IHC group, selection of patients most likely to benefit from combined AR/Akt inhibition is of importance for its future use. In IPATential150, PTEN loss was assessed using an IHC assay that defined PTEN loss as 50% or more of the specimen’s tumor area having no detectable PTEN staining (Ventana PTEN [SP218] assay).
“Caution is warranted in the clinical application [of the findings of IPATential150] unless this combination is subsequently found to improve overall survival.”— Hannah Dzimitrowicz, MD, and Andrew J. Armstrong, MD, ScM, FACP
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Additionally, the investigators used next-generation sequencing to explore and identify patients with predicted pathogenic alterations in PIK3CA/AKT1/PTEN. For this group of 250 patients, the stratified hazard ratio for disease progression or death was 0.63 (95% CI = 0.44–0.88), suggesting that additional alterations may predict benefit of dual AR/Akt inhibition (FoundationOne CDx next-generation sequencing assay). Further refinement of the ideal patient population for dual AR/Akt inhibition based on improved overall survival, including the optimal PTEN expression cutoff and/or inclusion of genomic alterations that may predict response, is of importance to improve outcomes in future studies.
Dual Akt/AR Inhibition: Mechanisms of Resistance and Future Studies
Because most patients, even those selected by PTEN loss, ultimately experienced disease progression, understanding the mechanisms of resistance to dual blockade of the Akt and AR pathways is of importance. Multiple mechanisms involved in resistance to abiraterone in metastatic castration-resistant prostate cancer, including alternatively spliced AR variants such as AR-V7 and lineage plasticity, and neuroendocrine differentiation, as well as alternative compensatory pathways that emerge from combined blockade, may be involved.6 Further work to examine tumor evolution during combined Akt/AR inhibition is important to better characterize resistance mechanisms and ensure that these mechanisms do not result in a more aggressive disease phenotype.
In IPATential150, 18% of patients received taxane-based chemotherapy prior to enrollment; however, patients did not receive a prior novel hormonal therapy such as abiraterone or enzalutamide. This differs from most patients now being diagnosed with metastatic castration-resistant prostate cancer in the United States, who will have received a novel hormonal therapy for metastatic castration-sensitive or nonmetastatic castration-resistant prostate cancer prior to disease progression to metastatic castration-resistant disease. Thus, it is not clear how applicable these findings of dual Akt/AR inhibition in previously untreated metastatic castration-resistant prostate cancer are to modern patients with metastatic castration-resistant prostate cancer, most of whom will have already received a novel hormonal therapy. With abiraterone now commonly prescribed for patients with metastatic castration-sensitive prostate cancer, the role of dual inhibition is perhaps most clinically applicable in this setting.
Building upon these findings in patients with PTEN-deficient metastatic castration-resistant prostate cancer, the ongoing CAPItello-281 study is evaluating the role of a selective oral pan-AKT inhibitor capivasertib in combination with abiraterone in patients with de novo metastatic castration-sensitive prostate cancer with PTEN-deficient tumors (ClinicalTrials.gov identifier NCT04493853). Although these results will not be available for several years, they will provide insight into the potential role of dual AR and Akt inhibition in patients with metastatic castration-sensitive prostate cancer.
Cautious Optimism
In the IPATential150 study, the addition of ipatasertib to abiraterone demonstrated significant improvement in radiographic progression-free survival for patients with PTEN-deficient metastatic castration-resistant prostate cancer, making this the first phase III study demonstrating clinically meaningful activity with dual AR and Akt pathway inhibition. The authors should be commended for harnessing the molecular understanding of reciprocal regulation of AR and PI3K/Akt and the role of PTEN loss in Akt signaling to improve outcomes for a common subset of patients with metastatic castration-resistant prostate cancer.
Although these results are promising early findings for dual AR and Akt inhibition in metastatic castration-resistant prostate cancer, caution is warranted in their clinical application unless this combination is subsequently found to improve overall survival, which remains the gold standard in this setting. In our opinion, the added costs as well as significant toxicities and pill burden for such modest improvements in an imaging-based endpoint alone without data on overall survival or quality of life do not merit approval nor use at this time. Further work is likely needed to examine resistance mechanisms and optimize identification of patients most likely to benefit from this targeted therapeutic approach.
Dr. Dzimitrowicz is a Hematology-Oncology Fellow in the Department of Medicine, Duke University School of Medicine, Durham, North Carolina. Dr. Armstrong is Professor of Medicine and Director of Research of the Duke Cancer Institute’s Center for Prostate and Urologic Cancers, Duke University, Durham, North Carolina.
DISCLOSURE: Dr. Dzimitrowicz reported no conflicts of interest. Dr. Armstrong has received honoraria from Dendreon, Janssen Oncology, and Sanofi; has served as a consultant or advisor to Astellas Scientific and Medical Affairs, AstraZeneca, Bayer, Clovis Oncology, Dendreon, Janssen Biotech, Medivation, Pfizer, and Sanofi; has served on the speakers bureau for Bayer, Dendreon, and Sanofi; has received institutional research funding from Active Biotech, Astellas Pharma, Bayer, Bristol Myers Squibb, Dendreon, Gilead Sciences, Janssen Oncology, Medivation, Novartis, Pfizer, Roche/Genentech, and Sanofi; received royalties or holds an institutional patent or other intellectual property for “circulating tumor cell novel capture technology”; and has been reimbursed for travel, accommodations, or other expenses by Astellas Scientific and Medical Affairs, Bayer, Dendreon, and Janssen Biotech.
REFERENCES
1. Carver BS, Chapinski C, Wongvipat J, et al: Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 19:575-586, 2011.
2. Robinson D, Van Allen EM, Wu YM, et al: Integrative clinical genomics of advanced prostate cancer. Cell 161:1215-1228, 2015.
3. de Bono JS, De Giorgi U, Rodrigues DN, et al: Randomized phase II study evaluating Akt blockade with ipatasertib, in combination with abiraterone, in patients with metastatic prostate cancer with and without PTEN loss. Clin Cancer Res 25:928-936, 2019.
4. Sweeney C, Bracarda S, Sternberg CN, et al: Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): A multicentre, randomised, double-blind, phase 3 trial. Lancet 398:131-142, 2021.
5. Halabi S, Roy A, Yang Q, et al: Radiographic progression-free survival as a surrogate endpoint of overall survival in men with metastatic castrate-resistant prostate cancer. 2021 ASCO Annual Meeting. Abstract 5057. Presented June 4, 2021.
6. Antonarakis ES, Lu C, Wang H, et al: AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 371:1028-1038, 2014.
