Separating the Pork from the Lamb Grillers

Memorial Day weekend is soon, so I can’t resist the barbeque analogy. Honestly, have you ever seriously messed up grilling pork ribs? All you need to do is slather on some barbeque sauce, place them on a medium-low heat grill and crack open a beer. The last part is optional but regardless they almost always come out tasting great. A rack of lamb, by contrast, will have you minding over it, jockeying constantly between the flame and simmer and back again to perfect that crusty surface and juicy medium rare center.   

In last month’s blog discussing the metastatic prostate cancer tumor microenvironment, I alluded to a recently published randomized phase 2 study of abiraterone actetate with the AKT inhibitor ipatasertib or placebo, and why this study may be an important paradigm for drug development in mCRPC.1 While preclinical studies inhibiting tyrosine kinase growth signals like IGF-1, and downstream targets like AKT, PI3K, and mTOR, have been promising, slapping them on the proverbial fire of metastatic castration-resistant prostate cancer (mCRPC) hasn’t translated into success.2-5 This ipatasertib study may explain why.  

Recognizing that PTEN status may suggest a potential genetic susceptibility to this pathway, and that inhibition of androgen signaling in the mCRPC setting is still important, this study enrolled heavily pretreated mCRPC patients, but also pre-specified a PTEN-null subpopulation that was determined by multiple assays, the results of which were kept blinded from patients and investigators. Mindful of this context, the median rPFS in patients with PTEN loss (43% of the overall population) improved from 4.6 to 11.5 months in the abiraterone alone versus combination with ipatasertib 400 mg /day (HR 0.39, 90% CI 0.22-0.70), while in PTEN intact patients there was no significant effect (HR 0.84 90% CI 0.51-1.37). Side effects aside for the moment, consider that this is the first positive study for a PI3K/Akt/mTOR-targeted therapy in a heavily pretreated mCRPC population, and partial validation of our preclinical models.

Was this random luck, or did the investigators masterfully prove a specific hypothesis, established preclinically, that inhibition of either androgen receptor (AR) or PI3K signaling results in a reciprocal activation of the other pathway?5,6 It is too early to tell, but maybe it was a bit of both. Interestingly, the clinical benefit seen in rPFS was not associated with a greater PSA response. This dissociation may be surprising to some, but it does not negate the clinical benefit seen. Although no difference in overall survival was seen in the PTEN-null cohort, the study was not set up for this endpoint. An ongoing Phase III trial (NCT03072238) will answer that question by testing abiraterone vs abiraraterone and ipatasertib in an earlier AR-targeted naïve, PTEN-null, mCRPC population. If these results are replicated they will not only define another role for the genomic profiling of tumors from our prostate cancer patients, but also offer validation that preclinical models can identify, beyond AR, actionable pathways that are clinical drivers of this disease.

Grill a perfect rack of lamb once and I am impressed. Do it a second time and I am coming over!  

Written by: Daniel J. George, MD, Medical Oncologist, Professor of Medicine, Professor of Surgery, Duke Cancer Institute, Durham, North Carolina

Published Date: May 20th, 2019

References:
1. Bono, Johann S. de, 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.” Clinical Cancer Research, American Association for Cancer Research, 1 Feb. 2019, clincancerres.aacrjournals.org/content/25/3/928.
2. Rieunier G et al. "Bad to the Bone: The Role of the Insulin-Like Growth Factor Axis in Osseous Metastasis," Clinical Cancer Research (Feb 2019) doi: 10.1158/1078-0432.CCR-18-2697. [Epub ahead of print] 
3. Kruczek K, et al. "A phase II study evaluating the toxicity and efficacy of single-agent temsirolimus in chemotherapy-naïve castration-resistant prostate cancer." Br J Cancer 109, 7 (2013): 1711-6.
4. Armstrong AJ, et al. "Phase II trial of the PI3 kinase inhibitor buparlisib (BKM-120) with or without enzalutamide in men with metastatic castration resistant prostate cancer." Eur J cancer 81, (Aug 2017): 228-36.
5. Yan Y, et al. "Evaluation and clinical analyses of downstream targets of the Akt inhibitor GDC-0068." Clin Cancer Res 19, 24 (2013): 6976-86.
6. Robinson D, et al. "Integrative clinical genomics of advanced prostate cancer." Cell 161, 5 (May 2015):1215-1228. doi: 10.1016/j.cell.2015.05.001.
7. Carver BS, et al. "Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer." Cancer Cell 19,5 (May 2011): 575-86. doi: 10.1016/j.ccr.2011.04.008.
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