Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway has been strongly linked with prostate cancer progression and metastatic potential.1 Loss of the inhibitory phosphatase, PTEN, leading to hyperactivation of PI3K/AKT/mTOR oncogenic signaling, occurs in 40-50% of metastatic castration-resistant prostate cancer.1,2 Not surprising is the fact that PTEN loss in patients with metastatic castration-resistant prostate cancer is associated with a worse prognosis and less benefit from androgen receptor (AR) blockade.3 Likewise, PTEN loss and subsequent Akt activation confer radiation4 and chemotherapy5, 6 resistance.
Highly relevant to therapeutic development in prostate cancer, PI3K/Akt/mTOR and AR signaling pathways regulate one another through reciprocal feedback mechanisms.7, 8 Since AR blockade is the hallmark of initial systemic therapy for men with advanced prostate cancer, the recognition that the PI3K/Akt/mTOR is subsequently activated, enabling prostate cancer cell survival, offers a rational therapeutic target in this situation.
Early attempts to inhibit this signaling pathway were dedicated to the inhibition of mTOR. Rapamycin offered a pharmacodynamic effect to inhibit the intended target, however, there was no significant antineoplastic activity.9, 10 TORC1 inhibitors, temsirolimus11, 12 and everolimus13, 14 also lacked significant efficacy. It was actually not surprising that these agents lacked efficacy, as sole inhibition of TORC1 will lead to downregulation of S6Kinase, a negative regulator of TORC2. TORC2 will then serve as positive feedback to further activate Akt.15 Hence, this theory and subsequent preclinical data supported the superior efficacy of dual TORC1 and TORC2 inhibition over TORC1 inhibition alone, and the result was prevention of prostate cancer invasion and induction of apoptosis.16 Unfortunately, early attempts at dual inhibition TORC1 and TORC2, with agents like dactolisib (BEZ2350)17, 18 and MLN012819 have been met with significant toxicity and limited efficacy.
As dactolisib is also a pan-PI3K inhibitor, early attempts at PI3K inhibition in prostate cancer have also been met with limited efficacy. PX-866 also had very modest single-agent activity and an attempt to add abiraterone to reverse resistance due to reciprocal activation between AR and PI3K/Akt/mTOR signaling was not successful.20 Buparlisib (BKM-120) is the most widely studied PI3K inhibitor in prostate cancer. The strategy to reverse resistance saw the addition of buparlisib to novel AR pathway inhibitors, abiraterone17, and enzalutamide,21 yet efficacy results were also disappointing.
Naturally, another key component of the PI3K/Akt/mTOR pathway to explore is to inhibit Akt. In the PROCAID trial, capivasertib (AZD5363), an oral pan-Akt inhibitor, was combined in a Phase I clinical trial with docetaxel and prednisolone for patients with metastatic castration-resistant prostate cancer, and a recommended Phase II dose was determined for this combination.22 Ipatasertib, an oral small molecule that binds to the ATP-binding pocket of all three isoforms of Akt, has been the most studied Akt inhibitor in prostate cancer. A randomized Phase II trial demonstrated that ipatasertib, in combination with abiraterone, led to prolonged radiographic progression-free survival (rPFS) over placebo with abiraterone.23 The effect on rPFS was even greater in patients with PTEN-loss in their tumors compared to those with intact PTEN.
As a result, the IPATential150 randomized, Phase III trial of abiraterone with ipatasertib 400 mg PO QD vs. abiraterone with placebo was recently performed, and an oral presentation was delivered at the European Society of Medical Oncology.24 The trial randomized 1,101 patients in a 1:1 fashion with co-primary endpoints of investigator-assessed rPFS by Prostate Cancer Working Group 3 criteria in the intention to treat (ITT) population and also in the PTEN-loss population.25 PTEN-loss was defined by immunohistochemistry using a different method than many other clinical trials, which typically require at least 90% of tumor area with no detectable PTEN staining. In this trial, only a minimum of 50% of the specimen’s tumor area with no detectable PTEN staining by the Ventana SP218 antibody was required to be included in the PTEN-loss group. These criteria were met by 521 patients. The most striking finding from the trial was that that rPFS was improved in the ipatesertib plus abiraterone group over the placebo plus abiraterone group (median rPFS 18.5 vs. 16.5 months, respectively), with a stratified hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.61-0.98, p=0.0335, statistical significance set at α=0.05). For practical purposes, rPFS in the next generation sequencing defined PTEN-loss population was also significant with a median rPFS 19.1 vs. 14.2 months, respectively (HR 0.65; 95% CI 0.45-0.95, p=0.0206). The ITT population was not statistically significant (median rPFS 19.2 vs. 16.6 months, respectively) with a stratified HR 0.84; 95% CI 0.71-0.99, p=0.0431, statistical significance set at α=0.01). Secondary endpoints of confirmed objective response, PSA response, and time to PSA progression all favored the ipatasertib arm. At this time, overall survival data is not yet mature.
The above data is incredibly intriguing. The body of evidence is that the PI3K/Akt/mTOR signaling pathway is highly important in advanced prostate cancer. Yet we just have not had the therapeutic agents or clinical trials to be able to conclusively prove clinical benefit. The hope is that the data with ipatasertib successfully matures and that we better learn how to identify and define the PTEN-loss population. In the meantime, there are multiple ongoing clinical trials with ipatasertib and other Akt inhibitors that we have an opportunity to accrue to. The promising results above should only encourage us to have greater enthusiasm to accrue to these trials below.
Highlighted trials testing Akt inhibitors in patients with metastatic prostate cancer:
- Phase 1b trial of ipatasertib in combination with atezolizumab and docetaxel for metastatic castration-resistant prostate cancer (NCT04404140)
- IceCAP – Phase 1 trials of ipatasertib in combination with atezolizumab for metastatic castration-resistant prostate cancer with PTEN-loss (NCT03673787)
- PC-BETS – ctDNA driven precision design including an ipatasertib cohort (NCT03385655)
- Phase 1b trial of ipatasertib or apitolisib with abiraterone vs. abiraterone alone in metastatic castration-resistant prostate cancer patients previously treated with docetaxel (also includes a lower ipatasertib 200 mg PO QD dosing arm) (NCT01485861)
- CAPItello-281 – Randomized phase 3 trial of capivasertib plus abiraterone plus androgen deprivation therapy vs. placebo plus abiraterone plus androgen deprivation therapy for PTEN deficient metastatic hormone-sensitive prostate cancer (NCT04493853)
- Phase 1/2 trial of afuresertib with androgen synthesis enzyme inhibitor, LAE001 in metastatic castration-resistant prostate cancer patients who have received at least 2 novel hormonal therapy agents and docetaxel or cabazitaxel (NCT04060394)
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2. Robinson, Dan, Eliezer M. Van Allen, Yi-Mi Wu, Nikolaus Schultz, Robert J. Lonigro, Juan-Miguel Mosquera, Bruce Montgomery et al. "Integrative clinical genomics of advanced prostate cancer." Cell 161, no. 5 (2015): 1215-1228.
3. Jamaspishvili, Tamara, David M. Berman, Ashley E. Ross, Howard I. Scher, Angelo M. De Marzo, Jeremy A. Squire, and Tamara L. Lotan. "Clinical implications of PTEN loss in prostate cancer." Nature Reviews Urology 15, no. 4 (2018): 222.
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5. Grünwald, Viktor, Linda DeGraffenried, Douglas Russel, William E. Friedrichs, Ratna B. Ray, and Manuel Hidalgo. "Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells." Cancer research 62, no. 21 (2002): 6141-6145.
6. Qian, David Z., Brooks LS Rademacher, Janet Pittsenbarger, Chung‐Ying Huang, Anne Myrthue, Celestia S. Higano, Mark Garzotto, Peter S. Nelson, and Tomasz M. Beer. "CCL2 is induced by chemotherapy and protects prostate cancer cells from docetaxel‐induced cytotoxicity." The Prostate 70, no. 4 (2010): 433-442.
7. Carver, Brett S., Caren Chapinski, John Wongvipat, Haley Hieronymus, Yu Chen, Sarat Chandarlapaty, Vivek K. Arora et al. "Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer." Cancer cell 19, no. 5 (2011): 575-586.
8. Mulholland, David J., Linh M. Tran, Yunfeng Li, Houjian Cai, Ashkan Morim, Shunyou Wang, Seema Plaisier et al. "Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth." Cancer cell 19, no. 6 (2011): 792-804.
9. Amato, Robert J., Jaroslaw Jac, Taqi Mohammad, and Somya Saxena. "Pilot study of rapamycin in patients with hormone-refractory prostate cancer." Clinical genitourinary cancer 6, no. 2 (2008): 97-102.
10. Armstrong, Andrew J., George J. Netto, Michelle A. Rudek, Susan Halabi, David P. Wood, Patricia A. Creel, Kelly Mundy et al. "A pharmacodynamic study of rapamycin in men with intermediate-to high-risk localized prostate cancer." Clinical cancer research 16, no. 11 (2010): 3057-3066.
11. Kruczek, K., M. Ratterman, K. Tolzien, S. Sulo, T. M. Lestingi, and C. Nabhan. "A phase II study evaluating the toxicity and efficacy of single-agent temsirolimus in chemotherapy-naïve castration-resistant prostate cancer." British journal of cancer 109, no. 7 (2013): 1711-1716.
12. Armstrong, Andrew J., Tong Shen, Susan Halabi, Gabor Kemeny, Rhonda L. Bitting, Patricia Kartcheske, Elizabeth Embree et al. "A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer." Clinical genitourinary cancer 11, no. 4 (2013): 397-406.
13. Templeton, Arnoud J., Valerie Dutoit, Richard Cathomas, Christian Rothermundt, Daniela Bärtschi, Cornelia Dröge, Oliver Gautschi et al. "Phase 2 trial of single-agent everolimus in chemotherapy-naive patients with castration-resistant prostate cancer (SAKK 08/08)." European urology 64, no. 1 (2013): 150-158.
14. George, Daniel J., Susan Halabi, Patrick Healy, Darius Jonasch, Monika Anand, Julia Rasmussen, Sarah Y. Wood, Charles Spritzer, John F. Madden, and Andrew J. Armstrong. "Phase 2 clinical trial of TORC1 inhibition with everolimus in men with metastatic castration-resistant prostate cancer." In Urologic Oncology: Seminars and Original Investigations, vol. 38, no. 3, pp. 79-e15. Elsevier, 2020.
15. Bitting, Rhonda L., and Andrew J. Armstrong. "Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer." Endocrine-related cancer 20, no. 3 (2013): R83-R99.
16. Hsieh, Andrew C., Yi Liu, Merritt P. Edlind, Nicholas T. Ingolia, Matthew R. Janes, Annie Sher, Evan Y. Shi et al. "The translational landscape of mTOR signalling steers cancer initiation and metastasis." Nature 485, no. 7396 (2012): 55-61.
17. Massard, Christophe, Kim Nguyen Chi, Daniel Castellano, Johann de Bono, Gwenaelle Gravis, Luc Dirix, Jean-Pascal Machiels et al. "Phase Ib dose-finding study of abiraterone acetate plus buparlisib (BKM120) or dactolisib (BEZ235) in patients with castration-resistant prostate cancer." European journal of cancer 76 (2017): 36-44.
18. Wei, Xiao X., Andrew C. Hsieh, Won Kim, Terence Friedlander, Amy M. Lin, Mirela Louttit, and Charles J. Ryan. "A phase I study of abiraterone acetate combined with BEZ235, a dual PI3K/mTOR inhibitor, in metastatic castration resistant prostate cancer." The oncologist 22, no. 5 (2017): 503.
19. Graham, Laura, Kalyan Banda, Alba Torres, Brett S. Carver, Yu Chen, Katie Pisano, Greg Shelkey et al. "A phase II study of the dual mTOR inhibitor MLN0128 in patients with metastatic castration resistant prostate cancer." Investigational new drugs 36, no. 3 (2018): 458-467.
20. Hotte, Sebastien J., Kim N. Chi, Anthony M. Joshua, Donsheng Tu, Robyn J. Macfarlane, Rirchard W. Gregg, Joseph D. Ruether et al. "A phase II study of PX-866 in patients with recurrent or metastatic castration-resistant prostate cancer: canadian cancer trials group study IND205." Clinical genitourinary cancer 17, no. 3 (2019): 201-208.
21. Armstrong, Andrew J., Susan Halabi, Patrick Healy, Joshi J. Alumkal, Carolyn Winters, Julie Kephart, Rhonda L. Bitting 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." European Journal of Cancer 81 (2017): 228-236.
22. Crabb, Simon J., Alison J. Birtle, Karen Martin, Nichola Downs, Ian Ratcliffe, Tom Maishman, Mary Ellis et al. "ProCAID: a phase I clinical trial to combine the AKT inhibitor AZD5363 with docetaxel and prednisolone chemotherapy for metastatic castration resistant prostate cancer." Investigational new drugs 35, no. 5 (2017): 599-607.
23. de Bono, Johann S., Ugo De Giorgi, Daniel Nava Rodrigues, Christophe Massard, Sergio Bracarda, Albert Font, Jose Angel Arranz Arija 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 25, no. 3 (2019): 928-936.
24. de Bono, J. S., S. Bracarda, C. N. Sternberg, K. N. Chi, D. Olmos, S. Sandhu, C. Massard et al. "IPATential150: Phase III study of ipatasertib (ipat) plus abiraterone (abi) vs placebo (pbo) plus abi in metastatic castration-resistant prostate cancer (mCRPC)." Annals of Oncology 31, no. S4 (2020): 1153-1154.
25. Scher, Howard I., Michael J. Morris, Walter M. Stadler, Celestia Higano, Ethan Basch, Karim Fizazi, Emmanuel S. Antonarakis et al. "Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3." Journal of Clinical Oncology 34, no. 12 (2016): 1402.