SUO 2018: Signal Transduction Pathways – ADT + AKT trials

Phoenix, Arizona ( The tumor suppressor PTEN is the gate keeper of the PI3K pathway, regulating down-stream signaling and protein expression. It is lost in 20% of prostate cancers and in 40% of castrate resistant prostate cancers (CRPC), and its loss has been shown to drive prostate tumorigenesis and result in aggressive prostate cancer resulting in the castrate resistant phenotype. The PI3K signaling pathway is involved in cellular metabolism and survival, protein synthesis and growth through the exchange of phosphates (e.g. PIP3). Inhibitors have been developed for multiple components of the pathway such as PI3K, AKT, mTOR 1 and/or 2.

Studies of PI3K pathway inhibitors in the preclinical setting have revealed tremendous feedback mechanisms in these pathways which modulate aberrant signaling to maintain homeostasis. It has been shown when inhibitors are utilized, there is relief of feedback inhibition leading to hyperactivation of upstream pathways. Inhibition of mTOR, for example, results in activation of androgen receptor (AR) targeted gene expression. Inhibition of PI3K similarly results in feedback inhibition of itself and other tyrosine kinases that are inhibiting AR signaling, resulting in increased AR expression. By combining multiple inhibitors of the pathway, there are up to 90% tumor regression rates. A Phase 1B trial of CC-115 (dual mTOR 1 and 2 and DNA-PK inhibitor) revealed that most of the inhibition results from mTOR and not DNA-PK inhibition.

A Phase II clinical trial of ipatasertib (AKT3 inhibitor) and abiraterone in men with chemo-refractory metastatic CRPC was performed. No patients had previously received abiraterone, and only 10% had previously been treated with enzalutamide. Overall, the treatment was well tolerated with a 10% discontinuation rate (2% had hyperglycemia, 2% had grade III diarrhea). They found that patients who had loss of PTEN had significant improvements in progression-free survival with treatment. For patients with wild-type PTEN, there was still a slight benefit, though it was not statistically significant. Given these study findings, a Phase III trial has been developed.

In summary, PI3K pathway alterations are important in metastatic CRPC. The PI3K and AR pathways are interconnected and reciprocally regulate one another through negative feedback, necessitating combination therapy for maximal efficacy. Results from recent Phase II clinical trials of ipatasertib and abiraterone have prompted the development of Phase III clinical trials in the first-line metastatic CRPC setting and in the neo-adjuvant setting in patients with high-risk prostate cancer. Defining mechanisms of response and resistance to these combination therapies remains important.

Presented By: Brett S. Carver, MD, Memorial Sloan Kettering Cancer Center

Written by: Selma Masic, MD, Society of Urologic Oncology Fellow, Fox Chase Cancer Center, Philadelphia, PA, @selmasic, at the 19th Annual Meeting of the Society of Urologic Oncology (SUO), November 28-30, 2018 – Phoenix, Arizona