A Multicenter Phase I/II Trial of Abiraterone Acetate + BEZ235 in Metastatic, Castration-Resistant Prostate Cancer

Prostate Cancer Overview:

Prostate cancer is the second most common cancer in men representing approximately 30% of all cancers diagnosed in men. When confined to the prostate gland the disease is curable with local therapy. However approximately 50% of men fail local therapy and develop incurable metastatic disease. Androgen deprivation (AD) therapy remains the mainstay of treatment, not only for advanced disease but also in the adjuvant and neo-adjuvant settings. Androgen deprivation therapy induces a remission in 80 to 90% of patients with advanced disease and results in a median progression-free survival of 12 to 33 months, at which time an androgen-independent phenotype usually emerges. This accounts for the median overall survival of 23 to 37 months from the initiation of androgen deprivation.

Androgen deprivation can be achieved surgically with orchiectomy, or using some form of drug treatment. Current approaches to AD utilize leutinizing hormone releasing hormone (LHRH) agonists. These act by continuous stimulation of the anterior pituitary resulting in inhibition of leutinizing hormone (LH) secretion, and hence a fall in testicular production of testosterone. Although AD is clinically effective in the majority of patients, studies have shown that extratesticular sources of testosterone represent an important alternative source of androgen stimulation in a significant proportion of prostate cancer patients. As much as 10% of baseline circulating testosterone remains in castrate men, due to the peripheral conversion of adrenal steroids to testosterone. Increased levels of androgen receptor confer resistance to antiandrogens in prostate cancer xenograft models. This could result in amplified signal output from circulating low levels of adrenal androgens and suggests a role for agents that target the adrenal androgen synthesis pathway.

As prostate cancer progresses to castration-resistant prostate cancer genetic events accumulate. One of the most consistent genetic findings in CRPC is amplification and over-expression of the androgen receptor (AR). Multiple groups have demonstrated that up-regulation of AR expression along with de novo synthesis of androgens by the adrenals and/or prostate cancer cells themselves is perhaps the most common mechanism by which prostate cancer cells progress despite castrate levels of circulating testosterone. This underlying biology is likely the mechanism explaining the recent success of Abiraterone Acetate.

An important genetic event found to be associated with progression of prostate cancer is loss of heterozygosity and subsequent homozygous deletion at the 10q23 locus containing the PTEN tumor suppressor gene. PTEN functions, in part, as a negative regulator of the phosphatidylinositol 3' (PI3) kinase - AKT pathway. Targeting the PI3K pathway and/or downstream targets of PI3K has been recognized as an important therapeutic strategy for some time. An important aspect of PI3K signaling is the PTEN mutation and the downstream events associated with PI3K signaling are not mutually exclusive with the aforementioned AR signaling pathway aberrancies that have yielded important therapeutic consequences. Preclinical data has demonstrated that PI3K inhibition upregulates AR expression, but that the net effect is antiproliferative and that concomitant anti androgen therapy is synergistic.

Introduction to BEZ235 and Abiraterone Acetate:

Preclinical data has demonstrated that PI3K inhibition upregulates AR expression, and that concomitant anti-androgen therapy has synergistic anti-tumor effects with PI3K inhibition. This study seeks to enhance the efficacy of Abiraterone Acetate in CRPC by concomitantly targeting PI-3Kinase activity with the novel agent BEZ-235.

BEZ235 is a potent pan-class I PI3K and mammalian target of rapamycin (mTOR) inhibitor belonging to the class of imidazoquinoline derivatives. BEZ235 is the investigational agent utilized in this study.

Abiraterone Acetate is now considered a standard of care for the treatment of Castration Resistant Prostate Cancer (CRPC) following docetaxel, and is likely to be considered such in the pre-chemotherapy setting based on recent results. Despite benefits in survival resistance to this therapy develops in virtually all patients.

Study rationale and purpose:

It is hypothesized that signaling through the PI3Kinase pathway is a major mechanism of resistance to Abiraterone Acetate therapy (and castration based therapy in general) and that inhibition of this pathway will enhance the clinical benefit of Abiraterone Acetate.

The addition of BEZ 235 to Abiraterone Acetate provides an opportunity to test if inhibition of PI3K along with TORC1 will attenuate the survival mechanisms co-opted by CRPC when treated with Abiraterone Acetate. We will conduct a Phase I study to determine the MTD for this combination and use that dose for this Phase II study. Biopsies of metastatic disease prior to and during treatment with BEZ235 plus Abiraterone Acetate will allow for the determination if mutations in the PTEN and/or PI3kinase axis in biopsied tumors are associated with response to therapy with the combination of BEZ235 and Abiraterone Acetate.

While PSA decline remains an imperfect surrogate marker for overall survival it remains a useful means of determining whether a positive clinical "signal" exists for a given treatment strategy and can be an efficient means of determining if an approach could proceed to more definitive testing according the standards of the Prostate Cancer Working Group 2 (PCWG2).