A randomized phase II study of bicalutamide (BIC) followed by placebo or gamma secretase inhibitor RO4929097 (RO492) in men with rising PSA.

Abstract

219 Background: Notch signaling is a key determinant of cell fate. RO492 is a selective γ-secretase inhibitor blocking cleavage of Notch. We hypothesize that anti-androgen therapy will lead to an enriched population of basal prostate cancer stem cells. Targeting Notch following anti-androgen treatment will lead to delay in re-growth of mature luminal PC cells. We are using a novel double blind, placebo controlled randomized discontinuation design to treat men with rising PSA. A non-castrating anti-androgen (BIC) was used to induce initial tumor regression Methods: Pts with rising PSA after primary therapy for PC, and no radiographic evidence of disease were enrolled in this ongoing study. All pts received BIC 50mg/day for 16 weeks (induction phase). Pts achieving a >50% (modified from 80% decrease after the first 8 pts) decrease in PSA were randomized to placebo or RO492 20mg orally 3 days on/ 4 days off per week (randomization phase). Primary endpoint is PSA progression (increase in PSA by 50% over nadir with minimum PSA rise of 2ng/mL) during randomization phase. Pts meeting primary endpoint could receive 12 months of RO492 and BIC (combination phase). Serum is collected for evaluation of soluble markers of gamma secretase inhibition. 29 pts/arm in randomization phase gives 90% power to detect a decrease in1 yr PFS from 80% to 45% with 5% alpha. Results: We report on the first 16 patients that have enrolled. Median pretreatment PSA was 6.3ng/ml (0.35 to 34). 9 of 16 pts on the induction phase came off study due to PSA progression, although 5 of 9 pts would have been randomized using the 50% PSA response criteria. 6 pts have been randomized to RO492 or placebo (1 pt not yet randomized) and 2 pts have proceeded to combination phase. Median PSA decrease during induction phase in 6 pts who went on to randomization was 86% (69–97). Overall decline in PSA in induction phase was 67% (7.3-99%). Placebo/RO492 has been well tolerated with 1 pt experiencing g1 fatigue, and 1 pt experiencing g1 nausea in the combination phase. 8/16 pts had g1 breast tenderness with BIC. Conclusions: In this ongoing randomized phase II trial, BIC decreased PSA by >50% in 12/16 pts. Placebo/RO492 is well tolerated. Enrollment continues with analysis of plasma correlates to be compared to clinical results.

Castration-resistant prostate cancer: potential targets and therapies

“… 80 , 82 The primary results of this randomized Phase II study show that bicalutamide decreased PSA by more than 50% in 12/16 patients and RO4929097 was well tolerated. 80 …”

“…Ligand-dependent activation of notch requires cleavage by gamma-secretase complex (see Stein et al80 and references therein). Gamma-secretase inhibitors have been tested for their anticancer potential in preclinical and clinical trials for various cancer types 80. Recent studies have shown that several natural compounds mimic gamma-secretase inhibitors and thereby inhibit CRPC cell growth by inhibiting gamma-secretase (see Kim et al81 and references therein).…”

“…Whether targeting gamma-secretase would be beneficial in CRPC patients is not yet clear due to the conflicting studies regarding role of notch in CaP. At present, a National Cancer Institute-sponsored clinical trial (Phase II) is underway to test gamma-secretase inhibitor RO4929097 alone and in combination with bicalutamide for treating CaP patients who previously underwent definitive local therapy for prostatic adenocarcinoma in humans 80,82. The primary results of this randomized Phase II study show that bicalutamide decreased PSA by more than 50% in 12/16 patients and RO4929097 was well tolerated 80…”

“… 79 This study showed that reactivating miR-200 causes a reduction in NOTCH-1 activity, thus inhibits the prostatosphere-forming ability of CaP cells. 79 Ligand-dependent activation of notch requires cleavage by gamma-secretase complex (see Stein et al 80 and references therein). Gamma-secretase inhibitors have been tested for their anticancer potential in preclinical and clinical trials for various cancer types.…”

“…Gamma-secretase inhibitors have been tested for their anticancer potential in preclinical and clinical trials for various cancer types. 80 Recent studies have shown that several natural compounds mimic gamma-secretase inhibitors and thereby inhibit CRPC cell growth by inhibiting gamma-secretase (see Kim et al 81 and references therein). Whether targeting gamma-secretase would be beneficial in CRPC patients is not yet clear due to the conflicting studies regarding role of notch in CaP.…”