A phase II study of the dual mTOR inhibitor MLN0128 in patients with metastatic castration resistant prostate cancer

Abstract

Background MLN0128 is a first-in-class, dual mTOR inhibitor with potential to outperform standard rapalogs through inhibition of TORC1 and TORC2. This phase II study was designed to assess antitumor activity of MLN0128 in metastatic castration-resistant prostate cancer (mCRPC). Methods Eligible patients had mCRPC previously treated with abiraterone acetate and/or enzalutamide. Five patients started MLN0128 at 5 mg once daily, subsequently dose reduced to 4 mg because of toxicity. Four subsequent patients started MLN0128 at 4 mg daily. Primary endpoint was progression-free survival at 6 months. Results Nine patients were enrolled and median time on treatment was 11 weeks (range: 3-30). Best response was stable disease. All patients had a rise in PSA on treatment, with a median 159% increase from baseline (range: 12-620%). Median baseline circulating tumor cell count was 1 cell/mL (range: 0-40); none had a decrease in cell count posttreatment. Grade ≤ 2 adverse events included fatigue, anorexia, and rash. The most common serious adverse events were grade 3 dyspnea and maculopapular rash. Eight patients discontinued treatment early because of radiographic progression (n = 1), grade 3 toxicity (n = 5), or investigator discretion (n = 2). Four patients had immediate PSA decline following drug discontinuation, suggesting MLN0128 could cause compensatory increase of androgen receptor (AR) activity. Correlative studies of pretreatment and posttreatment biopsy specimens revealed limited inhibition of AKT phosphorylation, 4EBP1 phosphorylation, and eIF4E activity. Conclusions Clinical efficacy of MLN0128 in mCRPC was limited likely due to dose reductions secondary to toxicity, PSA kinetics suggesting AR activation resulting from mTOR inhibition, and poor inhibition of mTOR signaling targets.

Keywords: MLN0128; Prostate cancer; mTOR.

Fig. 1

Time on study and reasons for discontinuation in patients with advanced prostate cancer (n = 9). Nine patients with castration-resistant prostate cancer were treated during the study. Median time in the study was 11 weeks. Eight patients discontinued treatment before the study endpoint was reached because of unacceptable toxicity (5 patients), radiographic progression (1 patients), and investigator discretion (2 patients)

Fig. 2

A) Maximal percent PSA change from baseline. The greatest percent PSA change from baseline for each patient at any time during the study is shown. This constituted a PSA rise for all 9 patients (range: 12%–620%). B) Upon withdrawal of MLN0128, 4 of 9 patients exhibited a PSA decline after >1 week. C) PSA kinetics with initiation and withdrawal of MLN0128 in patient 1

Fig. 3

Genetic alterations in biopsy specimens from patients with metastatic CRPC. Six of 9 patients had biopsy samples sequenced using the in-house proprietary targeted genomic sequencing test MSK-IMPACT. Biopsy site, temporal relationship to treatment, and specific genetic alterations are shown. * = stop codon

Fig. 4

Effects of MLN0128 therapy on downstream signaling targets. Immunohistochemical and immunofluorescence analysis was done on biopsy specimens for patients who had available specimens from before treatment and after 4 weeks on treatment. Tissues were stained for PTEN, the mTORC1 targets rpS6 and 4EBP1, and the mTORC2 substrate AKT. rpS6 phosphorylation was decreased in 2 of 3 patients posttreatment. However, AKT and 4EBP1 did not display any decrease in phosphorylation in the posttreatment setting. All representative images were taken at 20× magnification

Fig. 5

The proximity ligation assay (PLA) was used to assess eIF4E activity in pretreatment and posttreatment biopsy tissues. eIF4E activity is elevated in posttreatment tissues of 2 patients (out of 3). All representative images were taken at 20× magnification