A phase 2 study of the aurora kinase A inhibitor alisertib for patients with neuroendocrine prostate cancer (NEPC)

Background

NEPC is an aggressive androgen independent subtype of castration resistant prostate cancer. We previously showed that N-myc and Aurora A cooperate to drive the NEPC phenotype (Beltran et al, Cancer Discov 2011; Dardenne et al Cancer Cell in press). Targeting Aurora A with alisertib inhibits the allosteric interaction between Aurora A and N-myc and suppresses NEPC signaling and tumor growth in preclinical studies.

Methods

This is a multicenter Phase 2 study of alisertib 50mg BID x7d q21d for pts with metastatic prostate cancer and at least one: 1) NEPC morphology; 2) >50% NE marker IHC; 3) new liver metastases without PSA progression; 4) >3-5X serum NSE/CgA. Primary endpoint is 6-mo PFS, requiring 48 evaluable patients to detect > 30% PFS rate. Mandatory metastatic biopsy was assessed by whole exome/RNA-seq and pt-derived organoids were developed. Exploratory objectives are association of tumor molecular features and ctDNA with clinical features and response.

Results

59 pts (41 (70%) pathologic criteria, 26 (44%) clinical) were treated. Median age was 67 yrs (45-87), median PSA 1.13 ng/ml (0.01-514.2), and # of prior therapies 4 (15% enza/abi, 30% docetaxel, 29% platinum). Metastatic sites were bone (78%,), lymph node (73%), lung (37%), and liver (61%). Of 56 evaluable pts, median PFS was 8.7 wks (8.0-10.4), 6 mo PFS 11.1% (16.3% for path NEPC; 5-31.6%), and median OS 38 wks (29.4-52.3). For those with scans SD/PR/CR at C3 (n = 17), median PFS was 20 wks (17-121) and 6 mo PFS was 35.8% (18.1% - 70.9%). Grade 3/4 toxicities identified in 5(9%) pts. 2 pts achieved exceptional response including complete resolution of liver metastases and a 3rd pt has stable disease at 39 mo follow-up. Correlation of molecular alterations (AURKA/MYCN, AR signaling, RB1/TP53) with clinicopathological features and characterization of exceptional responders including organoids will be presented.

Conclusions

A subset of patients with clinical/pathologically defined NEPC may benefit from single-agent alisertib. Integration of clinical, pathologic, and molecular features and characterization of exceptional response may improve patient selection. No new toxicity concerns were identified.

Clinical trial identification

NCT01799278

Legal entity responsible for the study

N/A

Funding

Millenium

Disclosure

H. Beltran: Received research funds from Takeda/Millenium to conduct this study. All other authors have declared no conflicts of interest.