ASCO 2017: Rovalpituzumab tesirine as a therapeutic agent for Neuroendocrine Prostate Cancer

Chicago, IL ( Neuroendocrine prostate cancer (NEPC) represents a rare subtype of prostate cancer. NEPC represent a histologic subtype of prostate cancer that demonstrate low to absent AR expression and often have neuroendocrine features, and thus have low PSA production. As such, it may represent clinical progression and resistance to traditional therapies. 

Rova-T (Rovalpituzumab tesirine) an antibody-drug conjugate, has shown promising clinical activity against small cell lung cancer (SCLC). The antibody component targets the Notch ligand, Delta-like ligand 3 (DLL3), which is aberrantly expressed on the cell surface of SCLC and other neuroendocrine malignancies. Due to its presence on neuroendocrine cells similar to SCLC, the authors postulated that it may have efficacy in NEPC.

In this preclinical assessment, the authors evaluated the expression of DLL3 in a range of prostate tissues, and subsequently assessed in vitro efficacy of Rova-T. They utilized a 535 samples from a cohort of 395 patients, ranging from benign prostate (BEN), localized prostate adenocarcinoma (PCA), castration resistant adenocarcinoma (CRPC), and NEPC. 

First looking at mRNA and protein expression data, they found that DLL3 was expressed in the majority of NEPC (66%) and some CRPC patients (10%). Importantly, it was not expressed in any if the benign tissue or in the localized PCa samples. Looking at RNA-seq expression data, DLL3 was amongst the most differentially expressed genes in NEPC versus CRPC (p <= 0.0001, fold change = 71), and correlated with ASCL1 expression, RB1 genomic loss and inversely with AR expression. All of this suggested the DLL3 was indeed specific for NEPC rather than early prostate adenocarcinoma or CRPC.

In in vitro analysis of Rova-T in multiple prostate cancer cell lines demonstrated that it suppressed growth in DLL3-positive NEPC cell lines, but did not affect CRPC cell lines. Based on this preferential activity, clinical trials using Rova-T are currently recruiting (Clinical trial: NCT02709889). 

However, due to the rarity of the condition, I suspect accrual may be difficult. We eagerly await these results.

Presented By: Loredana Puca, MD, Weill Cornell Medical College, New York, NY

Co-Author(s): Verena Sailer, Kaitlyn Gayvert, Kumiko Isse, Michael Sigouros, David M. Nanus, Scott T. Tagawa, Juan Miguel Mosquera, Laura Saunders, Himisha Beltran

Institution(s): AbbVie Stemcentrx, San Francisco, CA; Sandra and Edward Meyer Cancer Center, New York, NY; Department of Medicine, Institute for Precision Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, NY; Stemcentrx, Inc., San Francisco, CA

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto
Twitter: @tchandra_uromd

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 - Chicago, Illinois, USA