ASCO 2019: Genomic Predictors of Benefit of Docetaxel and Next-Generation Hormonal Therapy in Metastatic Castration Resistant Prostate Cancer - Medical Oncologist Perspective

Chicago, IL ( While there are 6 FDA approved therapies for men with metastatic castration-resistant prostate cancer, there are no prospectively validated biomarkers to help clinicians decide on the best sequencing of available therapies. Some data presented at this conference suggest that early chemotherapy may be beneficial for patients with high-risk disease (Abstract 5003, Updated results from a randomized phase II study of cabazitaxel (CAB) versus abiraterone (ABI) or enzalutamide (ENZ) in poor prognosis metastatic CRPC (mCRPC)). Prior studies have suggested that certain genomic characteristics may predict for poorer prognosis, such as PTEN loss.1 This study evaluates whether or not certain genomic characteristics can help predict benefit from either abiraterone/enzalutamide or docetaxel chemotherapy.
This abstract provides data on 157 patients with targeted exome sequencing of biopsies. Patients with pure small cell histology were excluded in the final analysis. The primary outcome was time from therapy to clinical or radiographic progression. Therapy was divided into two groups – group NHT was “next generation hormonal therapy” (abiraterone or enzalutamide) and group D was docetaxel. In terms of the biomarkers, DDR gene loss was defined as biallelic loss and tumor suppressor gene alterations were defined by both monoallelic and biallelic.  

The median overall survival for the entire group was 4.5 years from the time of mCRPC designation from the original abstract. Genes of interest included PTEN, TP53, RB1, BRCA2, ATM, AR amplification, and AR mutation. The NHT group as a whole had a median time to treatment failure of 12.2 months and the median time to treatment failure (TTTF) of docetaxel was 5.1 months. 
Based on the gene alterations, PTEN and TP53 alone did not affect TTTF or overall survival. RB1 biallelic loss predicts shorter TTTF for both therapies. AR amplification did not change the TTTF on ABI or ENZA, but AR mutations appeared to confer benefit for patients treated with abiraterone or enzalutamide.  
On the original abstract, the authors created a 0 to 2 scoring system, with one point earned for PTEN loss and one point earned for biallelic RB 1 loss. For patients with 0 points, the median TTTF was 14.7 months, vs 12 months for those with 1 point, and 3.8 months for those with 3 points. Updated date presented on the poster shows that patients with a combination of RB1+PTEN loss had worse time TTTF as well as patients with RB1 and TP53 loss. 

This exploratory analysis found biallelic RB1 loss is present in 12% of tumors and these patients have a shorter TTTF with either hormonal therapy or chemotherapy. If patients also had an additional PTEN or TP53 loss, this would worsen prognosis and survival. It is unclear what the sequencing of therapies was for these patients, as many patients received both NHT and docetaxel and this sequencing may impact the TTTF. Regardless, this analysis is thought-provoking and future studies should prospectively incorporate genomic biomarker analysis so we can better identify which therapies are most beneficial for our patients at the right time. 

Presented by: Anis Hamid, MBBS, Medical Oncologist, Melbourne Australia, GU Oncology Research Fellow, Dana-Farber Cancer Institute Boston, Massachusetts

Written by: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, @TheRealJasonZhu at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

  1. Sircar K, Yoshimoto M, Monzon FA, et al. PTEN genomic deletion is associated with p‐Akt and AR signaling in poorer outcome, hormone refractory prostate cancer. The Journal of Pathology: A Journal of the Pathological Society of Great Britain and Ireland 2009;218:505-13.