SUO 2018: Targeting the Adaptive Molecular Landscape of Castration-Resistant Prostate Cancer

Phoenix, Arizona ( Following a glowing introduction by Dr. Christopher Evans and receipt of the Huggins Medal by Dr. Gleave, Dr. Gleave gave a talk on targeting the adaptive molecular landscape of castration-resistant prostate cancer (CRPC).

Targeting the androgen axis has been the mainstay of prostate cancer treatment for decades – but no matter how much progress has been made, the persistent problem is acquired treatment resistance. He delved slightly into his early foray into this area that led to his lifelong research in this field. He then briefly touched upon the recent work of the Stand Up 2 Cancer (SU2C) work looking at the genomic profiling of mCRPC, as a culmination of the work to date – and the identification of distinct treatment resistant histologic entities in the mCRPC space. These are landmark papers that will help further shape the future management of treatment resistance.

The treatment landscape right now in 2018:

Figure 1

However, molecular subclassification is the key to begin stratified approaches to treatment – along with availability of drugs that specifically target biomarker defined cancer vulnerabilities. One of those molecular subclassifications is the separation of CRPC into AR driven and AR Quiescent prostate cancers, along with further substratification into MSI and DNA repair deficient tumors. These have treatment implications for patients as well.

He made a point to emphasize that in the era of Precision Medicine, driven by genomics, the urologic oncologist is slowly being driven out of the decision-making process – so we need to take an extra effort to stay engaged and adapt! Otherwise, we may become obsolete in the process!

“Tissue is an Issue” – part of the problem with mCRPC is the limitations of tissue biopsy in these patients. Which lesion do you biopsy? Which is the driver lesion? Or do all the lesions (and the primary) have an impact on disease progression? If so, how do you capture the landscape as a whole? He feels the future is in liquid biopsies, and his team at UBC and the Prostate Centre are working on that. Liquid biopsies (from serum) homogenizes the heterogeneity, but still captures the intertumoral heterogeneity.
  • ctDNA was able to capture AR-mutation and AR-amplification, and was prognostic for short PFS
  • ctDNA was highly concordant with mCRPC tissue biopsy, but also captures intra-patient heterogeneity better than a single site biopsy
  • Somatic landscape amongst patients with quantifiable ctDNA was similar to prior studies of tissue biopsies
  • You can detect actionable mutations using ctDNA
  • ctDNA was also able to track treatment-induced AR genomic alterations, including those that would guide drug selection
  • Enables monitoring in the real-time as multiple samples can be taken over the course of treatment
However, he also made a point to note that there can be large discrepancies between the transcriptome and the proteins actually made – so further efforts need to be made to examine the proteome!

Lastly, he noted that stress responses are coopted by cancer cells to survive treatment and drive resistance. These may represent nodes to manipulate cancer cell sensitivity to therapy.
OGX-011, which targeted CLU, was one such agent that he was involved in – had great preclinical and presurgery phase II results. But, unfortunately, did not pan out in phase III studies.

Lessons learned:
  • Phase II proof of concept challenging in combo trials
  • Shifting treatment landscape
  • Preclinical modelling imprecise

OGX-427, which inhibits Hsp27, has also been shown to have response in CRPC
  • 50% reduction in PSA in 47% of CRPC patients (vs. 27% placebo)
  • Further work is pending with this agent

His take-home points are seen below:

Screen Shot 2018 11 30 at 9.43.44 AM

Presented By: Martin E. Gleave, MD, FRCSC, FACS

Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, @tchandra_uromd, @TjuUrology, at the 19th Annual Meeting of the Society of Urologic Oncology (SUO), November 28-30, 2018 – Phoenix, Arizona