Poster Presentation 27th Lorne Cancer Conference 2015

The predictive value of ARv7 expression in localized prostate cancer treated with "super-castration" therapy. (#192)

Natalie J Kurganovs 1 2 3 , Niall M Corcoran 1 2 3 , Nicholas Howard 2 , Pat Bugeja 2 3 , Michael Kerger 2 , David Clarke 3 , Phil Dundee 2 3 , Jeremy Grummet 4 5 , Justin Peters 1 3 , John Pedersen 5 6 , Andrew Ryan 6 , Anthony Costello 1 2 3 , Paul Ruljancich 7 , Phillip Parente 5 7 , Christopher M Hovens 1 2 3
  1. The University of Melbourne, Parkville, VIC, Australia
  2. Australian Prostate Cancer Research Centre Epworth, Richmond, VIC, Australia
  3. Department of Surgery, Division of Urology, The Royal Melbourne Hospital, Parkville, VIC, Australia
  4. Alfred Hospital, Prahran, VIC, Australia
  5. Monash University, Clayton, VIC, Australia
  6. TissuPath Specialist Pathology Services, Mt Waverly, VIC, Australia
  7. Eastern Health and Epworth Eastern, Box Hill, VIC, Australia

Background:

In response to chemical castration in prostate cancer (CaP) treatment, Androgen Receptor splice variants (ARvs) are up regulated, and can activate transcription in the absence of a ligand. Recent evidence has indicated that Arv7 expression in circulating tumour cells is an accurate predictor of lack of response to abiraterone and enzalutamide – providing clinical support for the potential of Arv7 up regulation as a key mechanism in castration resistance. Limited data exists, however, regarding the expression of Arv7 in clinically localized CaP – it is currently unknown if expression in the primary tumour is similarly predictive.

Aim:

To determine the expression of Arv7 in high-risk disease, and correlate this with response to an Abiraterone-containing castrating treatment.

Method:

An open label non-randomized Phase II neoadjuvant study of ‘supercastration’ was performed in men with high-risk clinically localized CaP using an optimal 2-stage design (ACTRN12612000772842). Treatment consisted of degarelix 240/80mg q 1/12, abiraterone 1000mg OD, bicalutamide 50mg OD and prednisolone 5mg OD for 24 weeks. The primary endpoints were safety/tolerability and pT0 response rate. ARv7 expression was determined by immunohistochemistry and qRT-PCR in both pre- and post treatment tumor specimens, and correlated with pathological response. Fresh specimens from resistant tumors are currently being profiled by RNA-seq.

Results

17 patients were recruited to the study. The combination treatment was well tolerated, with hot flushes and fatigue being the most commonly reported side effects, and all patients completed six months of treatment. Six patients with asymptomatic elevation of liver transaminases required Abiraterone dose reductions, and there were no unexpected toxicities. 16 patients proceeded to prostatectomy: a pT0 response observed in one patient, with minimal residual disease present in another three patients. ARv7 expression was uniformly present in all pre-treatment specimens - neither level nor localization of expression predicted tumor response.

Conclusions

ARv7 expression in primary CaP does not predict response to abiraterone-based castration.