ASCO 2023: GUIDE: A Randomized Non-Comparative Phase II Trial of Biomarker-Driven Intermittent Docetaxel Versus Standard-of-Care Docetaxel in Metastatic Castration-Resistant Prostate Cancer (ANZUP 1903)

( The 2023 American Society of Clinical Oncology (ASCO) annual meeting held in Chicago, IL between June 2nd and June 6th was host to a prostate, testicular, and penile cancers poster session. Dr. Ciara Conduit presented the rationale and study framework of GUIDE (ANZUP 1903), a randomized, non-comparative phase II trial of biomarker-driven intermittent docetaxel versus standard-of-care docetaxel in metastatic castration-resistant prostate cancer (mCRPC).

Docetaxel has been FDA approved since 2004 for the treatment of patients with mCRPC, based on the results of the TAX-327 trial that demonstrated that use of docetaxel (75 mg/m2 every 3 weeks x 6 cycles), compared to mitoxantrone, was associated with significant improvements in overall survival (OS) from 16.5 to 18.9 months (HR: 0.76, 95% CI: 0.62 – 0.94; p=0.009).1 However, docetaxel use is associated with significant toxicities that may impact treatment tolerability, particularly in older patients and those with significant comorbidities. As such, treatment de-intensification in well-selected patients may allow for improved tolerability and quality of life outcomes, without compromising oncologic outcomes.

It has been previously demonstrated that among patients with mCRPC receiving docetaxel, a reduction in serum circulating levels of promoter methylated glutathione S-transferase Pi-1 (mGSTP1) DNA to undetectable levels after 2 cycles of chemotherapy is associated with significantly improved OS.2 As such, mGSTP1 may act as a predictive biomarker allowing for the selection of patients that may benefit from treatment de-escalation. This study aimed to evaluate the efficacy and safety of intermittent docetaxel chemotherapy guided by the presence or absence of circulating mGSTP1 DNA in patients with metastatic CRPC.

GUIDE (NCT04918810) is a randomized, two-arm, non-comparative phase 2 trial that will recruit 120 patients across eight Australian centers. Initially, patients with Prostate Cancer Working Group-3 (PCWG-3) defined metastatic CRPC who are commencing docetaxel 75mg/m2 q3w will be pre-screened for detectable mGSTP1 at baseline and then subsequently after two cycles of treatment only if they have detectable mGSTP1 at baseline. Only those with detectable plasma mGSTP1 at baseline that subsequently becomes undetectable after two cycles of chemotherapy will be study eligible.GUIDE study flow

Prior to the 4th cycle, eligible patients will be randomized in a 2:1 fashion to either:

  • Arm A: No further docetaxel, unless mGSTP1 becomes detectable again
  • Arm B: Continue docetaxel 75 mg/m2 q3w in accordance with current practice

The primary study endpoint is radiographic progression-free survival (rPFS). Secondary endpoints include:

  • Time on treatment holidays
  • Safety
  • Patient-reported outcomes
  • Overall survival
  • Health resource use and cost associated with treatment. 

This study will require 240 patients with detectable mGSTP1 at baseline to be screened. Assuming 50% of patients have undetectable mGSTP1 levels after two cycles, this will allow for 120 eligible subjects. Assuming a 10% dropout rate prior to radiographic progression, this study will have 90% power, at a one-sided type-1 error rate of 2.5%, to detect an rPFS curve with at least 50% rPFS at 12 months. To date, 3/120 patients have been enrolled.

Dr. Conduit concluded that GUIDE is the first study to prospectively evaluate the clinical utility of a circulating epigenetic biomarker (mGSTP1) for the selection of treatment de-intensification in prostate cancer, building upon existing data supporting its analytical and clinical validity. They anticipate that mGSTP1 will allow for the safe selection of patients eligible for treatment de-intensification and thus improve quality of life outcomes for mCRPC patients.

Presented by: Ciara Conduit, MBBS, FRACP, Australian & New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group, Camperdown, Australia

Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 2 – Tues, June 6, 2023.

  1. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-1512.
  2. Mahon KL, Qu W, Lin H-M, et al. Serum Free Methylated Glutathione S-transferase 1 DNA Levels, Survival, and Response to Docetaxel in Metastatic, Castration-resistant Prostate Cancer: Post Hoc Analyses of Data from a Phase 3 Trial. Eur Urol. 2019;76(3):306-312.