APCCC 2024: Update on the IRONMAN Project

(UroToday.com) The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) meeting featured a Movember session, and a presentation by Dr. Alicia Morgans and Dr. Daniel George discussing an update on the IRONMAN project. Dr. Morgans started by highlighting that the IRONMAN Executive Committee is made up of the following individuals:

  • Daniel George, MD – Co PI, Professor of Medicine, Duke University School of Medicine
  • Philip Kantoff, MD – Co PI, CEO and Co-Founder, Convergent Therapeutics
  • Lorelei Mucci, ScD – Co PI, Professor of Epidemiology, Harvard T.H. Chan School of Public Health
  • Jake Vinson – CEO, Prostate Cancer Clinical Trials Consortium, LLC
  • Paul Villanti – Executive Director, Programs, Movember Foundation

Dr. Morgans notes that the IRONMAN project has several key objectives:

  1. Describe the practice patterns of therapeutic agents for treatment of advanced prostate cancer internationally
  2. Assess whether specific treatment patterns are associated with clinically significant adverse events, and evaluate potential interactions with concomitant medications or demographic factors
  3. Identify associations between treatment sequences or combinations and overall survival
  4. Define the patient experience of men with advanced prostate cancer and identify unmet needs in their treatment
  5. Identify clinical and molecular disease subtypes that predict response to individual treatments, combinations, or sequences

The schedule of assessments for a patient in IRONMAN is as follows:

As of April 2024, there are 115 active sites, 2 pending activation, and open in 15 countries:

As of March 29, 2024, 4,172 patients have been screened, 4,051 men have been enrolled (97%), with the following complete global enrollment summary: 

Currently, the highest enrolling countries are USA (34%), Spain (13%), Canada (11%), and England (11%):

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Originally, the study projected that accrual would be complete by the end of 2021. These projections were revised when it became clear that site activations would take longer than originally expected, mainly at ex-US sites due to strict regulations and complicated contract negotiations. As expected, accrual was slowed during the early stages of the COVID-19 pandemic with a modest increase in the latter half of 2020. However, only US accrual was significantly affected, and there was fairly steady rates of accrual in many ex-US countries. IRONMAN is currently on course to finish accrual by Q1 2025, but considering the rapidly changing landscape in prostate cancer treatment, there is consideration to increase accrual rates, especially in the US.

To date, among 4,051 patients, 62% are white/Caucasian, and 15% are Black/African American/Black/Black British/Caribbean:

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Moreover, 70% (n = 2,841) of enrollees have mHSPC and 29% (n = 1,194) have CRPC:

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Generally, biospecimen compliance and PROMs compliance has been quite good, but does vary by disease state and country. One sub-study within IRONMAN is EMPRO (Engaging Men in Patient Reported Outcomes), one of the first studies in the world to test whether using regular remote monitoring of prostate cancer symptoms to trigger follow-up calls by clinicians would deliver better outcomes for men than the current standard of care:

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Up to 180 men who are already part of the IRONMAN study will be recruited to take part in the EMPRO sub-study. The men will be asked to complete a simple five-minute online questionnaire on their health and wellbeing once a month. As of March 29, 2024, 140 participants have been accrued to EMPRO:

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A second substudy in IRONMAN is PRODIGY, an observational study to describe effectiveness of olaparib in subjects with metastatic castration-resistant prostate cancer who have failed prior treatment with a new hormonal agent and carry selected homologous recombination repair gene mutations. This study is being led by Dr. Dan George, who presented this portion of the talk. The following is an overview of the HRR gene profile in subjects screened for the PROfound study with a reported biomarker (n = 2,792)1:

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The further detailed study design of PRODIGY is as follows:

  • Registry-based cohort study of subjects with mCRPC and a qualifying HRR mutation whose disease has progressed following prior treatment with an NHA (abiraterone, enzalutamide, apalutamide, or darolutamide)
  • Subjects will be drawn from the broad pool of subjects who are currently enrolled in IRONMAN (if they are being treated with olaparib and have relevant baseline assessments) or who are prospectively recruited in the IRONMAN registry
  • Subject follow-up will commence from the date of first treatment with olaparib and continue until death, loss to follow-up, or end of study
  • The study period will be from 2021 (start of the feasibility phase) through 2028 (the end of data collection for the sub-study) and may include subjects starting treatment with olaparib beginning in 2020

Dr. George notes that the Executive Committee welcomes scientific proposals for data/biospecimen analysis and sub-studies. There are two types of proposals:

  • Data Request: A retrospective analysis using existing registry data
    • Data request form template will be distributed to all attendees
  • Sub-Study: A prospective study leveraging IRONMAN’s infrastructure & registry data that requires additional prospective data collection

To date, IRONMAN has approved three sub-studies and 25 data requests. One such study (presented at the 2024 AACR meeting) assessed all US patients with mHSPC enrolled from January 1, 2018 to January 1, 2023 with a completed Physician Questionnaire at enrollment. This study examined patient characteristics, first-line treatments for mHSPC, and guideline concordance of treatments. Guideline concordant treatment was defined as a treatment regimen listed in the first NCCN guidelines version for the year prior to treatment. Patients enrolled in clinical trials were excluded. Guideline concordant treatments by year is as follows:

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The prevalence of guideline concordant first-line treatment by year and the rates of guideline concordant mHSPC treatment by group is highlighted in the following tables: 

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Propensity-weighted overall survival by treatment slightly favored the ADT + ARPI group:

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Dr. Morgans and Dr. George concluded their presentation by discussing an update on the IRONMAN project by thanking the IRONMAN Executive Committee, sponsors of the study, the PCCTC IRONMAN staff, and country lead principal investigators.

Presented by:

  • Alicia Morgans, MD, MPH, Dana Farber Cancer Institute, Boston, MA
  • Daniel George, MD, Duke University, Durham, NC 

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 Advanced Prostate Cancer Consensus Conference (APCCC) Meeting, Lugano, Switzerland, Thurs, Apr 25 - Sat, Apr 27, 2024.

References:

  1. de Bono J, Mateo J, Fizazi K, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 2020 May 28;382(22):2091-2102.