Q&A with the STEEL Study Principal Investigator, Dr. Edwin Posadas
March 21, 2023
RTOG Foundation (RTOGF) recently interviewed Dr. Edwin Posadas, the Principal Investigator of the RTOG 3506 “STEEL” study for men with post-prostatectomy PSA recurrences with aggressive disease failures. Read more about Dr. Posadas’s experience with conducting his trial through RTOGF and the advice he has for investigators interesting in running their own trials with RTOGF.
Q: Can you describe your recently accrued RTOGF Foundation Trial: the patient population and the primary objective?
A: RTOG 3506, also known as the “STEEL” study, examines the role of intensification of androgen receptor (AR) blockade in salvage radiation therapy (SRT) for men who have experienced a recurrence of their prostate cancer following an attempt at curative surgery. RTOG 9601 was one of the key studies that led us to conceive the STEEL study as 9601 showed a benefit to AR blockade in patients undergoing SRT, most notably those with high-risk features such as a serum PSA concentration of 0.7 ng/mL or greater, lymph node involvement, T3 tumors or greater, Gleason scores of 8 or greater, and/or persistent postoperative PSA. As RTOG 9601 showed a benefit to AR blockade in this group, we sought to understand the role of the current and considerably more potent AR inhibitors in this space. The drug selected for this study was enzalutamide, a widely used, highly active, and well tolerated hormonal agent for prostate cancer. At the time the STEEL study was conceived, the bulk of work with enzalutamide was in the advanced, castration-resistant disease setting, but during development, newer data from the metastatic, castration-sensitive space came forward showing an improvement in survival even larger than that seen in the CRPC space. Through a partnership with Astellas and Pfizer, RTOG Foundation is now asking a timely and urgent question: can we further improve outcomes for men with prostate cancer using potent AR inhibition at an even earlier space in the natural history of prostate cancer: biochemical relapse? As such, the primary objective of this study was to show a substantial improvement in progression-free survival attributable to the addition of enzalutamide to the backbone of SRT with androgen deprivation in patients with high-risk biochemically recurrent prostate cancer.
Q: How did your trial end up in the RTOG Foundation portfolio? What are the key differences from the PI perspective in running a trial through RTOG Foundation vs. NRG Oncology?
A: RTOG 3506 was initially conceived as a registrational phase 3 study that was to be conducted through the National Cancer Institute (NCI) National Clinical Trials Network (NCTN) group NRG Oncology with support through our industrial partners: at that time Medivation and Astellas, and later Pfizer (without Medivation). NRG Oncology and RTOG Foundation Genitourinary (GU) Cancer Committee Chair, Dr. Felix Feng and I began these discussions with the Medivation leadership back in 2010 and as the idea matured, we moved the study forward as with any other cooperative group study. As many already know, this requires 2 endorsements from the NCI Cancer Therapy and Evaluation Program (CTEP): both Prostate Cancer Task Force and the GU Steering Committee. As we engaged with Task Force and GU Steering, our group faced the complexity of competition in the cooperative group trials landscape which results from a need to efficiently use the NCI supported mechanisms to maximize their impact on any disease entity. This process, however, was time consuming and required multiple rounds of revisions to address concerns raised by members while also needing to consider developing concepts that would be in the other cooperative group portfolios (not solely the NRG portfolio). After more than a year of discussion with CTEP, the concept was declined. As disappointing as this was, given its importance to the field, Dr. Feng and I persisted and pivoted the trial to the RTOG Foundation. Given the duration of development to this point, and the acquisition of Astellas by Pfizer, it became necessary to re-engage our industry partners who were actively reassessing their portfolio as well. Given the efficiencies of the RTOG Foundation mechanism, we were able to pivot and redesign a phase 3 study into a sizeable but robust randomized phase 2 study that would still address a clinically and scientifically important question with a readout that would still shape contemporary practice. While I see great value in learning how to develop a traditional cooperative group study, I now appreciate that there are certain questions and issues in the field of cancer that need a certain level of efficiency and focused expertise that may not be optimally served going through the CTEP-required route. In such circumstances, the RTOG Foundation is an important means of advancing science and clinical care that involves radiation therapy. While the speed is improved, there is no sacrifice in the quality of the science or its impact. The investigators and staff are those who have driven advancement in this field through RTOGF and NRG over the years. I would emphasize that the RTOG Foundation trials must still be vetted for scientific quality by peer scientists who are as accomplished and knowledgeable as any NCI-supported committee and so a high level of rigor is still required. Finally, as this is a mechanism that does not rely upon the NCI contract, a successful RTOG Foundation trial must have an industry partner who is willing to support the study in exchange for the time, expertise, and accruals that only RTOG Foundation can put forward.
Q: What advice would you give investigators who are interested in running a trial through RTOG Foundation?
A: I would first say that investigators should be aware of this important option. As academics, we focus often on cooperative group studies given their high value in scientific circles. RTOG Foundation studies are vetted and endorsed by peer scientists of the highest levels of experience and accomplishment. The experience of working through an RTOG Foundation study and bringing it to it closure and presentation involves all the rigor you will have with an CTEP-endorsed NRG study with greater efficiency. If an investigator has a concept and a willing partner, I suggest they reach out to Dr. Mark Mishra or myself as RTOGF Research Committee Co-Chairs to ask if this is a trial that maybe suited for the Foundation to put an extra option on the table. While the NRG cooperative group caries an important name, the RTOG Foundation is recognized as a founding pillar of this group. While RTOG Foundation trials are done at a greater cost to an industrial partner than an NRG trial, you may be surprised to find that industry partners are willing to pay for efficacy, expertise, and results at an earlier timepoint than what can be delivered by going through an additional route. Moreover, now that we have recognizing RTOG Foundation trial accruals as counting toward NRG credits, the academic credit with the group is now receiving higher value. Finally, it is well recognized that NRG trials do not provide enough reimbursement to cover the cost of the trial for participating sites. RTOG Foundation trials, however, are designed to provide better reimbursements per case that reduces financial strains for this type of research. As a final piece of advice, I would say to any interested investigator: pick good partners. The STEEL study has an outstanding leadership team who helped to support accruals and challenges and to work with RTOG Headquarters and our industry partners as well as all our participating sites. I feel fortunate that our GU Committee rallied to support the STEEL study with no less vigor than it has supported all our studies in large part due to our amazing team.
Q: When do you expect any results from your trial?
A: The STEEL Study has faced many challenges along its development as I have shared. When the trial finally opened, our world faced the opening of the COVID-19 pandemic in 2020. As such, all of our original accrual plans were set back causing us to actively engage with Pfizer and Astellas. Due to these strong partnerships and the ability to make adjustments to the study, despite the pandemic, our accrual finished early and will see its first interim analysis this November. This goal required adjustments to endpoints and site numbers that had to be justified internally and externally to ensure first and foremost that the value of the study would not be compromised. It is in these situations that you can see the true mettle of the RTOGF headquarters team that supports these studies to the point of completion. We are fortunate to have them in our corner as well as strong leadership from our Board who again came to support the study at every challenge we faced. Because of all of this, RTOG 3506 will be the first study to consider the impact of this type of systemic therapy intensification in a vulnerable group of individuals who are in need of optimized therapy.