For a recent Uromigos podcast, Dr Thomas Powles and Dr Brian Rini invited Dr Matthew R. Cooperberg and Dr Declan Murphy to discuss how guideline-recommended active surveillance is being implemented for patients with low-risk prostate cancer, and whether treatment trials should be conducted in this population.
Active surveillance (AS) was established as standard of care for low-risk prostate cancer in the late 2000s and is now endorsed by all the relevant professional organizations. Implementation of AS remains variable, however, and is especially low in the US. Despite having been studied as a management strategy in large cohort studies, questions are still raised about the safety of AS, well as the risk of progression. Treatment alternatives to AS had already been investigated in clinical trials like REDEEM,1 MAPPED,2 and CLIN1001 PCM301.3 However the recent publication of the ENACT (Enzalutamide in Patients With Localized Prostate Cancer Undergoing Active Surveillance) trial (NCT02799745),4 which suggested enzalutamide as an alternative to AS, was met with a wave of criticism in print5,6 and on social media, and suggestions that the trial should never have been carried out at all.
This controversy was discussed by Matthew R. Cooperberg, MD, MPH, professor of urology, epidemiology, and biostatistics and Helen Diller Family Chair in Urology at the University of California, San Francisco (UCSF), who was one of the ENACT investigators, and Declan Murphy, MB BCh, BAO, Consultant Urologist and Director of Genito-Urinary Oncology at Peter MacCallum Cancer Centre, Melbourne, and Honorary Clinical Professor, the University of Melbourne, Australia, who is one of the trial’s critics. Thomas Powles, MBBS, MD, (Barts Cancer Centre, London, UK) and Brian Rini, MD (Vanderbilt University, Nashville, TN) moderated their discussion.
Dr Cooperberg related how AS has been a major focus of both clinical practice and research at UCSF since the mid-1990s. In the early days, surveillance was reserved for men with small volume, low grade cancers, and involved an intensive schedule of follow up prostate-specific antigen (PSA) tests, biopsies, and imaging, he recalled. As more became known about the natural history of untreated prostate cancer, this evolved to anyone with low-risk disease, i.e., Gleason Grade Group 1, clinical stage cT1-CT2a, and PSA <10 ng/mL being a candidate for AS, which is now consistent across all the major guidelines. There are exceptions, including young men with high volume tumors, Dr Cooperberg noted.
What Dr Cooperberg referred to as “the frontier” in AS is men with intermediate-risk disease who are suitable for AS. These tend to be men with Gleason Grade Group 2 tumors, with a relatively low volume of Gleason pattern 4, especially where that pattern is fused gland type or poorly formed glands, or patients who have a high PSA level because they have a big prostate. These are the two most obvious cases for expanding AS into the so-called intermediate-risk group, he said.
In the US, the rate of AS is evolving very quickly, Dr Cooperberg observed. At UCSF, a study of the CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) registry, a longitudinal, observational database of approximately 15,000 men with all stages of biopsy-proven prostate cancer enrolled at over 40 practices, showed that throughout the 1990s and 2000s, the rate of AS was consistently under 10%.7 By 2013-14, however, the rate had risen to about 40%. Recent data from the newer AQUA (AUA Quality) registry, a much bigger database including about 26,000 men with low-risk disease at over 250 urology practices, showed that AS use had risen linearly to about 60% by 2020.8 “That’s rapid progress in the right direction, but it’s still not where we should be,” Dr Cooperberg commented. “If you look in countries like Sweden, their national data show rates around 80%, which is probably at least where we should be in the US.”9
A “massive” problem is variation, he pointed out. “Depending on which individual urologist’s door you happen to knock on with your low-risk diagnosis, your likelihood of getting surveillance ranges from fully zero to 100%,” he said. Although this variation is not unique to AS for prostate cancers, it is more evident in prostate cancer because it is only in the past few years that the guidelines have all consistently recommended AS, he maintained. In the absence of very clear guidelines, there will be many non-clinical factors driving this variation, such as physician comfort, physician preferences, patient preferences, financial incentives, legal concerns, and local culture, he believes.
Dr Murphy described how overtreatment of patients with low-risk disease is avoided in countries like Australia and the UK, which use magnetic resonance imaging (MRI) for early detection in men with a raised PSA instead of a prostate biopsy. That has not been widely adopted in the US outside academic centers like UCSF, he noted. Dr Cooperberg pointed out that although MRI has not been adopted universally, liquid biomarker testing is being done with the same goal of not biopsying men who don’t have clinically relevant cancer. So although the proportion of men with low-risk disease in the days when it was heavily overtreated was over half of all diagnoses, it is now down to about one third of all diagnoses in the US.
The number of men who will die because they chose AS and the cancer progressed is extremely low, Dr Cooperberg asserted. The likelihood of a patient on AS progressing to treatment or tumor reclassifying to higher risk within the first 3-5 years is 30-50%. “In most of those cases, the higher grade cancer was always there, and we happened to find it on the second or third biopsy,” he said. The proportion of cases where the cancer worsens over 2-3 years or progresses to an incurable stage within the first 3-5 years is also extremely low, he added.
Dr Murphy had no qualms about his opposition to treatment trials in AS patients. “When the ENACT trial was published in JAMA Oncology, there was genuine shock among most of the urology community around the world,” he declared. The Phase 2 trial, conducted between June 2016 and August 2020 at 66 US and Canadian sites, randomized a total of 227 patients with low- or intermediate-risk prostate cancer to enzalutamide 160 mg monotherapy for 1 year or continued AS. The primary endpoint was time to progression (≥1 increase in primary or secondary Gleason pattern or ≥15% increased cancer-positive cores or earliest occurrence of primary therapy). Treatment with enzalutamide was reported to significantly reduce the risk of prostate cancer progression by 46% vs AS (hazard ratio, 0.54; 95%CI, 0.33-0.89; P=0.02). The conclusion of the trial upset many people because it suggested that enzalutamide monotherapy was well tolerated, which it wasn’t, Dr Murphy complained. “Most of us find that completely lacking in equipoise,” he said. He pointed out that fatigue was reported in 55.4% and gynecomastia in 36.3% of patients.
“Most of us involved in this area do not like this messaging that we need trials and that we need to consider enzalutamide or even sipuleucel-T [autologous vaccine], which is currently in a trial in AS patients [ProVent, NCT03686683],” he continued. “It’s sowing the seeds of doubt in the clinical community to say, ‘we need to give them hundreds of thousands of dollars’ worth of drugs, because we have a problem with active surveillance’ when we don’t.” The problem is not that we’re worried about the terrible oncological outcomes when you select a patient for AS, we just need to do more surveillance, he stressed. “But remember, it is literally, do nothing; just keep an eye on your patient, and maybe do so with smart tools.”
“Every guideline recommends that men at low-risk or favorable intermediate-risk who it’s not clear will benefit from treatment, should be put on AS,” he pointed out. Many in the field have pushed very hard to try and educate physicians and patients about this to try and reduce the overtreatment that has “polluted the arena for the past couple of decades,” so why should these men be put on “a super powerful” systemic oncology drug like enzalutamide, he questioned. Asked by Dr Rini whether there might be a subset of the AS population that could be treated in a trial with a different type of therapy, Dr Murphy was adamant: “There is absolutely zero, nothing,” he said emphatically.
Dr Cooperberg acknowledged that there is “definitely” industry interest in treatments for low-risk AS patients, “But it’s early days,” he said. “To my knowledge, to this point, no one has thought of running a Phase-3 trial or going to regulatory agencies with any sort of intervention for low-risk, otherwise AS-eligible disease.” Dr Cooperberg believes that where there is legitimate discussion and room for different opinions is not the fundamental question of whether lower risk prostate cancer is a problem, but what we do about it over the next 5-10 years across the different healthcare systems.
“I think the jury is still out, and we need to continue to advance science along all these different directions, with different types of interventions, be they psychological or medical, as long as the impact of the intervention, the side effects, and the risks are low enough,” he said. “We need to continue to make progress in how we do surveillance, and how we improve the outcomes for all men with low-risk disease.”
Linda Brookes, MSc is a freelance medical writer/editor based in New York and London.