Prostate Cancer Working Group 4 redefines trial frameworks in era of PSMA-PET and precision oncology

At the 2026 ASCO Genitourinary Cancers Symposium in San Francisco, California, updated recommendations from the Prostate Cancer Working Group 4 (PCWG4) were presented,¹ marking the next evolution in shaping how clinical trials in advanced prostate cancer are designed and conducted. The guidance reflects nearly a decade of collaborative work among international experts to address the growing complexity of the treatment landscape, driven by advances in imaging, molecular profiling, and therapeutic options.

In the following interview, Andrew J. Armstrong, MD, MS, chair of PCWG4 and a medical oncologist at Duke University in Durham, North Carolina, discussed how the updated framework aims to modernize trial methodology in step with contemporary clinical practice. Building on prior iterations of the Working Group, the new recommendations expand beyond traditional end points and incorporate emerging tools such as prostate-specific membrane antigen (PSMA)-PET imaging, circulating tumor DNA (ctDNA), and patient-reported outcomes (PROs), while also redefining disease state terminology to better align with current standards of care.

Armstrong emphasized that PCWG4 introduces a more patient-centric and biologically informed approach to clinical research, with an emphasis on standardizing how response and progression are measured across studies. The recommendations also highlight the importance of integrating novel biomarkers and imaging modalities into trial frameworks, while acknowledging the need for ongoing validation and data collection. Together, these updates aim to improve consistency in trial design, enhance interpretation of outcomes, and ultimately support the development of more personalized treatment strategies for patients with prostate cancer.

Urology Times: What is the background/rationale for the Prostate Cancer Working Group 4 recommendations?

Armstrong: Let me just start by saying this was a real grassroots effort. It took 65 individuals working across more than 10 working groups over nearly 10 years of time. Howard I. Scher, MD; Michael J. Morris, MD; and I, as the co-chairs, oversaw this effort. The purpose of these working groups is to update the field every 10 years in terms of how to conduct clinical research and how to develop your protocol, whether that's an academic or an industry sponsor. There are aspects that continue to change. How to use [prostate-specific antigen] (PSA) as an end point was the very first Working Group back in 1999 when the PSA test was first coming out. How to use bone scans to interpret imaging in a hormone-resistant population was the second Working Group that accounted for bone scan flare, for example, and enabled the success of AR [androgen receptor] pathway inhibitors. The latest iteration is extending guidelines to the PSMA-PET scan, which is a new imaging modality that pretty much everybody is getting nowadays, but without a lot of information on how to use that in a clinical trial context, for a registrational end point to determine whether your patient's benefiting or to declare response or progression.

There are other things that Working Group 4 does besides imaging, which is to define some of the intermediate end points that might be useful in phase 2 studies such as PSA nadir, PSA declines, ctDNA, [and] patient-reported outcomes. We also totally changed the language of the disease.

Urology Times: What specific changes does the Working Group recommend for defining disease states?

Armstrong: We think about disease states as indications—regulatory indications, for example. If you're developing an agent, where would that fit in? The current landscape of prostate cancer has become much more complex in the past 10 years. Most patients are getting genetic testing [and] PSMA-PET imaging. We now have a wealth of options that have moved into earlier settings, like the AR pathway inhibitors, different taxanes, PSMA radioligand therapies, some immune therapies, and PARP inhibitors for patients with DNA repair defects. The landscape has changed in 10 years, trying to identify the indications where a company or an academic [center] may address an unmet need for the patients that they see in clinic, where we can try to improve upon those outcomes, helping patients live better and for longer, minimizing toxicity and disease burden, tracking who's benefiting the most, and identifying patients ahead of time that are benefiting the most.

We define disease states based on the real frontline standard of care, which is what we now call androgen pathway modulators [APM]. So, an APM is a broad basket term for androgen deprivation therapy—an AR pathway inhibitor like enzalutamide [Xtandi], apalutamide [Erleada], darolutamide [Nubeqa], and abiraterone [Zytiga], and a whole new class of drugs that are coming in the pipeline. That could be AR degraders, AR molecular glues like RIPTACs, AR co-factor inhibitors, and even bipolar androgen therapy could fit into this category, where essentially, you're modulating that pathway in all sorts of ways, not always just lowering testosterone or castration. A lot of patients don't like to be referred to as castrate, and a lot of doctors don't like to talk to their patients using that older terminology. APMN would be naïve to those therapies, APMS would be sensitive or responding to those therapies, and APMR would be resistant to those therapies. So, 3 real disease states: before the treatment, during the treatment, and after the treatment. That would apply to any treatment, so you could use that same terminology with a PARP inhibitor, a taxane, or a PSMA radioligand therapy.

Layered on top of those disease states would be other patient characteristics: their genotype—like BRCA2 or other alterations that have critical importance in prognosis or decision making—what symptoms they have, and the pattern or spread of their disease. Many other features could be layered on top of that to better characterize the patient in front of you and ideally link that to the new therapy that you're applying in a clinical trial.

Urology Times: How should PSMA-PET imaging be incorporated into clinical trial frameworks, especially in regard to progression criteria?

Armstrong: There are many guidelines about how to report PSMA. That's not what Working Group 4 is about, because there are excellent guidelines about using the PSMA-PET scan in place of CT and bone scan to accurately stage and risk stratify patients. We endorse those guidelines. What's not established is how to use the PSMA-PET scan over time to document responses to therapies. Those therapies could be systemic therapies or focal therapies, like metastasis-directed radiotherapy, for clinical trial end points for regulatory decisions. We're used to using conventional imaging for those end points to declare radiographic progression-free survival or metastasis-free survival—that's been a regulatory end point that led to approval, for example, of many of the AR pathway inhibitors. But PSMA-PET can pick up disease much earlier, it's more sensitive, it can see more disease than you would otherwise appreciate, and everybody's getting one. So, we needed to establish some clear metrics for when that's included in a clinical trial, what the field or the experts would generally regard as evidence of a response.

I don't think there's any argument about what a complete remission looks like—that's disappearance of all lesions. There are disagreements about in between that and progression. If you're seeing multiple new lesions, that's going to be progression. We use the rule of 5. So, if you have more than 5 new lesions, that's generally going to be called progression. We're going to generally require confirmation of progression if you have 5 or [fewer] new lesions.

I would throw out that even these guidelines are going to require validation. By themselves, they don't necessarily mean that you have to stop a treatment if you feel like the patient is still benefiting. If you want to apply, for example, metastasis-directed therapy to 2 new lesions and then the subsequent scan doesn't show progression, that doesn't mean you have to stop the therapy.

We do differentiate patterns of spread as well. So, for example, new lesions in the bone or the lymph nodes are not the same as new lesions in the liver. A liver metastasis is associated with the worst survival. Even 1 single new liver metastasis would be a declaration of progression because of its prognostic association. I'd encourage you to take a look at the tables in the Working Group 4 guidelines, because those are what we are recommending so that we all report it the same way in phase 2 and phase 3 studies. We also encourage the collection of data so that we can build on these guidelines for the next Working Group, so that we can further tweak and optimize those guidelines. There are a number of tools that are in development, such as using artificial intelligence to do full body quantification of the standardized uptake value and the pattern of spread or the total tumor burden. Why did we pick 5? Maybe it's 4, maybe it's 6. There are other thresholds that should be looked at to more optimally define progression for Prostate Cancer Working Group 5.

Urology Times: What reassessment schedule does the Working Group recommend for imaging biomarkers and patient reported outcomes?

Armstrong: This is an important question, because a lot of [clinicians], when they start a patient on like an APM therapy like enzalutamide or darolutamide, they're relying only on the PSA. I see a lot of patients who don't get any imaging, but we see what's called discordant progression in about a quarter of patients. That discordant progression means the PSA is low, but the imaging gets worse, and that is associated with a worse survival. There are a number of papers now documenting this—TITAN [NCT02489318], ARCHES [NCT02677896], ENZAMET [NCT02446405], and many of the darolutamide trials—suggesting that we should be doing imaging regularly.

Discordant progression tends to happen in the first 2 years. That's where most of the data are strongest. We would recommend regular imaging, particularly in those first 2 years of starting a new treatment. I like to do imaging at the beginning, and then after 3 to 4 months of treatment to document remission. If you're using docetaxel, maybe that's 4 to 6 months to allow for the completion of that induction chemohormonal therapy, and then regular imaging. It doesn't have to be every 3 months like we did in the trials, that's probably excessive, but every 3 to 6 months is very reasonable and is not creating too much of a burden on patients. That's in order to pick up these progression events that would otherwise be without symptoms but would cause a management change.

In more advanced APMR settings, imaging is going to be done much more regularly, because these are the patients where their median survival is only like 2 or 3 years. You have a lot of options, and you want to pick up that progression so that you can switch therapy. [You don’t want to just] rely on PSA, which may not report on clones that are not AR positive or more neuroendocrine [tumors] that are not secreting PSA, and that becomes a much bigger issue in later lines of therapy.

Urology Times: How does the guidance recommend integrating patient-reported outcomes into trial end point frameworks?

Armstrong: That's an important question. The patient should have a voice in each of these trials. When you have a combination of drugs or a new therapy, we would like to know about toxicity. But most toxicity is assessed by the [physician] and documented and not necessarily done by the patient. There are a number of common toxicity scores that the patient fills out, but there’s also quality of life scores that tell you how the patient is feeling, whether there's functional impact, a pain impact, a symptom scale, or a global scale. Some of these things are not very sensitive to minor changes. I think combining toxicity data at a granular level with a bigger picture quality-of-life [data] can tell you a little bit about whether delaying progression and disease burden can impact quality-of-life favorably, and whether the risks of the drug impact quality-of-life negatively, so you get a net balance of how that patient is feeling overall. Generally, this is not going to be a primary end point on most studies, but I think it can be complementary to know if that survival benefit or delay in progression is worth it.

Urology Times: What are some of the questions that remain unanswered?

Armstrong: The biomarkers that we are developing are becoming much more sophisticated. When I first entered this field, there was no such thing as plasma DNA or circulating tumor cells. Now we're able to much more precisely not just count the amount of DNA in a tube of blood or circulating tumor cells, but we can characterize at very deep levels the whole genome, the whole transcriptome, the epigenome, methylation profiles, and phenotype. You can measure disease burden probably a little better than PSA, since PSA is only measuring the PSA producing part of the cancer.

In terms of the liquid biopsy field, I'm particularly excited about some of the advances in precision medicine that allow us to phenotype and genotype our patients, and monitor that over time to understand how the disease changes beyond just imaging and PSA. The molecular imaging has also gotten a lot better. There are a number of novel PET tracers that go beyond PSMA, and this is allowing us to, at a whole-body level, identify patients that might benefit from targeting certain antigens or cell surface markers like B7-H3, PSCA, hK2, or STEAP1 or STEAP2. There are a number of AR positive cell surface markers. There are also a number of neuroendocrine markers that you can now visualize on a PET scan or a liquid biopsy. The ability to more deeply characterize our patients should allow for more personalization of therapy, so that you're not treating everybody the same way, and you're not exposing some patients who are not going to benefit to drugs that don't work for them.

Artificial intelligence is also emerging. We're using it now for our searches and vacation plans instead of Google. We're also using medical AI for digital pathology to make informed decisions. We're seeing the emergence of imaging-based AI to reinterpret scans. I think it would be great to validate those in prospective studies and specific contexts, so that maybe Working Group 5 will have many more AI-enabled medical technologies that can distill tons of information into biomarkers that could inform treatment. I don't think we want to forget about the patient voice, though. I think PROs will always be a part of our guidelines, but doing this in a way that is patient-friendly [will be important]: using validated surveys, tablets, and information that patients can get when they're out in the community, like wearable devices that integrate with what we're doing in the clinic.

REFERENCE

1. Armstrong AJ, Morris MJ, Antonarakis ES, et al. Trial design and objectives for prostate cancer: Recommendations from the Prostate Cancer Clinical Trials Working Group 4 (PCWG4). Presented at: 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium. February 26-28, 2026. San Francisco, California. Abstract 162. https://www.asco.org/abstracts-presentations/256407/abstract