From Vintage Imaging to Cutting-Edge Trials: The Future of Prostate Cancer Management

At the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium, a roundtable of expert panelists convened to discuss the latest research and practice updates related to metastatic hormone-sensitive prostate cancer (mHSPC). Dr. Tanya Dorff of City of Hope Comprehensive Cancer Center was joined by Drs. Dan Childs, Andrew Hahn, Cora Sternberg, and Vadim Koshkin in the discussion.

In the final part of the roundtable, the panel concludes by highlighting the limitations of conventional imaging in detecting disease progression at undetectable PSA levels, the evolving role of PSMA PET scans, the potential benefits and risks of metastasis-directed therapy, and key findings from the meeting, including the TALAPRO-2 trial on enzalutamide and talazoparib, testosterone recovery’s impact on survival, and emerging molecular and radiopharmaceutical treatments.

View the previous segments.

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Dr. Dorff: I suppose the other key point is that when using conventional imaging, prostate-specific antigen (PSA) levels are likely to rise. Let us say a patient is on doublet therapy for metastatic hormone-sensitive prostate cancer, and their PSA is increasing, but conventional scans remain unchanged. How do you determine when a patient has truly become castration-resistant to the point where therapy needs to change?

Dr. Sternberg: May I add something? We are about to publish, along with Dr. Dan George and others, data showing that even among patients who have been on androgen deprivation therapy (ADT) and undergone radical prostatectomy (RP) with a PSA of zero, 20% will still have detectable disease on conventional imaging. So you cannot simply assume that a patient is disease-free based solely on an undetectable PSA; conventional imaging remains necessary.

Dr. Dorff: How often would you recommend imaging in those cases?

Dr. Sternberg: Once a year.

Dr. Dorff: Yes, that is my approach when PSA is suppressed. However, when PSA is rising, I tend to scan more frequently.

Dr. Childs: We have taken a similar approach at Mayo. We analyzed PET scan data to determine how often disease progression occurs despite an undetectable PSA, and we found a nearly identical result; approximately 20% of patients still had progression. Dr. Jack Andrews at Mayo Arizona is currently investigating PSA-zero progression using PSMA PET scans.

I struggle somewhat with the idea of using PSMA PET scans for surveillance. I agree with all of you that the supporting data is currently lacking, but it feels counterintuitive to order scans that none of us consider the most effective for detecting disease. Someone at this meeting referred to conventional imaging as “vintage imaging,” and I do not want to be a “vintage” doctor relying on outdated tools. I want to use the most effective imaging modality available.

If you believe in metastasis-directed therapy—and I do—then you want to use the scan that detects the highest number of metastases during follow-up imaging. I think there will eventually be a way to define oligo-resistant clones and selectively eliminate them, which could potentially delay the onset of castration resistance. While we are not there yet, it is an exciting area of research, and I suspect that in five years, our practice will be quite different from how it is today with conventional imaging.

Dr. Dorff: Even if it does not delay castration resistance, I believe that as castration resistance develops, it remains clinically meaningful. Dr. Howard Scher published on this several years ago in the context of enzalutamide, in what must have been a castration-resistant prostate cancer (CRPC) setting, where PSA was rising but imaging was unchanged. They found that treating oligoprogression with radiation led to a PSA decline and allowed for continued systemic therapy.

As more patients with mHSPC receive doublet therapy, I have adopted a similar approach. Interestingly, I am still primarily using conventional imaging rather than PSMA PET, but I recognize that individual tumors within the same patient can have distinct clonal differences.

Dr. Hahn: I want to highlight Dr. Chad Tang, who presented here on his EXTEND oligo-progression trial. I do believe we need clinical trials in this space. We often assume metastasis-directed therapy is harmless, but it is not—it can lead to downstream fractures and other radiation-related complications. The key question we are all grappling with is whether treating oligoprogression (defined as fewer than five progressing lesions) with metastasis-directed therapy provides a benefit over changing systemic therapy.

Right now, we do not have definitive data to answer this, particularly in the PSMA PET era, but I expect that to change in the coming years. Many of us are already incorporating metastasis-directed therapy into practice ahead of trial data, but we need higher-level evidence to guide us.

Dr. Dorff: We should certainly prioritize enrolling patients in clinical trials, as that is the best way to compare metastasis-directed therapy to other approaches, such as switching to newer agents. As we wrap up, I would love to hear from each of you: what was the most interesting prostate cancer presentation at ASCO GU this year?

Dr. Sternberg: I found the TALAPRO-2 data extremely compelling. While I am not necessarily planning to treat all patients without first performing genomic testing, I found the results quite striking: enzalutamide combined with talazoparib for nearly all patients. However, I will continue to rely on genomic testing and reserve PARP inhibitors for patients with homologous recombination repair (HRR) abnormalities. I also do not see myself prescribing the combination for patients who are already receiving combination therapy at baseline.

Dr. Childs: What excites me most is walking through the last row of ASCO GU each year, where the “trials in progress” posters are displayed. Seeing the ongoing research into molecular strategies for hormone-sensitive disease and the development of radiopharmaceuticals for CRPC—not just targeting PSMA but also other cell surface markers—is always the highlight for me.

Dr. Dorff: I was surprised by the presentation in the definitive setting showing that testosterone recovery was associated with improved survival, regardless of the duration of hormone therapy received. We often focus on PSA, but this highlights the need to pay closer attention to testosterone recovery and its impact not only on prostate cancer outcomes but also on overall health.

Dr. Hahn: I also found TALAPRO-2 fascinating, but to add something different, I will mention Dr. Schweitzer’s presentation on Pfizer’s EZH2 inhibitor. It is still early-phase data, but when added to enzalutamide, it showed a hazard ratio of 0.5—a 50% reduction in the risk of disease progression. It is a promising approach that is now being tested in later-line settings, and I think it will be interesting to follow.

Dr. Dorff: That was in mCRPC, following prior AR pathway inhibitor exposure, unlike TALAPRO-2, which could make it more clinically relevant. EZH2 has been an intriguing target for years, so it is exciting to see progress in this area.

Dr. Hahn: And EZH inhibitors tend to be well tolerated. While I am not familiar with the specifics of this particular agent, our experience with EZH inhibitors has generally been positive, so I am eager to see how it develops.

Dr. Koshkin: At the risk of being repetitive, I will also highlight TALAPRO-2 because I believe it was the most significant prostate cancer presentation at this meeting. The data are certainly compelling, particularly the demonstrated benefit in the overall population. However, I have concerns about widespread adoption.

In academic settings, we do not frequently see patients who have not already been exposed to an androgen receptor pathway inhibitor. There are also valid concerns about toxicity and whether non-HRR patients will derive significant benefit. Nevertheless, the results are quite interesting, and it will be fascinating to see how this strategy evolves in clinical practice.

Dr. Dorff: AR pathway inhibitors are moving into earlier disease settings, including biochemical recurrence (with trials like EMBARK) and salvage radiation (still in clinical trials but not yet in practice). Over time, we will see more patients with prior exposure to these agents.

Ultimately, every patient’s journey is unique, and it is invaluable to have multiple treatment options. By integrating genomics, advanced imaging, and clinical judgment, we can tailor the best approach for each patient. Thank you all for your insights. It has been a pleasure speaking with you today.