Praful Ravi, MB, BChir, MRCP, Dana-Farber Cancer Institute, Boston, Massachusetts, reviews the rationale and emerging data supporting the earlier use of PSMA radioligand therapy (Lu-PSMA-617) in metastatic hormone-sensitive prostate cancer. Highlighting results from the phase 3 PSMAddition trial, he discusses the improvement in radiographic progression-free survival (PFS) alongside immature overall survival (OS) data, increased toxicities, and a possible decline in quality of life. He also emphasizes the importance of optimizing dosing, scheduling, and trial design to balance efficacy with potential long-term toxicities as PSMA radioligand therapy moves earlier in disease.

Transcript:

My name is Praful Ravi, I’m a GU medical oncologist at Dana-Farber Cancer Institute and the medical director of GU theranostics at Dana-Farber. I’ll be giving an overview of the presentation I gave at the SNMMI Theranostics Summit in November 2025, looking at balancing the risks and benefits of treatment of PSMA radioligand therapy earlier in the course of disease.

I think it's important, when we think about this, to get an understanding of the overview of how prostate cancer develops from early stages with localized disease through to non-metastatic disease to metastatic hormone-sensitive disease and then ultimately to metastatic castration-resistant disease and we have different therapies across that spectrum that we use. 

In the localized setting, we have radical prostatectomy, radiotherapy and hormones, radiotherapy plus hormone therapy plus or minus an AR pathway inhibitor like abiraterone. When we start getting into the non-metastatic setting, and maybe non-metastatic castration-resistant prostate cancer [CRPC], we have the ARPIs and potentially radiotherapy to the primary in the metastatic hormone-sensitive setting and that's the setting in which we start using things like ARPIs, docetaxel, and triplet approaches. Once we get into the metastatic CRPC setting is where we have taxane chemotherapy, ARPIs, if they've not already been used, the alpha-emitter radium-223, which tracks to bone, as well as PARP inhibitors potentially in the BRCA or the homologous recombination repair-deficient patients. 

In terms of radioligand therapy, despite these advances, which have really been made in the last 20 years, metastatic prostate cancer is incurable. The average survival of hormone-sensitive disease is maybe between 4 to 7 years. In castration-resistant disease, it's 1 to 3 years. Lutetium-PSMA-617, or Pluvicto, first approval came in the advanced CRPC setting, the post-chemo, post-ARPI setting, where it led to an average 4-month benefit in overall survival compared to best standard of care or supportive care. If we look at how that places amongst all the other therapies in that space, the other approved CRPC therapies, that median of 4-month survival is around about the same as what the other drugs also lead to, the abiraterones, the enzalutamides, the docetaxel, cabazitaxel, or radium. 

When we look at moving therapies earlier, we have data now from therapies that have been used in CRPC, hormone-sensitive setting, as well as the adjuvant or high-risk localized setting from docetaxel, abiraterone, enzalutamide. And generally, we see that as you move the therapies earlier, for example, with abiraterone, enzalutamide, and docetaxel, the median OS benefit in hormone-sensitive disease is 10 to 20 months, you're getting a year or 2 survival benefit by using these things in the hormone-sensitive space, whereas only 3 or 4 months in the castration-resistant space. 

In the adjuvant or high-risk localized setting, which is even earlier, the bar to demonstrate OS or [metastasis-free survival] benefit is much higher, and the point to illustrate here is that as drugs get moved earlier, the hormone-sensitive space is probably the space where there are the most opportunities to meaningfully improve survival but, the bar to demonstrate benefit in these settings is already quite high because of the activity of the ARPI doublets and taxane triplets in this space already. 

That comes to where PSMA [radiolignad] comes in, looking to move it earlier, and really the main data to discuss is the PSMAddition trial. We always think about what we are trying to achieve when we move therapies earlier [and] we have 2 goals: live longer, improve survival, and live better, maintain and improve quality of life– and I think we have to view any data through that lens. This was a trial taking patients with untreated or minimally treated metastatic hormone-sensitive disease, diagnosed on a conventional scan. Minimally treated means up to about 6 weeks of ADT plus ARPI was allowed [and] they were screened with PSMA PET and at least 1 positive lesion was needed on the PET scan, there was no requirement for negative lesions. Interestingly, about 13% of patients screened negative, even with minimally treated disease, maybe even a few weeks of ADT plus ARPI downregulates PSMA and there was no PSMA expression. They were then randomized 1:1 to ADT plus ARPI, which was the control arm or ADT plus ARPI plus the addition of Lutetium-PSMA-617 (Pluvicto) for 6 cycles every 6 weeks. The primary end point was radiographic PFS (rPFS) by conventional imaging, and the key secondary outcome was overall survival. 

In terms of the primary end point, it was clearly a positive trial– the hazard ratio was 0.72. There was a significant improvement in rPFS with the addition of Pluvicto compared to ADT plus ARPI alone [and] if you actually dig deeper into the curves, you can sort of see that the curves are tracking until about 10, 11 months, and then they start separating, which to me implies that Lutetium-PSMA-617 is actually, rather than rescuing maybe the 10% to 15% of early progressors, helping deepen the initial response to ADT plus ARPI, it's sort of acting not immediately, it's deepening that response, consolidating that response perhaps.

When we look at secondary end points, overall survival, which is immature, it was an interim analysis, and we'll wait further follow-up, there was no significant benefit yet observed at this point, although the hazard ratio was 0.8, which is maybe heading the right way, but remember, crossover is involved in this trial so we might see that hazard ratio drift back up again. Interestingly, in terms of adverse events, there were higher adverse events, particularly in terms of cytopenias, which are a known side effect of Lutetium-PSMA-617, as well as secondary malignancies and renal dysfunction in the Lutetium-PSMA-617 group. Now this is important because these patients are destined to live probably 4 to 7 years on average so if you develop a secondary malignancy, especially a bone marrow malignancy or renal dysfunction, you're going to be living with that for the remaining period of your time and that may impact the ability to get other therapies potentially.

The quality-of-life data, as measured by the FACT-V, which is a global quality-of-life assessment, there was actually a detriment in quality of life in the Lutetium-PSMA-617 group. The hazard ratio was 1.14, it was not statistically significant, but again, the quality-of-life curves dipped in the Lutetium-PSMA-617 group at around 4 to 5 months in which I think raises questions about the dosing and the schedule of the drug. This is a drug where the target is PSMA, which is dynamic, as you start getting treatment in, even ADT plus ARPI, PSMA gets downregulated and therefore maybe at 4 months in, which is around cycle 3 or 4 of Lutetium-PSMA-617, maybe there's not that much PSMA there for the drug to attack, and maybe it's just going to the salivary glands, causing dry mouth or maybe it's going to the kidney and the bone marrow, causing toxicity without that much efficacy. I think that's interesting and I think that really merits further study and raises questions about what the right dose and the right dosing regimen and schedule are to use with PSMA radioligand therapy in the hormone-sensitive space, where PSMA is a very dynamic biomarker.

In terms of other data to support going even earlier, and the PSMAddition is the big trial, really the phase 3 registrational trial, there have been a couple of other smaller phase 2 trials: one was the BULLSEYE trial, which is in oligometastatic disease of Lutetium-PSMA-617, 2 cycles plus another 2 vs observation, which showed a PFS benefit, and the recently published LUNAR trial, which is in oligorecurrent disease, which compared Lutetium-PSMA-617 neoadjuvantly for 2 cycles followed by SBRT vs SBRT alone and again, a PFS benefit was seen.