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Thomas Zilli: These are my disclosures. So when we are discussing total therapy with metastasis-directed therapy for metachronous low-volume or monosensitive prostate cancer, I think we have three open questions. The first one is, what is the evidence to support MDT in this setting? The other one is, should we intensify MDT using systemic therapy? And last but not least, how should we treat our patient with MDT in 2024?

So in 2017, three of the panelists that we have here and are honored to have here today described for the first time the Pokemet concept. The Pokemet concept is to treat with MDT all the disease sites that are visible on PET-CT, with the main goal to avoid the potential toxicity from androgen suppression.

We had two main prospective phase II trials, small but very important: the Belgian STOMP and the ORIOLE trial from Baltimore, both randomized patients to receive MDT versus just observation. Primary endpoint: ADT-free survival in STOMP; progression at six months in ORIOLE. Both trials were positive using MDT. So we know, based on that, that we can postpone ADT use. We can improve progression by treating with MDT.

MDT can be safely done, so we know that we can achieve very good disease control—mostly 97% of disease sites that are treated with MDT—and this could be achieved with limited toxicity: less than 3% of grade 2 adverse events based on this meta-analysis.

Another important point is that MDT alone can be curative. These are two sequential prospective phase II Canadian trials of all 74 patients with oligorecurrent non-metastatic or monosensitive prostate cancer. All patients had negative standard imaging but up to five lesions on PSMA PET-CT, and all these patients were treated with radical prostatectomy and prostate bed radiotherapy.

When the patient was treated with MDT without the use of ADT, we had an overall response rate of 51%. But what is more important is that 20% of these patients, after a median follow-up of 24 months, were able to achieve a complete PSA response.

Now, the Pokemet strategy is clearly evolving, so we are not treating with MDT alone anymore. We are associating MDT with systemic therapies. The first trial, already presented just before the EXTENT trial from M.D. Anderson, included 87 oligorecurrent men, all low-volume, mostly on monosensitive conventional imaging. Seventy-five percent were randomized to receive intermittent hormone therapy—including 40% of the patients receiving even ARPI—or the same treatment, but combined with MDT to all disease sites. Where you can observe the PFS and even the time of hormone therapy in terms of PFS, you can see that the addition of MDTI to intermittent hormone therapy can improve these outcomes.

The question is, if you are treating the patient with MDT alone, if we add systemic therapy—in this case, standard ADT—can we improve the outcomes? We don’t yet have prospective data, but this is just a freshly published paper suggesting that when we add systemic therapy to MDT compared to MDT alone, we can improve progression-free survival.

We have many ongoing trials. This is just a selection. Looking in the metachronous settings through the combination of MDTI with different systemic therapies—in this case, ADT, ARPI or even radioligands—we will have the answer in these different treatment associations in the next years.

The other question is, what about the patients who progress after MDT? These are retrospective data of oligorecurrent men, mostly with metachronous prostate cancer after radical prostatectomy, all treated with MDT alone. As you can observe, what’s quite clear is that a patient with M1 disease has a worse prognosis compared to a patient with M1. But what is important is that predictors for metastasis-free survival were the presence of bone or visceral metastasis, high pathological Gleason score at radical prostatectomy, and high tumor burden on next-generation imaging. These patients had a worse outcome after MDT.

Another important point is that the molecular phenotype can help us have a further stratification of these patients. This is a pooled analysis of data from the STOMP and ORIOLE trials, looking at high-risk mutations. As you can observe, a patient having high-risk mutations—ATM, BRCA1 and 2, or B1 or TP53—has the poorest outcome when just observed. On the other hand, when we have patients without high-risk mutations and we treat these patients with MDT, these are clearly the patients that have the best outcome: 30 months of PFS versus three months only.

I think it is important that probably when we discuss metachronous low-volume, monosensitive prostate cancer, we are not discussing the same entity; not all these patients are the same. So we can probably stratify these patients into two risk categories based on some clinical factors—like a very low baseline PSA level, PSA doubling time more than 12 months, ISUP grade group less than four, and a long interval between the primary treatment and the metastatic disease. Patients who have a PSMA-positive but conventional-imaging-negative status, with a limited number of disease sites mostly in the nodes and without high-risk mutational signatures, could be defined as having low-risk disease. On the other hand, patients having a rapid PSA doubling time and bone disease—these are metastases that are clearly in patients who have the poorest outcome.

When we try to define the role of MDT based on these two risk classes, we need to start from the standard-of-care treatment. So if we think just about the low-risk patient—there are conventional imaging narratives about PSMA positivity—we can probably, when you have a PSA doubling time more than 12 months, just observe this patient or in some cases use intermittent ADT.

For this patient, when we consider the role of total therapy with MDT, we probably have different goals. So if we have some frail elderly men, the goal of MDT used alone is just to postpone ADT use and improve quality of life, because we know that these patients have quite a good prognosis, and MDT can be done safely and is very well tolerated.

Other, younger patients can probably combine this treatment with systemic therapy—ADT, ARPI or even electing another radiation; it depends on the sites—but with the goal of achieving a complete biochemical response with a curative intent.

On the other hand, when we have high-risk patients, we know that the standard of care when we have non-metastatic or monosensitive prostate cancer is now to combine based on EMBARK criteria. So we discussed just before to use ARPI with or without ADT as a standard of care. Of course, when we have conventional imaging as well, we need to use double therapy. In this setting, probably MDT can help us delay progression. The use of second-line therapies improves MFS, and this should be done by combining MDT with systemic therapy. The duration—intermittent, continuous, ARPI, not-ARPI—remains an open question, and we think we will soon have new data suggesting which is the best treatment strategy.

So I think, in conclusion, MDT is certainly a rapidly evolving field, even if not yet standard of care for these kinds of patients. MDT can provide an excellent disease control with minimal toxicity. In combination with systemic therapies, MDT can improve outcomes compared to systemic therapy alone. But of course, there is an open question of optimal duration and type. I think the most important message is just to have a multidisciplinary discussion and try to enroll these patients in trials or prospective cohorts. Thank you so much.