Welcome, Mika.
Mika Matikainen: Thank you very much.
Neeraj Agarwal: We really enjoyed your talk at the APCCC 2026 meeting. It was a very pertinent topic on de-escalation strategies as far as systemic therapy in metastatic castration-sensitive or hormone-sensitive prostate cancer is concerned. I think all of us are worried about the long-term side effects in those patients who have exceptional responses, and we are looking forward to new strategies which may allow us to take a break from systemic therapy in our patients.
Could you tell us more about the update on De-escalation strategies of systemic therapy in patients with metastatic hormone-sensitive prostate cancer?
Mika Matikainen: Thank you, Dr. Agarwal. That's a pleasure and an interesting topic, as you mentioned. De-escalation is a very interesting thing at the moment here in Europe and I guess also there in the United States. And the rationale for the de-escalation of hormonal treatment is, as you mentioned, to reduce the long-term toxicity of ADT treatments and improve patients' quality of life and potentially also delay castration resistance because there are many cases where the cancer proceeds under the ADT.
There are historical studies, let's say 15, 10 years ago published which suggests that there is no clear overall inferiority in intermittent ADT versus continuous ADT. And still, there are some very good proof that it improves quality of life. However, it seems to be working only in selected patients, mostly with low-grade disease and long doubling time of PSA, for example. And there are still questions what we have not been able to answer. For example, PSA thresholds would be the ideal ones. And at what point to interrupt the treatment and what point to potentially intensify the treatment once again. And the PSA is still the marker in most studies to be used.
The EMBARK trial was the first one to really show the structured treatment suspension of ARPI medications, and that however was in non-metastatic phase but there was a scheduled break of the treatment if the PSA went down to 0.2 level at weeks 36 and then the therapy was stopped in all three arms of the treatment phase. And we could see in EMBARK study that there were very long treatment pauses after the de-escalation. For example, Combination Group, about 37% of patients didn't require treatment over 24 months of the pause. And even in Monotherapy Group, there were patients about 15% who didn't require treatment over 24 months of the pause period. However, current status is that standard medication in metastatic hormone-sensitive prostate cancer is still a continuous ADT plus ARPI in nowadays. But there is strong interest, for example, in low-volume disease and oligometastatic disease to use de-escalation strategies, and especially in deep PSA responders.
There are a lot of ongoing studies in metastatic hormone-sensitive prostate cancer to de-escalate mostly in oligometastatic phase. I would raise up the three of them, LIBERTAS and EORTC 2238 and A-DREAM. LIBERTAS with Apalutamide, there's de-escalation of ADT and continuing with APA by itself. In EORTC study, both ADT and ARPI are paused in de-escalation. And in A-DREAM, that's one arm study only but there's interaction of ADT and ARPI both of them. A bit different approaches. And then there are adaptive studies, for example PEACE study, in this case PEACE-6 where the good responses after six to eight months of ADT are put to de-escalation arm. And we'll see how these studies are bringing the results in the upcoming years.
Which patients and when? Exceptional responders are the one group especially. And then there are patient factors, individuals experiencing treatment toxicity, especially many patients ask that can be stay without ADT and elderly patients with comorbidities. And then if we have disease factors low-volume disease, Lower Gleason, and longer PSA doubling time, that would be the best option for de-escalation. However, in current phase, the guidelines don't suggest intermittent treatment in metastatic phase as a first choice. Still, the ARPI plus ADT is the treatment of choice there suggested but emerging interest we see with the studies, especially in oligometastatic disease. Most suitable candidates, low-volume disease or oligometastatic disease, biochemical recurrence, especially non-metastatic but risk to progress to metastatic phase, and the PSA responders and favorable tumor biology.
Thank you.
Neeraj Agarwal: Thank you, Dr. Matikainen, for walking us through the de-escalation strategies in metastatic prostate cancer, both in non-metastatic and metastatic hormone-sensitive disease. Thank you for talking about the SWOG S9346 trial which was done about 15, 20 years ago, which was started in 1990s. And I cannot even imagine how pertinent that study has become again in 2026 because those are the only data we have in the metastatic hormone-sensitive setting that de-escalation strategies may allow some patients to take a break.
But as you rightly mentioned, that was done in the context of single-agent ADT. And we need studies in the context of ADT plus ARPI or even more intensified therapies nowadays which are coming up. And you also mentioned the EMBARK trial in the non-metastatic setting where patients who achieved a less than 0.2 PSA level after 36 months of treatment, a substantial number of patients, about 1/3 of patients in the combination arm were able to take a break for about two years which is remarkable. And then you discussed about the ongoing trial such as the LIBERTAS trial, the EORTC trial, and the A-DREAM trial in the metastatic hormone-sensitive setting, and we really hope to see the results of some of these trials.
Coming back to one of the major points you made, which is that we don't have evidence to take a break right now. We should not be taking break from ADT plus ARPI or combination regimens without reason, unless patient are reporting severe toxicities or really they want to take a break, we should not be taking a break until we have evidence. Is that correct?
Mika Matikainen: That's true. That's very true. But there are a lot of patients who wish to have a break because the side effects are quite severe in many patients. And even in metastatic phase, they feel that they don't feel good with ADT. And most of the patients are doing quite well so they bear the side effects. But then there are patients who are on very serious side effects. And in those patients, we really have to consider even in a metastatic phase.
Neeraj Agarwal: Absolutely. Especially in elderly frail patients, as you mentioned.
Mika Matikainen: That's true.
Neeraj Agarwal: Say I saw an 85-year-old man who had a great response in his PSA and the patient is clearly feeling very fatigued and is at a high risk of fall, I do feel comfortable taking a break in these patients, especially with low-volume disease metachronous disease. Thank you.
Mika Matikainen: The testosterone stays low quite a long time after pausing the treatment. In many old patients, especially the ADT still goes on quite long without adding a treatment there.
Neeraj Agarwal: Correct. That is a nice segue to the next topic I'd like to get your opinion on, and that is testosterone recovery. We know that we give them GnRH agonist injections. And when we take a break, many of these patients don't recover their testosterone for a long time and they're essentially being treated with ADT monotherapy during this time. Correct?
Mika Matikainen: That's true. That's true.
Neeraj Agarwal: What is the role of GnRH antagonist in these patients where we say start with Relugolix, for example, Relugolix with one of the ARPIs and then continue ADT plus ARPI for six, seven months, see a PSA level of less than 0.2 and we are ready to take a break now. The big advantage I personally find with Relugolix is the testosterone recovers quickly. Within three to four weeks, it starts recovering. And most patients have achieved the baseline testosterone by three months, as opposed to GnRH agonists like Eligard, Leuprolide, Goserelin, it takes much longer. Do you use Relugolix in your clinic where you are contemplating intermittent therapy?
Mika Matikainen: Yes. Actually, that's a very good question. And thinking that because in antagonist recovery is, as you said, much faster, and especially in patients who have been on ADT only six months to eight months so then the recovery is still with... Especially antagonist is much quicker. And we use also Relugolix in Finland and also antagonist injections but majority of patients still get Leuprolide or other LHRH agonists in Finland.
Neeraj Agarwal: Sure. What are the main factors in your experience which allow good testosterone recovery? Baseline testosterone for example, or it is age of the patient, or it is the duration of GnRH agonist therapy, if the patients have received four or five doses of Leuprolide versus one dose of Leuprolide. Which one of these factors are the most important factors leading to testosterone recovery in your experience?
Mika Matikainen: Yeah, I would say that age and time on ADT treatment. If it has been over one year or two years, even after four years especially, then the recovery even in antagonist treatment is much averse.
Neeraj Agarwal: And you mentioned increasing risk of cardiovascular events as our patients are living longer, much longer fortunately, and they are living longer with low testosterone. Those are real issues-
Mika Matikainen: That's true.
Neeraj Agarwal: ...so hopefully we will see the success of many of these trials in the near future, which will allow us to use intermittent therapy in our patients with metastatic hormone-sensitive prostate cancer. Are you looking forward to completion of these trials and good results from these trials?
Mika Matikainen: Very much with especially hopes with ARPI treatments to have more effects in the first phase. And then as shown already in non-metastatic phase in EMBARK study, we can expect that both times also in metastatic phase could be longer than with the ADT only. And I remember I've been involved in Finland some 15 years ago with FINNPROSTATE-7 study with ADT, and there were also especially good responders for only ADT treatment and they had pauses two to three to four years even on that study only. And then if we could do that study in Finland with ARPI medications at the moment, based on the old data, I would expect that we get very much better results.
Neeraj Agarwal: Thank you, Dr. Matikainen, for sharing your insights and wisdom. We really enjoyed your talk. Thanks for taking the time.
Mika Matikainen: Thank you very much.