Maha Hussain: It was my honor, my dear.
Neeraj Agarwal: Let's talk about intermittent therapy first. Dr. Maha Hussain doesn't need any introduction, but still, for the sake of completion, Dr. Hussain is the professor of medicine and oncology and deputy director at the Northwestern University Cancer Center.
Maha Hussain: Yes.
Neeraj Agarwal: Welcome, Maha.
Maha Hussain: Thank you.
Neeraj Agarwal: First of all, let me discuss the intermittent therapy. You started the story of intermittent ADT with SWOG 9346 trial.
Maha Hussain: Yes.
Neeraj Agarwal: And it showed that intermittent therapy was not, not inferior to continuous therapy. And first time I thought it was in the context of metastatic hormone sensitive prostate cancer, somebody really asked this question. And now we are visiting intermittent therapy again and our patients are living longer. So how do you see the field evolving moving forward as far as intermittent therapy is concerned? Should we be revisiting that whole concept and in which patients?
Maha Hussain: Yeah. Thank you so much. The intermittent therapy was a topic that I was very passionate about. And just to clarify for the audience, the reason to do it has nothing to do primarily with quality of life. It was actually all about quantity of life because work, by God bless his soul now, Dr. Nicholas Bruchovsky from Canada, which basically showed that if you keep the cancer addicted to the hormone, to testosterone, the chance of prolonging responses to treatment is longer. So consequently, you treat, you stop, you allow testicular recovery and then retreat again.
And when we designed the trial, we designed it as... The whole idea was to see that can we show at least at a minimum that intermittent therapy is as good as continuous therapy, not necessarily superior to that, which was the design of a non-inferiority trial design. It took over, I don't know, 3,000 patients to be screened or something. It was like several thousand. It was actually an international study. It was done through SWOG, but the US cooperative groups, Canada and Europe. At the end of the day, just by the design, and this is an interesting story about the not non-inferior, because this was a whole debate with the New England Journal editor, but the bottom line was that technically, when you look at the curves, intermittent therapy is not as good as continuous therapy.
Now, the issue of quality of life is important, but remember also that cancer out of control can destroy quality of life. So judging everything and looking at it. Now, where we are right now, I think in a setting whereby we have much more intensified treatment, more effective treatment, life prolonging treatment. So one of the questions that I think would be worthy of asking is... I wouldn't call it intermittent therapy, more of an intensify therapy to try to eradicate as much cancer as possible, but then after several years of remission, potentially consider a treatment holiday.
And the issue comes up with a treatment holiday that I think is going to be critical is when do you anticipate testosterone recovery? And I have to say, I have many patients who opted for a treatment holiday after five years of treatment, even though stopping their LHRH treatment, gonadal suppression therapy, their testosterone did not recover. And so the other question comes up is, again, balancing all of this and monitoring closely to see what happens next.
The flip side is the patient's comfort level and there's other patients who have been literally on treatment for 10 years and they are in remission with scans being very stable and they are uncomfortable stopping treatment because they feel they came this long way, they don't want to stop. So I think a randomized trial addressing both the issue of quantity and quality, the quantity of, in terms of life prolongation, the quality of life, and then seeing in fact, can you actually get away with stopping the treatment after a certain period of time and continue to monitor?
As you know, we have the A-DREAM, but that's a phase two type trial. So we'll be interesting to see what the data that comes from that one.
Neeraj Agarwal: So patient selection for intermittent or treatment holidays.
Maha Hussain: Yes.
Neeraj Agarwal: You also showed for the first time in JCO 2006, 20 years ago, I can't believe it, from 9346 trial, the patients achieving a PSA response, optimal PSA response, that was defined as 0.2 or less. And now several intermittent therapy trials are using the same criteria.
Maha Hussain: Yes.
Neeraj Agarwal: So those patients who achieve a PSA level, which is undetectable, whether you call it less than 0.2, less than 0.1, depending upon the technology and the machine, looks like across the trial, you showed in RSN, in TITAN, ARCHES, the patients who achieve undetectable PSA level have much better survival outcomes ultimately. So how do you see these patients as potentially better candidates for intermittent therapy or treatment holidays? And is it okay to start thinking about designing further trials, starting a treatment break at seven-month mark or 18-month mark?
Maha Hussain: Yeah. I mean, as I always say to my patients, the PSA is a flag. Ultimately, what you want to do, achieving when we published it from the intermittent trial, clearly a 50% decline was good, but the ultimate Cadillac of responses was the less than 0.2 or less, technically the undetectable range where people did live longer. The issue I think is going to be the durability of that. And this is where I feel like a combination factors of, yes, having a favorable response by imaging, favorable response by PSA, treating for a duration because you cannot assume just because the PSA is down that the cancer is dead. Cancer cells could be sleeping. And as you know, there are some cancer cells that are potentially going to be resistant and over time they will grow.
So this is where I would say sort something similar to the A-DREAM potential. And I'm hoping we can see the results from that coming in and consideration of then interrupting treatment and see how the patients go. I just deep down, don't feel that a seven months of treatment is going to be enough because ultimately what we want to do is show prolongation of life. And to date, I am not aware of any trial that treated for seven months and showed that life was exactly the same or longer. And I do think in an area that we live in, where we're seeing prolongation of life is we've seen it with intensified therapy, not under treatment.
But I agree at some point, and I would say this is a discussion I have with my patients, especially the low volume patients. So I have a good chunk of patients who are low volume disease, mostly lymph node metastases, definite mets. And we're talking not just PSMA PET, but they're enlarged lymph nodes, potentially limited disease in the bone, but technically low volume. This is where I would say intensified therapy in these patients, including targeted RT and watch how they're doing and then go from there. And a good number of them are in remission, but as I said, the level of comfort of the patients is the other factor.
Neeraj Agarwal: So for our colleagues out there who are viewing this video across the world, if patients really want to have a break and are having side effects, which landmark you feel more comfortable taking the break? Six months, 18 months and three years? This is the last question in this one.
Maha Hussain: Yeah, no, I would say I usually talk to them depending on the magnitude of their disease, but if it was, let's say like disease, I call it, based on PSMA PET, lymph node, no bony metastases, not necessarily de novo and all of that stuff, I feel like we have a conversation about a two to three years, just from advising them that maybe that would be the best way to go and that's what I say. For people with high volume, unless they're really out quite a bit, I feel a bit uncomfortable offering them stopping treatment at a short time because as you know, the cancer cells are still there. They're not dead and that's the worry about it.
Neeraj Agarwal: Right. And hopefully genomics and other markers will help us down the line.
Maha Hussain: Yes, absolutely. Yeah.
Neeraj Agarwal: Well, thank you Maha for talking about starting the story of intermittent ADT in metastatic prostate cancer and continuing that to date.
Maha Hussain: Thank you.
Neeraj Agarwal: Really appreciate sharing your wisdom with us.
Maha Hussain: Thank you. Thank you. Absolutely.