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Alicia Morgans: Hi, my name is Alicia Morgans and I am a GU Medical Oncologist and an Associate Professor of Medicine at Northwestern University. I'm so excited to be speaking today with Dr. Philip Kantoff, a Professor of Medicine and a GU Medical Oncologist at Memorial Sloan Kettering, and Anthony D'Amico, who is a Professor of Radiation Oncology at Harvard Medical School Dana-Farber. Thank you so much both of you for being here today.

Anthony D'Amico: Thank you.

Philip Kantoff:  You are welcome.

Alicia Morgans: Wonderful. I want to speak with both of you about a recent presentation at ASCO 2021, where we heard about some results from a study that has been ongoing for quite some time, looking at patients with localized prostate cancer who are receiving radiation and hormonal therapy, some of who also got treatment with docetaxel chemotherapy, Dr. Kantoff, can you tell us a little bit about the impetus for this trial and how it was designed,

Philip Kantoff: Sure, Alicia. So this trial builds on a trial that Anthony and I started, believe it or not in the mid-1990s, where we asked the question in patients with intermediate and high-risk prostate cancer, localized prostate cancer, whether or not the addition of six months of androgen deprivation therapy to radiation would improve outcomes over radiation alone. That trial too took about 10 years to reach its endpoints and did demonstrate an improvement in prostate cancer-specific survival, and overall survival. So building on that and with the development of docetaxel in the metastatic castration-resistant prostate cancer context, we decided to add docetaxel to the combination arm and compared radiation plus ADT for six months, compared to radiation plus ADT for six months, plus docetaxel. The docetaxel was given as 60mg/m2 every three weeks prior to the initiation of radiation. And then building on a phase one/phase two trial of a combination of docetaxel plus radiation in localized prostate cancer, we used 20mg/m2 of docetaxel weekly for seven weeks during the course of radiation.

Alicia Morgans: Great. That's certainly a combination that is potentially intense. I, we can talk about toxicity when we get to the end, but Dr. D'Amico, can you share with us a little bit about what you found? What were the findings of this trial?

Anthony D'Amico: So there were two findings. One was not expected, but important. And that was the use of docetaxel appeared to reduce the incidence of radiation-induced cancers. That is those in the juxtaposed bladder neck and anterior rectal wall significantly, such that the number of radiation-induced cancers between the two arms was one in the docetaxel alarm, and eight in the radiation hormonal therapy control arm. The second finding was more hypothesis-generating, and that is in men whose PSA was less than four, and who had high-grade cancers, a population that was thought to be ADT resistant. Docetaxel appeared to be associated with a reduction in mortality. Although again, the PSA level used for stratification prior to randomization was 20 and not four. And also because that association had a 95% confidence interval on the point estimate of 0.33, that included one.  We have to consider those results were hypothesis-generating.  A meta-analysis of the docetaxel radiation trial is planned in the future to look at that particular subgroup and its impact on docetaxel on survival, and that was bad.

Alicia Morgans: Well, that certainly will be interesting for the overall population though. Was there a benefit to adding docetaxel in this unfavorable risk population?

Anthony D'Amico: No, there was not.  Similar to past studies, once you get out to a median follow-up of 10 years, that benefit was not seen. However, similar to past studies like the RTOG 0521, when you look at six years and you look at the survival curves, you can actually see there is a splitting, favoring the docetaxel arm. And this caused us to raise the question of how can this be?  Early benefit and then no benefit later. And that, you know, prompts the possibility that a small subgroup like PSA, less than four high-grade cancers, may be very well to men who do benefit. You see the early benefit, but then it washes out as the vast majority of people do not have a PSA less than four on any of these studies, on the RTOG, and others. And so that benefit then is lost with time.

Alicia Morgans: It's really fascinating, and just to remind everyone, RTOG O52 was a study looking at a similar population. But I think this was a high-risk localized population who received treatment with adjuvant ADT and docetaxel versus ADT alone, and initially was reported to have a one-sided p-value, a benefit of adding that docetaxel in this high-risk population. So really interesting that there was a similar split initially that then necessarily, did not persist. And Dr. Kantoff, I wonder, we heard Dr. D'Amico's take on that? What is your take on that? Is there a population that may be benefiting sort of preferentially, such that there is an early, early separation of these curves that then is lost over time?

Philip Kantoff: Right. You know, that study was an interesting study and we did see that separation early on and our initial hypothesis was that perhaps the docetaxel was having a beneficial effect in some other way, rather than in a prostate cancer-specific fashion, perhaps by reducing cardiovascular toxicity during a period of time. But that, that finding washed away. It is entirely possible that there is a subset of patients, who do benefit early on from the use of docetaxel. I think what Anthony did speak to, that is the population with PSA's less than four, it's a good hypothesis.

It needs to be tested, in a meta-analysis and perhaps prospective studies, I specifically find the finding of the difference in infield or radiation-induced cancers to be fascinating. I couldn't imagine what the mechanism is, but at this point, but you know, that's a pretty strong finding. There are 5% of the patients who received, who received just ADT and radiation alone that had infield cancers as opposed to less than 1% in the docetaxel arm. It's important to point out that there is a background of cancers that occur in this population so that those numbers may be an overestimate, but since it's a randomized study, that difference is probably real.

Alicia Morgans: So agreed. And that was actually surprising to me, too.  Dr. D'Amico, as a radiation oncologist, you are probably more familiar with rates of occurrence of secondary malignancies than I am. Does this finding, this rate within this population seem consistent with other studies or with maybe real-world data that you are aware of?

Anthony D'Amico: Yeah, actually, Michael [inaudible 00:07:43] published a report about 10 years ago now where he looked at the rate of second cancers and found, in fact, the rate was in about the 4% range and we have about 5% at 10 years. And I think that as Dr. Kantoff just pointed out, we have to remember that there is a baseline incidence of bladder and colorectal cancers that we expect that was not adjusted for because we didn't have a radical prostatectomy control arm. However, since the hazard ratio that compares the two arms would subtract out that baseline rate, given the randomization, the hazard ratio was robust.

One of the points I'd like to make is that you know, seeing an early separation in the curves and survival at six years and no benefit in cancer-specific survival is noteworthy because it suggests that there must be something else at play, in addition to possibly a small survival benefit in the PSA less than four subgroups to create an overall survival benefit without a benefit in prostate cancer-specific survival. And that could very well be a lowering of death from second radiation-induced cancers in the docetaxel arm. That's one way to see a survival benefit without a concomitant improvement in prostate cancer-specific survival.

Philip Kantoff: It is important to mention Alicia, that these secondary malignancies are, are very lethal. About half the patients did die of their secondary malignancies.

Alicia Morgans: You, you read my mind Dr. Kantoff, because that's exactly, I'm sure many people who are listening in clinical experience. I mean, these are not easy cancers to treat. So I'm not saying that I would suggest that we should give docetaxel in this setting to prevent these secondary malignancies, but, they are clearly a problem. And something that we, as a field need to continue to work to reduce in any way that we possibly can. And certainly limiting exposure to radiation when unnecessary or using docetaxel when appropriate. Those are two approaches.

But one of the other things that I wanted to highlight from this study is really the multidisciplinary collaboration that the two of you have had over the years with this work and that I'm sure you had clinically when you were both in the same institution, over a long period of time as well. And that's not always easy. And I'm wondering as we move many of our systemic therapies into the earlier settings, in combination with radiation or in the adjuvant setting post-radiation, how can teams best navigate that? What are some best practice tips, and what did you learn from working on this study and in clinical practice that might be helpful.

Anthony D'Amico: I'll start by just saying that you can't advance anything in medicine or oncology specifically without a multidisciplinary approach. Cancer requires a multi-disciplinary approach actually to improve outcomes. The expertise that we have actually compliments one another and we learn from one another. And that is how we can create novel ways of looking at new therapies, going down the road. I also want to just say that, you know, Phil, you mentioned earlier about radiation and these cancers now being extremely lethal, half of the men die from it in the study. How could it be that docetaxel impacts that, and there is a, there is a plausible explanation, which is as the radiation dose falls off, you know, it's lower in the anterior rectal wall and the bladder neck. Here is your prostate, here is the anterior rectal wall, and here is the bladder neck, the radiation dose is getting lower and lower and lower, cells can survive that lower radiation dose in the anterior rectal wall and bladder neck, and mutate and go on to become second cancer. That's the mechanism we believe in.

So how does docetaxel help? Well, docetaxel is a radiosensitizer, so that lower dose in the anterior rectal wall and bladder neck that would have survived now with the docetaxel on board, that lower dose is accentuated and therefore the cells don't survive and they die. So I think that is a possible explanation as to how docetaxel can be impacting radiation-induced cancer incidents. Simply by accentuating the dose and the penumbra in that fall-off region causing cells that could have been viable to no longer survive.

Philip Kantoff: Alicia, to your original question, I think, Anthony and I really were a part of a much bigger team when I was at Dana Farber, of radiation oncologists, medical oncologists, and urologists who really work extremely well together clinically. And we met frequently and developed clinical trials like this and, and others, as you know, the neoadjuvant trials came out of a collaboration with urology, that Mary Ellen headed up. And we have a similar environment at Memorial Sloan Kettering where we have the disease management groups that work together across disciplines. I think it is absolutely essential for there to be that type of collaboration, both clinically and in the investigation.

Anthony D'Amico: And to Phil's point, 60% roughly of the accrual came from Dana-Farber/Brigham and Women's hospital. The other 40% came from all the other sites with the [inaudible 00:13:16], being from Australia and New Zealand, which was wonderful, it made it an international study and more generalizable. But yes, we were able to put a lot of patients on a study in Boston as a result of that type of collaboration. There are weekly meetings to discuss protocols, both new and ongoing, which fosters the interest in supporting the studies. And I think that, in addition to radiation and medical oncology, urology was involved as well, even though you don't think there might have been a role for them in the treatment aspect, there was a role for them in the diagnostic aspect and referring patients for consideration for these trials.

Alicia Morgans: Absolutely. So thank you both for emphasizing the importance of that multidisciplinary approach. At least good communication, knowing who your partners are, and trying to connect regularly are things that we can all do no matter where we are and try to ensure, that allows us to then I think treat our patients as appropriate and get them the best outcomes, certainly the ones that we wish for them.

So thank you both so much for your expertise. I really appreciate the time that you took, certainly your efforts on this trial, and for really digging into some of the details with us as a team here. Thank you very much.

Philip Kantoff: Thank you.

Anthony D'Amico: Welcome.