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Alicia Morgans: Hi. I'm so excited to be here today with Dr. Carsten Ohlmann, who is the head of the Department of Urology in Bonn, Germany, as well as being a professor of urology at Saarland University in Germany as well. Thank you so much for being here with me today to talk about the randomized phase two trial, called the SPARE trial, for patients who have chemo-naive metastatic castration-resistant prostate cancer.

Carsten-Henning Ohlmann: Thank you for the invitation, Dr. Morgans. It's a pleasure for me to talk to you about the results of our trial.


Alicia Morgans: Well, it is a pleasure for me too, Professor, and why don't we look at some of your slides.

Carsten-Henning Ohlmann: So, a couple of days we were able to publish the results of our exploratory phase two trial, the SPARE trial, comparing the standard of care with ADT plus abiraterone plus prednisone versus abiraterone plus prednisone without continuation of ADT in patients with progressive castration-resistant prostate cancer. So, this is the trial design. As I mentioned, we randomized the patient with CRPC, asymptomatic or mildly symptomatic, similar to the COU registration trial of abiraterone which was published a couple of years ago. So, the patient were randomized to receive either ADT plus abiraterone plus prednisone versus abiraterone plus prednisone alone. We did regular assessments of imaging, including CT, MRI and bone scans every three months. And the end point of our trial was the rate of radiographic progression after 12 months. Secondary end points include a PSA-response, objective response, and we looked at different hormones, different serum levels of testosterone, LH, FSH, as well as safety. So, these are the baseline characteristics.

We randomized 34 patients in every arm. Median age was comparable in both arms, as well as the ECOG performance status. Baseline PSA was a little bit different, but not statistically different in both arms, a little bit higher in Arm A, 31.9 nanogram per ML, where there's 19.5 nanogram per ML. And testosterone levels were also quite similar except for one patient who was included in the trial without having castrate levels of testosterone. That's why, in Arm A, the range of testosterone exceeds the castrate level.

This is already a look at the PSA response rates. And as you can see, there seems to be no big difference in PSA response rates between both arms. And also in the primary endpoint rPFS after 12 months, we didn't see a big difference. Again, mentioning that this was just an exploratory phase two trial. So, the trial was not powered to identify a difference between both arms. But as you can see, the curves run quite similar. So, we don't even see a signal that there might be a difference in rPFS between both arms. These are some of the further results of the efficacy analysis. rPFS rates at months 12, actually, you've just seen the couple of markers are quite similar, 0.84, where there's 0.89 in Arm B. We have same PSA response rates in both arms and also the PSA progression rates after 12 months are similar.

We also looked at the objective response rates in both arms, at least in those patients with measurable disease, and we see that there were similar rates of patients having complete partial response and stable disease. For me, most interesting was the look at the serum levels of different hormones. As you can see, serum testosterone levels in both arms, on the left Arm A and Arm B on the right side, dropped far below castrate levels of testosterone even in those patients not receiving ADT anymore. That's because abiraterone is high efficacy and more efficient than ADT alone in lowering testosterone. And on the lower panel, you can see the LH levels and the results were as we expected, because in Arm B, in patients who did not continue ADT, in these patients their serum levels of LH increased very early after the start of therapy.

And that's because the negative feedback of the LHRH analogs did not affect or did not work anymore. So, the LH levels increased in these patients as we expected. And the blue line is Arm A, the patient that continued ADT, and in these patients serum LH levels were nearly zero as expected. And in some of the patients from Arm A, those patients who did not receive ADT when they stopped abiraterone, we saw a rapid and early recovery of testosterone due to the high LH levels, which is the red line. Again, the serum levels of LH. You can see that in these patients, the LH levels increased as in all the other patients. And then when the abiraterone treatment was stopped, they had kind of a boost of testosterone levels. So, in conclusion of this trial, we did not see a difference in efficacy in both arms. And that's why we think that at least this trial is a hypothesis generating that it might not be necessary to continue ADT in patient with castration-resistant prostate cancer when they start treatment with abiraterone.

Alicia Morgans: So, thank you so much for going through that. I wonder from your perspective, this is obviously a phase two so it's very early days, but is this something that you think warrants further exploration and investigation, especially as we're trying to make sure that we're using resources to treat our patients most wisely? And whether that is as necessary, maybe, in Germany or the United States, I think we all want to save resources, but especially in places where resources are scarce to begin with, it is of utmost importance that we do. So, what are your thoughts in terms of further investigation?

Carsten-Henning Ohlmann: Yeah. I would love to go on doing a phase three trial, for example, but it's not easy to get funding in Germany for trials like this because pharmaceutical industry is not very interested in trials like this. However, I think it would be very worthwhile for the patients to deescalate treatment, and especially in those getting abiraterone, but also in other patients with CRPC., we know that not every patient needs ADT anymore. However, most of the drugs that are available for treatment, they need continuous ADT because of the label of the drugs. And that's a big problem, I think, and the patients would really benefit from a deescalation of therapy.


Alicia Morgans: I think that that's probably true, if not from a financial standpoint, even just from not having more interventions in their system. And I think it was very, as you said, hypothesis-generating or thought-provoking that there was a relatively swift recovery of testosterone with cessation of treatment. And I mean, I could envision that that may be useful perhaps even in settings where we are not dealing with metastatic CRPC, but maybe intensifying therapy for clinical node positive disease, as we are doing now per the stampede approach where we have patients with very high risk localized disease, and we're using ADT and abiraterone for two years. If we only had abiraterone, we would save the patients from being exposed to the ADT, but then also might have faster testosterone recovery on the back end, which may be helpful for them. Are these things that might be of interest to you and your team?

Carsten-Henning Ohlmann: Yes. I think that, for example, the concept of intermittent ADT would be a lot more feasible using just abiraterone because of the faster testosterone recovery. But you have to control testosterone levels so very closely just to be able to restart abiraterone then early enough before the patients progress. However, there was a trial in South America, the LACOG trial, investigating abiraterone plus APALUTAMIDE without ADT. And surprisingly, some of these patients did not reach castrate levels of testosterone. So, this was a different patient setting. This was a hormone-sensitive disease. And I'm not sure about the reason for these effect that some of the patient did not receive or did not reach castrate levels of testosterone. This is probably a difference to the SPARE trial in which we treated castration-resistant prostate cancer patients, and we did not see any patient who did not have testosterone levels far below castrate levels. So, that's a point that you have to be aware of.

Alicia Morgans: I think that's a very important point. Certainly a cautionary message that, in the different settings with different durations of castration before patients might go onto this type of an approach, if you've never been on hormonal suppression before, as in the hormone-sensitive state, you may not reach castration. Whereas if you've been on these medications for years and have a very suppressed hypothalamic pituitary gonadal access, so that thing that is shut down, then you're dealing with a different situation. And maybe that's the time for abiraterone single agent to be possible.

Carsten-Henning Ohlmann: Yeah, I fully agree. I would love to do, I would call it a testosterone-driven treatment. So, if you'll stop ADT in patients with castration-resistant disease, you can measure testosterone levels. And there will be, of course, some patients who recover with testosterone, but many others will not because of their long-lasting ADT treatment. And in these patients, you will not have to continue ADT. And also in some of the patients who recover from testosterone, they may not have an ADT-sensitive disease. So, even in those patients, you may not continue with ADT so may not need ADT anymore. And I would love to do such a trial, but it's a complex design and I'm not quite sure if this is feasible. But I would love to do it. I mean, you certainly know about the bespoke treatment or trial design by Chris Sweeney in hormone-sensitive diseases. It is also very complex, but it will enable a very individual treatment in the future because it really focuses on the biology of the disease and will lead to individualized treatments. This is very straightforward trial design, and I would love to do such a trial in CRPC patients.


Alicia Morgans: Well, I look forward to seeing that. I think continued conversations and perhaps cooperative groups, whether they're multi-country or even within a country, perhaps at some point we can put something like this together. It seems like a non-pharma supported approach may be the right way to go, especially as we're really trying to conserve limited resources and really stop subjecting patients to unnecessary treatments whenever it's possible. So, I really commend you and your team for the Herculean effort it takes to complete this kind of work, because these are not necessarily the most easy trials to do when we're not talking about a new blockbuster drug with a lot of hype around it. But these are the most practical studies that we need to do to make sure that we are the best stewards of care for our patients. So, I do congratulate you and I thank you for your time and your expertise today.

Carsten-Henning Ohlmann: Thank you too, for this interview, and I hope we can go on with this work and study some more details on sparing ADT.