JM:      Hello, greetings from Chicago. My name is Joaquin Mateo, I’m a medial oncologist at Vall d’Hebron Institute of Oncology in Barcelona and I’m delighted to have with me two esteemed colleagues, two experts in the field of early drug development – Dr Parsonson and Dr Baldini. We are going to be discussing about new developments, new agents with new mechanisms of action, for prostate cancer that are being presented here today at ASCO. Can I maybe before we start ask you to introduce yourselves to our audience?

AP:      Absolutely, thanks for having me. My name is Andrew Parsonson, I’m a medical oncologist working out of Sydney, Australia, out of Macquarie University, the phase I unit. I’ve been involved in several phase I studies in the GU space but also other solid tumours.

bM:      Thank you.

CB:     Good morning, I’m Dr Baldini, a medical oncologist working at Gustave Roussy in the phase I department. I’ve been focussing on GU cancer recently as a PI in different areas and with different drugs.

JM:      Thank you very much for being here today with us. So in the field of prostate cancer for the last 20 years or so we’ve seen a lot of hormonal agents, taxane chemotherapy, maybe we have seen a bit of targeted agents with PARP inhibitors, maybe we have seen a bit of radiopharmaceuticals with quite a lot of success. But we are seeing now a new wave of agents that work by completely different mechanisms of actions. We are still learning how to optimise the use of these drugs and particularly I’m focussing on ADCs and T-cell engagers. There is very interesting data being presented at this ASCO conference with drugs with both mechanisms of action and actually we are very happy to have you because you are presenting data on interesting studies, phase I trials with new drugs. So maybe can I ask you to summarise a bit the highlights of the study that you have presented?

AP:      Yes, absolutely. So just before I do so, in background ADCs have been very prominent in several other solid tumour areas and we haven’t quite seen anything in prostate cancer yet that’s been a definite drug of interest. The study that I’ll be presenting is a B7-H3 targeting ADC from Duality Biologics termed DB-1311 or BNT324 that is an ADC with a potent topoisomerase-I-inhibitor payload targeting B7-H3 that tends to be ubiquitously presented on prostate cancer cells. This study was part of a phase I and II study with many solid tumours and prostate cancer was one of these tumour types of interest. In total 393 patients were enrolled from all solid tumours for this study of which 73 patients were castrate resistant prostate cancer. Of these, the patients were largely heavily pretreated, median prior lines of treatment was 4 and up to one third of patients had five or more prior lines of treatment. Generally the take-home message, really, from this study has been that this has been a very promising, encouraging drug in this field where the objective response rate, which has been updated since the time of the publication of the abstract, 42%, disease control rate 90% and 6-month progression free survival rate of 67%. Certainly it appears to have been a safe drug to use as well so they did do some drug optimisation, dose optimisation, during this study where particularly at the lower dose, 6mg/kg, grade 3 adverse events were around 27%, largely gastrointestinal, haematological, things that we’re quite used to managing as oncologists. Certainly dose discontinuation or drug discontinuation rates were low, around 10% also. So certainly I’m very excited about this molecule and where it’s going to go next and I’m very happy to discuss that as well.

JM:      The data is quite promising, good response rate but also the tolerability. The tolerability is something that has worried many of us in the field of ADCs for prostate cancer with the experiences we have had. What do you think is the advantage of this new wave of compounds? Why are we seeing better tolerability? Are we just better at managing it or..?

AP:      I think there are many factors that come into this, of course, around the design of the ADCs. ADCs, of course, are not new, they’ve been around for a long time but even in the prostate cancer field where there have been several drugs which unfortunately haven’t made it through the entire drug development process. But I feel that with these new agents coming through with several novel parts of the ADCs, including the target being B7-H3, the proprietary cleavable linker as well as the potent and effective payload in this setting is very encouraging and very exciting to see. Certainly we’re now seeing that playing out in the clinical setting. The main question in my mind about where this goes next is sequencing, about where this potentially fits in with all the other agents that you mentioned earlier as well.

JM:      Perfect, thank you. And Dr Baldini you have presented data on a study that has raised a lot of interest at this ASCO conference, it’s a study on a bispecific antibody, a T-cell engager targeting KLK2 for patients with prostate cancer. Can you maybe give us some high-level view of the results that you have presented?

CB:     Yes, of course. First of all, I think this is very promising because prostate cancer usually is known as a cold tumour in terms of immune infiltration. So that was very interesting to see how patients were going to respond and tolerate as well this new type of drug. The other point that was very interesting with this study is the target. It’s, as you mentioned, a bispecific T-cell engager targeting Human Kallikrein 2 which is a novel target, never tested before. It’s really specific to prostate cancer cells, we don’t see any expression on normal tissue. So this is really interesting. In terms of mechanism of action, it’s pretty classical so it binds to CD3 and KLK2 with a lysis [??] of T-cell activation and a lysis [??] of cancer cells. So this mechanism of action is pretty common.

So in this study actually it was the phase I, both dose escalation and dose expansion phase. All patients received prior ARPIs and they were similar to the ADC compound, they were heavily pretreated. Median prior lines of treatment of 4, ranging from 1 to 13. So various numbers of patients with different treatment and medical histories. In terms of adverse events… Regarding study design, first, the study was started first with sub-Q dosing for the dose escalation phase and then the IV dosing was introduced later because the purpose was to reach higher doses of treatment. With immunotherapy we are very accustomed to not seeing MTD reached, so in this study, similar to others with immune checkpoint inhibitors or other immune targets, we didn’t reach the MTD. RP2D was defined as step-up dosing so we used a smaller dose of 3.5mg on day 1 then a subsequent dose of 18mg on day 8 and then the full dose of 300mg every six weeks schedule and we decided to go for IV at the end.

So all together the drug, the [??] was very well tolerated. The most frequent treatment-related adverse events were actually fatigue and infusion-related reaction but they were low grade. Interestingly, we didn’t have to use steroids or epinephrin to manage the infusion-related reaction. The other concern, usually, with T-cell engager is the CRS rate because we have been used to other drugs and we know that it can be challenging for patients, especially for outpatient dosing in community centres. But what we saw with this drug is a very low rate of CRS, lower than 10% grade 1 with only fever, and we never used tocilizumab which is pretty amazing for patients. So in terms of high-grade treatment-related adverse events it was mainly transient [??] AST/ALT increase, nothing special and we didn’t find any DLTs during this phase I.

So in the dose expansion phase of the study it’s very particular because in terms of eligibility criteria patients should not have visceral disease at enrolment. So a very few number of patients obviously in the overall population of patients treated had liver metastases and lymph node metastases. In terms of efficacy for this study the overall response rate was 8% and the median duration of response was almost 9 months. So when we looked at the rPFS curve it was also very interesting because we could see a small tail effect, like we could see with immune checkpoint inhibitors actually, which was really interesting. So we saw a durable disease control and overall a great tolerability profile with the drug.

JM:      You mentioned an 8% response rate, I guess you were also observing PSA responses, is that correct?

CB:     Yes. So the PSA50 was achieved in more than 40% of patients and we had 36% of confirmed PSA50.

JM:      That’s very interesting and also the fact of giving the drug every six weeks that you mentioned and the use of steroids. I guess that for many of these T-cell engagers we are giving steroids as pre-medication, I don’t know if that was the case for this?

CB:     So we did use steroids as a pre-medication for the first injection and administration, of course, during step-up dosing and then we did not require and we didn’t use any steroids.

JM:      Interesting. I think that from the tolerability perspective and the long-term use, both the frequency and the use of steroids are relevant topics, right? So we will need to see more data on these drugs as they advance through phase II trials but let’s imagine that these and other compounds of similar mechanisms of action hopefully demonstrate benefit for our patients. We are going to be in a scenario where we’re going to have ADCs, T-cell engagers, probably also other drugs like radiopharmaceuticals, that are actually going after the same target. So we have talked about B7-H3, we have talked about KLK2, we are seeing also compounds targeting STIP1, STIP2, obviously PSMA – we have a lot of radiopharmaceuticals against PSMA but we also now have bispecific antibodies and ADCs. So how are we going to navigate this scenario where the same proteins are the target of multiple drugs with multiple mechanisms of action? For one single patient are we going to stick to one target or are we going to alternate the targets with the same mechanism of action? How do you envision this happening?

AP:      I think it’s a really interesting question and something that we don’t quite know the answer to yet. The ADCs, at least, I feel that they appear to be effective even in those patients that we tend to worry about with prostate cancer, so those with visceral metastases, with liver metastases for example. We didn’t have data necessarily on aggressive variant prostate cancer in this study, however certainly the physical and clinical characteristics of these patients, that tended to be those with higher risk features, still appeared to have a very good response to here. So certainly, from my personal opinion, I feel that those patients where we’re worried about quite quick progression or quite aggressive disease, those sorts of patients would benefit from an ADC. Certainly I think with the phase I data at least and the phase II data we can also see that even if patients are quite heavily pretreated, even if they have had multiple lines of treatment, they still appear to tolerate this quite well there as well. So even if it is used as a later line therapy we know we could potentially salvage some of these patients who don’t have many good standard of care options by that stage.

JM:      So my question, Dr Baldini, would be after a patient progresses to one of these agents would you rechallenge with another drug with the same mechanism of action or would you still with a different mechanism of action but the same target?

CB:     Yes, I think this is definitely a key question. We don’t know yet, I’m thinking mostly about ADCs because the question is do you do sequential, do you keep the same target and change the payload or the other way around. So now we don’t really know. But I think it’s going to be interesting to see the strategy but I think the biomarker area will also be very important to really describe and to define the population that is benefiting the most from the treatment, ADCs versus T-cell engager bispecific. It would be also very interesting in my opinion to see how the combination could work. Because sometimes for immune cell engagers to work, in order for them to work you also need to debulk a little bit the disease. So maybe that could be the role of the ADC and then you have the immune cell engager to enhance the response and to achieve the best treatment option. Of course this is…

JM:      You raise two very important topics, combinations but also biomarkers. So in the field of prostate cancer for the last few years we have worked a lot in implementing genomics for stratification but these drugs need a different approach. We are talking about the expression of surface proteins so how do you think that we can stratify patients for these drugs, or what was your experience in the trial? Did you do any prospective or retrospective work looking at expressions of the markers?

AP:      So this wasn’t presented as part of the abstract or the presentation but B7-H3 was retrospectively tested in these patients. Generally speaking, as expected it was quite widely expressed across most prostate cancer and, of course, this data will be later analysed more closely but there did not appear to be an obvious correlation between expression level and response in this study. So certainly at this stage there’s no biomarker testing requirement for this drug.

JM:      What about your study?

CB:     Yes, so for the KLK2 compound it’s pretty similar. We don’t have, actually, the data, they are currently looking at it. So we are looking forward to seeing the results. What we know in terms of expression is that KLK2 is expressed in castration resistant disease but probably not, or less, in visceral disease and also in some cancers that are starting to differentiate into the neuroendocrine part of the disease. So that’s mainly what we know now and we don’t have clearly a test to say that this patient will benefit because of the high level of KLK2 right now.

JM:      Correct, but also you mentioned the evolution of the biomarker changes.

CB:     Yes.

JM:      This is important, KLK2 is partially regulated by AR so that’s probably going to change as the disease evolves. Probably for B7-H3 it’s not that clear, there is data coming out, papers from the labs of Himisha Beltran and [??], saying that it’s more of a stable biomarker. [??] but I guess that we need to take that into account when we stratify patients.

AP:      Absolutely.

JM:      So these are the biomarkers to select the target but do you think that we also need to work towards biomarkers to understand which patients could benefit from one or another mechanisms of action? Would there be a subgroup of patients that primarily benefit from T-cell engagers, for example, [??] because of the immune component or is it the same for ADCs?

CB:     In my opinion the sooner the better for immune cell engager because you don’t risk T-cell exhaustion that you can have with chemotherapy. ADCs, they are still targeted chemotherapy so they have an impact also on the immune system. Again it’s what we’ve seen in this study, actually, where the benefit was the most durable in patients with bone disease. So probably we need also to target the right population and to define the best setting also based on the immune component. We don’t have yet the data because we can test, for example, patients in terms of immuno-senescence and do immuno-monitoring to look at the immune status of the patient. So we don’t have yet these data but similarly they are looking at it currently.

JM:      Very interesting. In this congress we have also seen data on new radiopharmaceuticals, combinations of radiopharmaceuticals, combinations of PARP inhibitors with drugs with different mechanisms of action. So we are entering into a space where drug combinations are going to be playing a role in prostate cancer. So particularly for ADCs how do you envision these combinations? Combinations with taxane chemotherapy in prostate cancer have failed one after another. With these ADCs as a smarter chemotherapy do you think that we have more room to combine these drugs?

AP:      That’s a really good question. I guess also on the point of earlier lines of treatment we did see in our study that patients that were treated earlier, so for second line and third line settings, did have a higher objective response rate, around 58%, 6-month PFS rate of 100% for these patients. So certainly earlier is better, I do agree with that for a lot of these drugs. But it’s going to be difficult, particularly when we talk about all the other drugs and how that fits in and whether we combine it or whether we use it sequentially here. So far there hasn’t been much data about that in the clinical setting where we’ve combined it with other agents but that’s only been looked at. So another B7-H3 targeting ADC, ifinatamab deruxtecan, which is a bit further along the drug development pathways – now testing that in a study called Ideate-Prostate02 – which is being looked at and being started across the world. Certainly that study is looking at it in combination with several ARPI agents there as well and seeing whether that can potentially mount a better response and a better overall outcome.

JM:      Perfect. And maybe to close this session my question goes towards the practising clinicians that are seeing these drugs with new mechanisms of action. We are going to have to learn how to manage these drugs. Any advice on what is important for even the younger generation of clinicians that are being trained? How are they going to manage these drugs?

CB:     Again, with T-cell engager what is the most worrying is the CRS because obviously when you reach high-grade CRS you are worried about the patient and the outcomes. So what was reassuring with this drug was the low rate of CRS that actually allowed outpatient dosing and I think it’s really key. As you mentioned, it’s a population of patients that is usually older with comorbidities and frail so you also need treatments that are definitely well tolerated.

JM:      What about ADCs? What’s the key concept we need to learn about managing patients on ADCs?

AP:      So I guess this is a relatively new area in prostate cancer especially, but we’re a little bit further ahead in other tumour types. So breast cancer, for example, where we’ve had a larger experience with using topoisomerase-inhibitor based ADCs. I think we can learn a lot from these other tumour groups, so certainly the most common adverse effects, these are not side effects that as oncologists we are unfamiliar with managing. So things like nausea tend to respond very well to 5-HT3 antagonists. Side effects such as haematological toxicities tend to be easily managed with dose reduction or with growth factor support if necessary for treatment-emergent adverse effects. I suspect that is just in regard to getting a bit of experience with using these agents, just like other oncologists in other tumour groups have done so.

JM:      Well, thank you very much. I think we have focussed the discussion on ADCs and T-cell engagers because of your expertise, but, again, we are in a very exciting time for drug development in prostate cancer with the advent of these new mechanisms of action, combinations with radiopharmaceuticals, with PARP inhibitors. We are also seeing drugs targeting the methylation or the adaptive methylation as their [??]. I think that we have hope that many of these drugs may make it and may demonstrate that they help patients so I hope that we can meet again, maybe at ASCO 2026, seeing the progress of your studies. Congratulations on completing your studies and hoping to see that they actually make a difference for patients soon. Thank you very much and thank you very much to all our audience for joining us today.