Charles Ryan: Hello to this Virtual ASCO 2021, I'm Chuck Ryan from the University of Minnesota. I'm joined by two guests from Spain today to talk about some real-world data that they presented on the management of CRPC in that country. First off is Dr. Elena Castro, a Medical Oncologist with a specialization in GU tumors. She's at Virgen de la Victoria University Hospital in Malaga, Spain, where she leads the Malaga Biomedical Research Institute. Then, there's Fernando Lopez-Campos, who is a Consultant Radiation Oncologist at the Hospital Universitario Ramón y Cajal, which is in Madrid. Thank you both for joining us. I'm really, really glad you could take some time to talk with us about your work.

Fernando Lopez-Campos: Thank you very much for having me.

Charles Ryan: Dr. Lopez-Campos, let's start by setting the table here and introducing the work that you presented on real-world data in Spain on the use of enzalutamide and abiraterone.

Fernando Lopez-Campos: Okay. The availability of multiple treatments in metastatic castration-resistant prostate cancer mandates the need to identify, as well as validate, prognostic and predictive factors applicable to clinical practice. In this context, PSA value is widely used for monitoring treatment outcomes in mCRPC patients in the clinical real-world setting. However, early PSA changes are not considered in the definition of PSA progression due to the potential for spurious “flare” reactions, and international guidelines don't recommend specific treatment monitoring. So, in our analysis, we aim to evaluate the significance of early PSA progression in metastatic castration-resistant prostate cancer patients treated with enzalutamide or abiraterone in terms of overall survival.

Charles Ryan: So, these were patients who were prescribed these medications at the choice of their treating clinician. They were not part of a clinical trial, so there probably are some differences between the types of patients who might be prescribed abiraterone versus those receiving enzalutamide. Dr. Castro, are there differences in what we're seeing in terms of the state of disease or baseline PSA, those types of things, between these two medications?

Elena Castro: Right, yes. These were patients who were chemo-naive metastatic castration-resistant prostate cancer patients. The data was collected. These patients were treated between 2011 and 2020. So, probably, nowadays we will be seeing fewer patients who have not been treated with chemotherapy or another androgen receptor signaling inhibitor at the time that they become metastatic castration-resistant. But we were able to collect data on over 500 cases treated during this period of time. We did not see significant differences between patients treated with abiraterone or treated with enzalutamide in this setting, with the only exception that bone-only metastases were slightly more frequent among patients treated with abiraterone, and there were some more patients treated with visceral disease treated with enzalutamide in our cohort.

Charles Ryan: That's interesting because I might imagine that, for example, older patients might be more likely to receive one or the other, but there's not any pattern like that in Spain, correct?

Elena Castro: No, the median age of treatment for the patients enrolled was 77 for patients treated with abiraterone, and 75 for patients treated with enzalutamide. So, not really a very significant difference.

Charles Ryan: Okay. And you mentioned something, you said over time, we are probably not going to be seeing as many patients who are chemo-naive receiving abiraterone or enzalutamide. Is that because most patients now start their treatment with metastatic castration sensitive disease, and therefore get docetaxel as frontline therapy?

Elena Castro: Yes, I would say that in Spain, unlike what is being reported in ASCO and in other meetings, it is now common practice that patients with hormone sensitive metastatic prostate cancer receive either docetaxel or an androgen receptor signaling inhibitor together with ADT, and ADT alone is not the standard of care anymore.

Charles Ryan: Okay. Understandable with the evolution of new treatments that we have. So Dr. Lopez-Campos, let's talk a little bit about the data. In your data presentation, you focus mostly on PSA progression, which is a little different from the way that we commonly talk about the relationship with PSA to therapy. We talk about PSA response a lot. We create waterfall plots, but here you're focusing only on that subset of patients who do versus do not develop progression, correct?

Fernando Lopez-Campos: Correct. In fact, PSA progression in our study at four weeks after enzalutamide or abiraterone is significantly associated with shorter overall survival, and may help identify patients not benefiting from this treatment before clinical, or radiographic progression. So, we think that this is important. However, prospective validation studies are needed to confirm these results and establish the value of PSA progression as a highly predictive biomarker of overall survival in mCRPC patients.

Charles Ryan: I found that your data were very consistent with what we saw from the clinical trials that led to the approval of these agents, in that it was a pretty small proportion of the patients overall who experienced PSA progression as their best response, really less than 10% or so of patients.

Elena Castro: It was 12% of patients who, in our cohort, had presented PSA progression before or at 12 weeks of treatment. I think what is beyond what Fernando said, I think what is also important is that we've seen that early PSA progression will help us understand which patients we need to monitor more closely, because, for whatever reason, there may be biological reasons or things that we don't understand, but these patients are likely to do poorly with different treatments that we may use. It's true that one of the limitations of our study is that we did not collect the subsequent therapies that patients received. But in the different analyses, it's quite consistent that PSA progression at week four, week eight, or week 12 correlates with shorter overall survival.

Charles Ryan: Correct. Now Dr. Lopez-Campos, let's talk about this. So, you looked at three different time points, progression at week four, progression at week eight, and progression at week 12. I actually found it quite interesting that there was actually, it looked like a trend and almost an improvement in survival between those having progression at week four versus progression at week 12. So for example, in the abiraterone arm, those who had progression at week four, had a 26-month median survival, whereas there was a 14-month median survival for those having progression at week 12. It wasn't as good with the enzalutamide group. It was the opposite. Can you help us interpret that?

Fernando Lopez-Campos: Yes, PSA pattern progression in association with overall survival seems to be different depending on which drug is used, abiraterone or enzalutamide. We didn't expect to find these differences and it's something that we have to analyze in depth. Subsequent treatments, mechanisms of action, and many more factors could contribute to this result, but we are working on that.

Charles Ryan: That's a very interesting finding. Dr. Castro, so there is a lot of work obviously being done in our field now, and you're involved with it, in the genomic markers or the genomic predictors of poor outcome in CRPC. Do you have any genomic data? Are you collecting that from this dataset, so that we can look at that early progression group? And if you don't, what would you speculate would be the genomic findings in that group?

Elena Castro: Right. Yes, we've collected the samples, but we still don't have definitive results on this cohort of patients. But with the data that is being released, one of the things we know is that patients with germline DDR alterations may respond to these therapies, but progress faster. So, maybe, probably some patients with these characteristics, we also know that patients with CDK12 loss, which is quite common up to 6% of patients may have CDK12 inactivation will also progress quicker on abiraterone or enzalutamide. And patients with RB1 loss, as well, have been reported to progress faster on these therapies. So, yes, there are a lot of genomic signatures that could be underlying this. We don't know whether lumina or basal phenotypes also correlate to response to these therapies in the castration-resistant setting. So, yes. A lot of work to be done.

Charles Ryan: A lot of work to be done, but some really interesting hints. You said RB1 loss, CDK12 alterations are significant predictors for this early progression. RB1 loss is going to be fairly prevalent in perhaps, maybe, 20 to 35% of cases, depending on where you look at it. So, Dr. Lopez-Campos, what is the take home message then for the clinicians who are faced with a patient, who four weeks into enzalutamide therapy, the PSA has only gone up. What would you advise them to do?

Fernando Lopez-Campos: Perhaps for the moment, much work remains to be done to change clinical practice, and considering modifying treatment, or adding complementary treatment based only on early PSA determinations. But this is a starting point, so we will see in the future.

Charles Ryan: Right. In my experience, your data is very telling, because I have seen very few patients in my own practice, who have a rise in PSA very, very early, and then subsequently go on to develop a robust response, or experience a fairly significant clinical benefit. So, your data is fairly welcome, because it supports, I think, early termination and early change in therapy, which is probably something, Dr. Castro, that we want to prove prospectively, I would imagine. So, if we were to take this data and design a clinical trial on it, what would you propose that we do? Incorporating what you just said about genomics, which I think is fascinating.

Elena Castro: Yes. But I think also the field is moving, and we are likely to use these therapies, these androgen receptor signaling inhibitors, probably in earlier stages, rather than as first-line therapy for mCRPC. And yes, definitely, in any prospective trial, it would be very interesting to analyze the genomics, either by analyzing the primary tumor, or circulating DNA to really understand what is behind or the molecular mechanisms underpinning these early progressions.

Charles Ryan: Right. It'll be a great day in this field when we can select patients for a therapy consistently based on genomics predicting their response. But also, and I think your data point to this, we can spare patients a potentially costly and ineffective therapy in some cases, if we know that they're not going to benefit from it. And we can potentially spare them that psychological disappointment of taking a therapy that doesn't manage their disease. So, Dr. Lopez-Campos, let's talk about the future. You have this database that's growing. My understanding is it's across the entire nation of Spain, and it's many, many hospitals. That would seem to me, there's a lot of potential here for how you could use these data coming from this data set, to inform clinical practice, not only in your country, but around the world. Tell me, what's next for you on this?

Fernando Lopez-Campos: Well, perhaps in the future, we can consider not only evaluating the PSA level, but also other biomarkers such as circulating tumor DNA, CTCs, and not only in this setting, but also in other clinical settings. So, I think that it's really interesting to try to expand this study to other countries, to get more samples, to get more results. Yeah.

Charles Ryan: I think that's great. I congratulate you both for this work, and I understand Dr. Lopez-Campos, this is part of your PhD thesis that you're working with Dr. Castro on. And so, congratulations on that as well. As always Dr. Castro, great to talk to you. Any closing thoughts, Dr. Lopez-Campos, on these data?

Fernando Lopez-Campos: Nothing in particular.

Charles Ryan: Nothing in particular. Okay. Dr. Castro, your advice for clinicians reading this.

Elena Castro: Well, my reading of this data is that when we're treating a patient with any of these therapies, and we see that during the first week, the PSA starts to go up, we should not only consider a change of treatment, but we should also consider that these patients may have... The tumor in these patients may have some characteristics that make it especially aggressive. So, we probably would need to consider monitoring these patients very carefully, to offer these patients a clinical trial, if possible, because it's likely that with therapies currently approved, these patients are going to do poorly.

Charles Ryan: Yeah, I would agree. Well, thank you both for your time, and your excellent work on this topic. We look forward to future insight from this database. Thank you.

Elena Castro: Thank you.

Fernando Lopez-Campos: Thank you.