AM: Dear ladies and gentlemen, welcome again. We are sitting here at GU ASCO in San Francisco, USA. My name is Axel Merseberger, I’m a urologist from Germany, northern Germany, I’m located at Lübeck University and I’m head of the department of urology in Lübeck. I’m very honoured and flattered right now to sit here with Professor Neal Shore from the United States. You are also a urologist, is that correct?
NS: Yes.
AM: OK, can you briefly explain your expertise, your background, where you come from, where you were trained?
NS: So I was trained at Duke University Medical School and New York Hospital, Cornell Medical Center and Memorial Sloan Kettering Cancer Center. My interest has been, starting in the late 1990s, in advanced GU oncology. We had a big unmet need for most of our patients who progressed after androgen deprivation therapy; we really had a complete lack of therapies. Of course now we have so many therapies to choose from.
AM: Thank you, and that was also the topic of your presentation from yesterday and I found it to be very, very interesting. It’s a discussion on the sequence in metastatic castration resistant prostate cancer but also an ongoing discussion whether you can combine compounds like, in your case, radium-223 and abiraterone acetate. Could you summarise the findings of your presentation from yesterday?
NS: Sure, I appreciate doing that. But first the fact that since 2010 we have had six new therapies in the CRPC space and they’ve all been approved so quickly, we’ve had little time to do head to head trials, we’ve had little time to do adequate prospective sequencing studies and we’ve had little time to do combination trials. So once radium-223 was approved, and interestingly in my clinic in our centre we gave the first dose post-approval worldwide, so I was proud of that. We submitted an investigator initiated grant to see about how radium-223 would work in conjunction with abiraterone acetate, the first of the orals approved for ablation of the androgen-androgen receptor axis. So we received an investigator initiated grant, we wanted to see in a cohort of about 40 patients how they would tolerate these two distinct CRPC approved therapies.
AM: And were there any issues with regards to safety? Since the mechanisms of action are very different so from the gut feeling it should work but what did you experience?
NS: That’s a great point and that was why we wanted to do the study. The mechanisms of action are entirely different, one is a calcium mimetic, goes to mineralisation sites, works on improvement in double-stranded DNA breaks, as opposed to the abiraterone which is working on the androgen biosynthesis pathway. What we found was no change in the safety profile. We monitored the traditional safety adverse events one would expect with abiraterone – potentially hypokalemia, fluid retention, LFT abnormalities – and we looked very carefully at the radium adverse events of interest, potentially for myelosuppression. Combining the two together and we gave everyone the full six cycles of radium and 80% of our patients were started concomitantly with abiraterone - within 30 days of starting their abiraterone they received their first cycle of radium. We found no new safety signals, we had no changes in serology looking at PSA, alkaline phosphatase, that we would not have naturally expected. Yesterday here in San Francisco at ASCO GU I presented our interim analysis. We’ll have the final full analysis report, including our CT scan data, either at AUA or at ASCO in June. Additionally we looked at quality of life questionnaires and additionally brief pain index scores. We found a real advantage as opposed to using each agent in a sequential monolithic fashion.
AM: And how did you interpret the results that were presented at last year’s ASCO with regards to, in the subgroup analysis, prolongation of overall survival for the combination of abiraterone? Might this be also a mechanism of action? Won’t you tell?
NS: I look forward to the larger phase III trials combining this to really prove the efficacy benefit. Our trial was designed to really show that these can be used in conjunction safely and I think we’ve established that.
AM: Excellent, thank you. And if I would be one of your residents and would ask you what is the ideal candidate, ideal patient, for this combination, what would you answer? What would be the ideal? More bone metastatic lesions, more visceral disease or both? What would be your recommendation?
NS: Definitely enrol patients for on label, so as it relates to abiraterone acetate it can be asymptomatic to minimally symptomatic M1 CRPC. We excluded patients with visceral metastases. As regards to radium-223, bone predominant, they could have soft tissue up to 3cm, no visceral metastases. The bone metastases within the label is to have some level of symptomatology. Now the symptomatology doesn’t necessarily have to require a narcotic or it could but that would be sort of the ideal patient.
AM: OK. Thanks a lot and looking at your other presentation from yesterday I thought it’s going even more further. You have a dual CYP17 inhibitor, so something, could you explain to the audience what a dual CYP17 inhibitor is and how this might work or even overcome some resistances in first line treatment of patients with metastatic CRPC?
NS: Yes, this is an oral agent that we’ve done a series of phase I and phase II studies called VT464. What we’ve looked at is dose escalation, dose limiting toxicity trials early on starting off with a BID dosing now going to a QD dosing. Now unlike abiraterone this drug is oral as well, like abiraterone, but it can be taken with food. There is no steroid requirement and it has a selective lyase inhibition as well as preclinical evidence of an actual androgen receptor degradation to it. So we now have patients that we have looked at who are either abiraterone or enzalutamide naïve, we have patients in our cohort who have progressed on either abiraterone or enzalutamide or both and that is some of the data that we’re reporting at ASCO this year.
AM: A lot of discussion is focussing on the splice variants, ARV-7 and also an abstract on ARV-9. Might this dual CYP17 inhibitor is this also influenced by the splice variants or do you think this might be the solution where you have resistance for abiraterone or enzalutamide?
NS: I think it’s a really important question for our field, for taking care of our patients. We know that there’s a small percentage of patients who are M1 CRPC, maybe 8-12%, who have a primary resistance and won’t necessarily benefit from abiraterone or enzalutamide. If they are benefitting over a period of time they invariably will require some level of secondary or acquired resistance. The field now eagerly awaits better validation of these commercial assays, looking at whether it’s V7 or other variations, there’s at least 25V9, there was a poster presented here today. But what we’re getting to understand is there are somatic mutations as well as even germline mutations that can help us better understand what’s the best drug therapy for the right patient at the right time. So I think it’s very exciting, VT464 might be one of these drugs, we need more data.
AM: OK, thank you. When you look at the presentations with regards to screening there has been an observation from our European side that screening, PSA screening, is not recommended that broadly as it used to be in the US. Having this in mind we see more and more primary metastatic prostate cancer patients where we have data from Chris Sweeney from CHAARTED that up front chemotherapy and also the STAMPEDE trial from Great Britain makes sense. What is your opinion with regards to up front chemotherapy in hormone naïve metastatic prostate cancer patients? Would you differentiate between low volume and high volume disease or would you advise your residents or your team just go for it when you have a hormone naïve metastatic prostate cancer patient, use docetaxel, six cycles up front and then see how it develops?
NS: So a very, very important question. I have embraced the CHAARTED and the STAMPEDE data, I think the primary authors and their entire teams should be heartily congratulated. Great work by Chris Sweeney and Nick James and his group. So, yes, anyone who meets the criteria of high volume, as defined by four bone metastases and/or visceral metastases, I am routinely now offering to my patients, and have administered maybe somewhere north of ten patients now, chemo-hormonal. I think the data is incontrovertible for the high volume group. As it relates to patients with low volume disease or the oligometastatic disease I think we’re still trying to sort that out. I think there’s controversy in terms of do we address the prostate, do we recommend extirpative procedures such as prostatectomy or radiation and then aggressively attack the small number of lesions, depending upon where they are, with focal radiation and/or with systemic ADT? We need clearly more prospective data, multi-institutional. So I’m holding off on my oligometastatic, my low volume, I’m not championing that just yet. I want to see more data.
AM: OK, that is also the motion, what we see and how we treat in Europe. So thank you, thank you very much. It has been a great honour having you here in the interview and I hope you also enjoyed watching us here in San Francisco at the GU ASCO conference. Thank you very much.
NS: My pleasure, thank you.