Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Moving to the castration-resistant space, Johann, we’re lucky to have so many therapeutic agents available to us now. But this brings in the topic about sequencing and potentially therapeutic layering. What do you think the rationale is for therapeutic layering, if any, in the castration-resistant space?

Johann de Bono, PhD, MB, ChB: I think, first of all, I should say that we haven’t got a rationale, to give a very brief answer. I am concerned that a lot of assertions are being made, based on these trials we’ve been discussing, that earlier is better than later. And I want to say again, very clearly, that actually, we have no evidence yet that earlier abiraterone is better than later abiraterone, or that earlier docetaxel is better than later docetaxel. My understanding is that both LATITUDE and STAMPEDE control-arm patients who died on those trials and drove those survival curves—many of them, most of them—had not had abiraterone. So, it really concerns me that patients are now getting a lot of these drugs very early on and we’re not giving them later.

However, biologically, it does make sense that combinations could be better than single agents, if you have the biology right. I think, for example, radium and hormonal therapy makes perfect sense. I discussed the reasons for this earlier. You inhibit DNA repair via hormones, and actually, if you have a strong biology for synergy, giving those drugs in combination to trying and improve long-term benefit is important. But we have no data, so we cannot make those claims or assertions, and we have to do the appropriate trials. What concerns me is that we’re using resources—patient resources, fiscal resources—to run trials that are not really addressing the key questions, in my mind. And I’m being very critical here.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Chris, do you have anything to add to that with regard to the layering and the rationale for it, or the current practice with that?

Chris Parker, MD, FRCR, MRCP: I agree with everything Johann said. We don’t have good evidence to answer the question. I mean, it seems to me that so-called therapeutic layering is halfway between sequential therapy on the one hand and combination therapy on the other. We don’t even know whether or not there’s any benefit to combination therapy rather than sequential therapy. I guess we need to answer the simple questions first.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: In radiation oncology, we’ve been combining therapies like external beam radiation with ADT [androgen deprivation therapy] for many years. I suppose the concept in many cancers of combining multiple drugs has been common practice, initially in the lymphomas and testicular cancer. So, I suppose it’s a concept that’s widely used in oncology. But, Bertrand, I don’t know if you have any thoughts on that.

Bertrand Tombal, MD, PhD: I think it means, what do you layer with what? When it comes to a drug like radium-223, your trial was layering, because it was radium on standard of care versus standard of care. The problem is that we’re not speaking about the same standard of care. So, when it comes to adding radium-223 on top of enzalutamide, I’ve got less problems with that, for instance, than adding abiraterone on enzalutamide. We know that doesn’t work. We have the PLATO trial. So that’s a perfect example that layering is not like a cake. You still need rationale to add on top of the layer.

Johann de Bono, PhD, MB, ChB: I do think that’s an important point you make, because, actually, people are giving a lot of enzalutamide after abiraterone or abiraterone after enzalutamide. I think the PLATO data for me are one more reason why we shouldn’t be giving enzalutamide after abiraterone or abiraterone after enzalutamide. The PLATO data have shown quite clearly that if you’re progressing on enzalutamide and you add abiraterone, there’s no benefit. I think there are now a few data to convince me personally that we shouldn’t be doing abiraterone after enzalutamide or enzalutamide after abiraterone, and other drugs should be used instead.

Bertrand Tombal, MD, PhD: When I see people who want to add docetaxel and cabazitaxel, we may have toxicity coming on. You have to be careful. Yes, layering is intellectually very appealing, but it has demonstrated very little clinical or potential economic benefit and greater patient toxicity. So, we have to be smart with the exception—the historical exception, I would say—of bone-targeted therapy in general, because that makes more sense. But for the rest, we should be careful.

Chris Parker, MD, FRCR, MRCP: I think we should be careful for bone-targeted therapy as well.

Bertrand Tombal, MD, PhD: Yes, I know. I was sure you would say that.

Chris Parker, MD, FRCR, MRCP: You’re talking about denosumab and zoledronate. It seems to me that the evidence behind using them at all is basically rather outdated. Do we know it still applies with all of the current new therapies? And we know that SREs [skeletal-related events] are much less common now than they were when the role of zoledronate was established.

Bertrand Tombal, MD, PhD: Or, they’re appearing very late.

Chris Parker, MD, FRCR, MRCP: Yes.

Bertrand Tombal, MD, PhD: And, after the time they were developed, there was something we would never have seen coming, which was response in bone. And now, with abiraterone and enzalutamide and modern technology, we see a fair proportion of patients who have complete responses in bone. If they don’t have any bone metastases, they don’t need this.

Chris Parker, MD, FRCR, MRCP: Yes, we’ve got much better drugs preventing SREs now than we had then. They’re called abiraterone, enzalutamide, docetaxel, and radium.

Transcript Edited for Clarity