Silke Gillessen: With that, we have heard a lot of triplet therapy, and now it's about treatment intensification. Thank you very much, Chris. And we going to invite you if you are in Adelaide or in Boston.

Christopher Sweeney: All right, that means so very much. But first of all, Mary-Ellen, thank you. I actually, welled up, that was really, really sweet. It'll be au revoir, not goodbye. And for those who do not know Mary-Ellen Taplin, she's not only a great doctor and investigator, she's also a great captain of all Dana-Farber research, and there's a lot of research at Dana-Farber. She's very, very generous and very, very funny. Mary-Ellen is a special lady.

So, here are my conflicts related to not only working with Mary-Ellen, but also being a consultant with compensation, research funding, and biases possibly related to being a part of leadership of CHAARTED and ENZAMET with Ian Davis. So, what are life-prolonging treatment options for men with metastatic hormone-sensitive prostate cancer? We do know that weak androgen deprivation therapy with testosterone suppression alone is better than no therapy by virtue of combined androgen blockade is better than testosterone suppression alone, which is better than bicalutamide monotherapy. We do know that. We now know that potent ADT is better than weak ADT, whether it be with Abiraterone or [inaudible] of choice. We know that weak chemo hormonal therapy is better than weak hormonal therapy alone, most consistent benefit with de novo high volume, and radiation to the prostate, as we've heard, a clear and overall survival benefit with de novo low volume, with just recapitulating what we've heard just here already.

I'm going to focus on the red box down at the bottom, the triplet therapy, be it with chemotherapy, additive potent hormonal therapy, weak hormonal therapy, or radiation for the PEACE-1 to weak hormonal therapy. But let's just take a minute and realize that multiple life-prolonging options for men with hormone-sensitive prostate cancer exist. And for this to happen, the treatment effect in the hormone setting has to be large enough to overcome the impact of sequential therapy for metastatic CRPC. But also some patients may not be able to receive subsequent therapy due to clinical deterioration, especially if they've been on hormonal therapy for five, six, seven years, developed myocard infarction, congestive heart failure, et cetera, et cetera.

They may just not be a candidate. But which patients benefit from a given regimen is the big question. And we need to choose a treatment plan for each individual patient in front of us. So, let's go back to basic oncological principles. The most successful strategy for developing anti-cancer combination therapies calmly adhere to the following: distinct mechanisms of action, single agent activity, and non-overlapping toxicities. That's how we got to BEP for germ cell tumors, CHOP for non-Hodgkin's lymphoma and the like. So, let's go through the four different groups. We know that weak hormonal chemotherapy is better than weak hormonal therapy alone, and that's consistent in the three trials and the STOPCaP IPD. We'll be at ASCO 22 mapping this out more clearly. Stay tuned. Again, we see a clear treatment effect with hazard ratios for overall survival of .5 to 0.7 across all the studies in high volume, whether it be Abiraterone or an [inaudible], very consistent, love biology when it's consistent.

We also know weak hormonal chemotherapy is better than testosterone suppression and docetaxel alone in PEACE-1 and in ARASENS in the M1 high group, be it de nova with the PEACE-1 and presumably, I think, mostly in high volume in the ARASENS by virtue of the ADT docetaxel. And we're having the same median survival as CHAARTED ADT docetaxel over 48 months, so mostly [inaudible] high volume. So, that makes sense. And here we have the accumulating data, and this is an adaption of our current slide from ASCO. And this was put together by a research fellow working with me, Irbaz Riaz. Hormonal therapy alone, 33 months, ADT docetaxel, 40 to 48 months, Abi, about 50 months, and PEACE-1, we've finally breached that five-year median survival. ARASENS dials in there for the ADT docetaxel, and there for the triplet.

ASCO will have more data from ENZAMET, and Ian Davis will be presenting it on behalf of the ENZAMET team. We saw the slide earlier also from the Irbaz Riaz. This is the aggregate meta-analysis, but the IPD is more potent and powerful and [inaudible] will be at ASCO 2022. And we see de novo low volume is a bit of a watershed between metachronous low volume and high volume in terms of its benefit from chemotherapy. A hazard ratio of about .86. And I ask you to reread the CHAARTED JCO where we map this out as a watershed between de novo high volume and metachronous low volume. Here we see prostate radiation therapy plus weak ADT better than ADT alone, as Mary-Ellen just showed earlier. And that's a stronger and more consistent effect and less toxicity than chemotherapy. So, I agree with what Karim said. I wouldn't be using testosterone suppression and docetaxel in de novo, low volume.

And again, we have a clear survival benefit for low volume across the whole spectrum of the hormonal therapy trials, including patients with metachronous. And here we see no survival benefit clear with small numbers shortage follow up for this group. And we await the results of testosterone suppression plus prostate Rads versus Abiraterone versus testosterone suppression plus prostate Rads. But we don't have the alternative of potent hormonal therapy plus Rads versus potent hormonal therapy alone, or potent hormonal therapy plus docetaxel versus potent hormonal therapy. It's all a bit of a tongue twister. So, here's the metachronous high volume, and in all the studies, it's a smaller number. Here's the outcome with ADT docetaxel and from CHAARTED with about 48 months. And you can see, again, the 60% overall survival was about 48 months as well in the ADT docetaxel from ARASENS against small numbers, but there was a treatment effect that was seen there. That's impressive, but I suspect most of these patients are metachronous high volume by that.

But again, we do not have potent hormonal therapy versus weak hormonal chemotherapy, oh, but versus the triplet I should say. And here again is that slide from Dr. Riaz, the research fellow, where there's a clear benefit between metachronous low volume and de nova and high volume, where there is a chemotherapy effect. So, wouldn't use docetaxel here. We see radiation to the oligometastatic lesions as defined by Choline PET, delayed ADT, but no big impact on CRPC free survival or overall survival, presumably. But we do see a significant impact with testosterone suppression or potent hormonal therapy over weak hormonal therapy with an increase of three-year survival from 83% to 92%. And wait until you see the data at ASCO for the five-year survival data. So, what we do not know, the potent hormonal therapy doublet versus potent chemo hormonal therapy triplet in hormone-sensitive prostate cancer. So, can we learn from ENZAMET, where we have a potent hormonal therapy contemporaneously accrued patients and/or a STOPCaP IPD?

I think it's essential we get the STOPCaP IPD and do a meta analysis of all the hormonal therapy trials. Will a trial be done with potent hormonal therapy versus the triplet? I don't know. And if the triplet is shown to be better than potent hormonal therapy, which patients? We also have the question of a triple of SBRT for patients with oligometastatic disease, potent hormonal therapy followed by SBRT for oligoprogression versus do it all upfront versus SBRT followed by potent hormonal therapy. All good questions, and we need to do trials. And I'll just give a prelude to what would be at ENZAMET. So, patients had testosterone suppression with or without docetaxel at the investigator's discretion as the standard of care chosen by the physician. 45% received concurrent docetaxel.

We allowed up to two cycles prior to randomization. So, 108 got one cycle, two got 62, so basically concurrent. And the choice of docetaxel was chemofitness deemed beneficial by the physician. All subgroups are represented de novo high and low volume, metachronous high and low volume. And it is an opportunity to explore and describe the outcomes of each group. We were not compared because of the confounding, and patients were treated contemporaneously who met eligibility for the same trial. And we have this potent hormonal therapy arm that we can look at contemporaneous, no comparisons, no P values. I promise.

So, here we are. I'll finish with this. And following up with what Mary-Ellen said, metachronous low volume potent hormonal therapy is the backbone, maybe SBRT. Metachronous high volume potent hormonal therapy is the backbone, maybe docetaxel intermediate with the de novo low volume with the prostate and class potent hormonal therapy and prostate radiation, desperately waiting the results of PEACE-1. And for the poor risk potent hormonal therapy, and if you're chemofit at docetaxel, but trials, trials, trials, trials, trials, trials, and with that, [inaudible], thank you.