How to Treat Men With Newly Diagnosed cN1 cM0 Prostate Cancer - Systemic Therapy Options - Nicholas James

October 30, 2019

Nick James presented on the systemic therapy options for men with node-positive hormone-sensitive prostate cancer (HSPC), including whether the primary tumor should be treated, and which treatments can be combined at the 2019 Advanced Prostate Cancer Consensus Conference (APCCC). Also highlighted in his presentation is the role of docetaxel in M0 and M1 HSP, abiraterone’s role in high-risk M0 HSPC, the choice of whether to give docetaxel and AR therapy.  Available data suggest a synergistic effect with abiraterone and radiotherapy and there is evidence supporting ADT + radiotherapy + 2 years of abiraterone in node-positive prostate cancer patients.

Professor Nicholas James BSc, MB, BS, FRCP, FRCR, Ph.D., Institute of Cancer and Genomic Sciences NIHR Senior Investigator, Consultant in Clinical Oncology at the Queen Elizabeth Hospital Birmingham and Professor of Clinical Oncology at the University of Birmingham.


Read the Full Video Transcript

Nicholas James: Thank you. Great pleasure to be here. I'm going to open my talk with a bid for the Twitter prize by tweeting a picture of the audience. My Twitter address is up there. Please, follow me and tweet.

I'm going to talk about clinically node-positive newly diagnosed prostate cancer, so a slightly different focus to Mack's talk. These are my disclosures.

I'm going to focus on newly diagnosed patients only, not oligorecurrence or node recurrence. I'm going to say a bit about treatment of the primary because I think the recent data we published from STAMPEDE in low-volume and high-volume metastatic disease is relevant here. Then, I'm going to address of which systemic therapies we can combine. I'm not going to say too much about imaging because there's a lot of imaging in other talks already (Fanti, Davis).

I think, in the context of radiotherapy, not in the context of surgery, that androgen deprivation therapy (ADT) remains a fixed part of therapy for newly diagnosed patients, so I'm not going to say too much about that. We also know, and I'll show you some data, that radiotherapy improves survival in low-volume metastatic disease and also in node-negative nonmetastatic disease. So, it seems to be intrinsically very unlikely that for the bit in between, the patients with node-positive disease but no mets, you haven't also got a survival advantage. On that basis, I would argue radiotherapy is a bolted-in component of therapy for these patients. The issue for me comes down to what systemic therapies you add to the radiotherapy assuming you're not going to go down the Declan Murphy route and dismantle their pelvis.

I think we have some data on a number of different combinations. We've got good data, broadly, on ADT plus radiotherapy both in the node-negative and the metastatic setting. We've got very good data, and I'll show you some meta-analysis data on ADT plus docetaxel. We've also got some data on ADT and abiraterone which comes mainly from STAMPEDE and I'll show you some data which we haven't published yet that I presented previously at ESMO. Within the context of that, in red I've highlighted two areas that I'd like to focus on which is, can you combine or should you combine docetaxel and radiotherapy? And, can you combine and should you combine abiraterone and radiotherapy? Then, there's a further three/four-way combination that there is literally no data on this, so I'm going to say nothing further about.

Treating the primary, just very briefly. These are the data that we showed at ESMO and published simultaneously in The Lancet. The right-hand two boxes are patients with high metastatic burden, newly diagnosed disease. They were randomized to ADT only, ADT plus radiotherapy. You can see there is no impact on overall survival, the top right-hand box, nor on failure-free survival. If you look at the left-hand two boxes, these are patients with low metastatic burden as per charted. You can see, bottom left, you've got a big impact on failure-free survival from irradiating just the prostate and that translates into a survival gain only in the low-burden group. This is from a meta-analysis and from Chris Parker's slides from ESMO by the HORRAD trial which did an exploratory analysis which split the patients in the same way and, as you can see, produced an identical hazard ratio to that which we reported in STAMPEDE. On the basis of that, we know that prostate radiotherapy to all metastatic patients doesn't improve survival but it did improve it in the low-volume patients. It mirrors the benefit that's seen in the exploratory analysis in the HORRAD trial so, therefore, it implies that for the bit in between this and the nonmetastatic node-negative patients, you should have a benefit from radiotherapy.

Moving on docetaxel. There's a number of trials looking at docetaxel in the nonmetastatic setting and these are pulled meta-analysis lead by Claire Vale from the MRC Trials Unit in London at UCL and I'll show you some data from this. First, looking at the M1 docetaxel patients on failure-free survival, you've got a very clear benefit. It's translating into a 15% reduction in failure at four years from upfront docetaxel. If we look at failure-free survival in the M0 setting, we see a very similar effect. So, there's a number of trials, they're listed on the left-hand side of the slide. There's a roundabout at 8% absolute reduction in failure from 70% to 62% for four years from upfront docetaxel in the M0 setting, there are no M1 patients in here.

When we look at survival, as we all know, for docetaxel in metastatic disease, that translates into a survival advantage at 10% absolute improvement in survival at four years from 40% to 50%, absolutely huge effect. When we look at the M0 patients, although we've got 2,000-odd men in the meta-analysis, it doesn't translate into a significant survival improvement but you can see the trend is definitely there. It's a potential 5% improvement from 80% to 85% at four years. On failure-free survival you've got robust evidence of benefits in M0, on overall survival, you've got a trend towards a benefit. So, you've got a potential case for adding docetaxel here. My conclusion from this was that you've got a very consistent effect on failure from docetaxel which, on its own, might be sufficient to justify using it because you're sparing patients relapse therapies by making them relapse later. The individual trials are underpowered with respect to overall survival but there is a trend seen.

The question arises. What's the interaction between giving radiotherapy to these patients and giving docetaxel? Have you got a potential dual benefit? There's obviously very limited data on this but within STAMPEDE we've been broadly very inclusive. We've let people have this sort of, what you might call a "Frank Sinatra approach" to the control arm, which is you do it your way, and we've just stratified the randomization by what you chose to do. Then, we can look at these different stratifications and one of them was whether or not you were planning to give radiotherapy to the M0 patients because mostly we recruited these patients prior to SPCG-7 and PRO7 coming out and that's the result down here. It looks as if ... This is not randomized, obviously ... You only got a benefit from docetaxel in M0 if you didn't get radiotherapy, it's an either-or benefit. So, that's the suggestion, that there's an interaction between radiotherapy and docetaxel that we saw in STAMPEDE. You're only getting a docetaxel benefit if you didn't get radiotherapy and vice versa if you did get radiotherapy, you didn't get a docetaxel benefit.

There is more data that we're going to show on this at ESMO, so I'm not going to do what Ros did and show data and ask you not tweet it, but we will be publishing a more detailed long-term analysis at ESMO but you can guess what we're going to say.

We've done the same analysis for abiraterone from the M0 part of STAMPEDE, so this is how we arrived at the patients. Again, we've got a split between radiotherapy and no radiotherapy, in this case, purely in the node-positive patients because for the node-negative patients, by this time, we knew that we should be giving them radiotherapy. Now, these are the forest plots. There is a test interaction for treatment effect between M0 and M1 with our abiraterone data and what it shows is in the M0 patients, we appear to see a bigger benefit from abiraterone than we do in the metastatic patients. We've got an 80% improvement in time to failure with upfront abiraterone in M0. When we split that down by whether or not radiotherapy was planned, again, you've got a significant test for interaction and it suggests that the benefit is seen most in the patients that had radiotherapy. The hazard ratio is now down to .18 an 82% improvement in time to failure if you had radiotherapy and abiraterone as opposed to just abiraterone.

Just to show you the Kaplan–Meier's, in this the dotted lines are the node-positive patients, so given that the talk is on node-positive focus on the dotted lines. Green is with abiraterone, black is with ADT only. I draw your attention to the fact that in this part of STAMPEDE the patients only got two years of therapy, so the treatment stops at 24 months. If you look at the right-hand side of these curves at 48 months, you'll see you've got absolutely vast separation in the node-positive group between ADT alone and ADT plus abiraterone. This is failure-free survival mostly driven by PSA. If we boil that down to metastasis-free survival in M0 patients, we've still got a difference that is actually statistically significant and as per Chris Sweeney's ICECaP data, we would predict this would translate into a survival advantage in due course.

For survival, the curves are also separated but the survival is actually very good, so we are underpowered. We're going to do an updated analysis on this in due course and we also, of course, have the abiraterone/enzalutamide arm in STAMPEDE, so we can do, potentially, a pooled analysis there in the M0 patients. We think that might allow us to nail a survival advantage definitively in these groups of patients with just two years of therapy. So, the summary of this is that you've got a failure-free, metastasis-free survival from adding abiraterone and the suggestion is that there's synergy with radiotherapy.

Can we choose between docetaxel and ART? Really, there's only STAMPEDE data on this and Matt Sydes is talking about this later on but there is an overlap of around 600 patients between the docetaxel and the abiraterone parts of the trial which we previously showed and published. For the early outcomes like failure-free, progression-free, metastatic-free survival, these outcomes all favor abiraterone over docetaxel in a head-to-head randomization as an exploratory analysis within STAMPEDE. There's no survival difference at any aspect of this in the head-to-head comparison with STAMPEDE.

So, the question is, does failure-free survival on its own justify a selection of abiraterone over radiotherapy? We've done some analysis on what the impact is on preventing failure on your quality of life. We published this with the University of York Group that does the healthcare economic analyses for NICE. What we looked at in the STAMPEDE model was, what happens to your quality of life if you delay relapse by giving docetaxel? So, this is the impact of docetaxel on quality-adjusted life-years split by quartiles. So, the left-hand four quartiles are the M0 patients, the right-hand four quartiles are the metastatic patients. You can see that giving docetaxel upfront gives you a consistent gain in qualities. For the M0 patients, there's no survival difference between the two groups, with and without docetaxel. So, this gain is purely driven by that fact that by delaying relapse, you're delaying exposure and reducing exposure to CRPC therapies. You've got around a 40% reduction in skeletal events which also impacts on quality of life.

So, in summary, delaying relapse is good for your quality of life. We've done a parallel analysis which, again, I can't show you, with abiraterone and the effect is exactly the same. Delaying relapse improves your quality of life whether or not it improves your quantity of life. So, the conclusion is that ADT plus one-drug therapy improves failure-free survival and increases qualities in M0 HSPC. It doesn't matter whether that's abi or doce, the effect is the same. ADT plus radiotherapy improves survival in low-volume M1 and in node-negative M0, so it implies that the group in between should benefit, so they should have radiotherapy. The available data from docetaxel, limited as it is, suggests, actually, you've got an either-or benefit with docetaxel. You don't get a dual benefit with docetaxel and radiotherapy. In contrast, the data from STAMPEDE strongly suggests synergy between abiraterone and radiotherapy in the M0 patients getting both. So, my conclusion would be that this supports ADT, plus radiotherapy, plus two years of abiraterone as being what should be maybe adopted as standard of care for this group of men.

These are the key references. Thank you for your attention.