Episode 6 – A/Prof Christopher J Sweeney

I’m Joseph Ischia

And I’m Nathan Lawrentschuk.

And we’re talking Urology where we discuss the key points of the landmark papers that guide your practice everyday. Our goal is to empower doctors to develop a deeper understanding of the literature to ensure we apply the right evidence to the right patient.

We are all about “bringing the literature to life”.

Joseph:  Today we are talking CHAARTED. But we have some great papers coming up:

• Hein Van Poppels’s Outcomes after Partial vs. radical nephrectomy
• Francesco Montorsi’s landmark paper penile rehab tadalafil following radical prostatectomy with
• Victor Nitti talking botolinum toxin A in OAB, and
• Neil Fleshner discussing his REDEEM study on dutasteride in men on AS for prostate cancer.
• Stephen Boorjian monitoring the SRM

 Nathan:

• Title: “Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer”
• NEJM August 2015
• CHAARTED- ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer
• First author Chris Sweeney
• Great paper- unprecedented improvement in overall survival and significant change in practice.
• We had a fantastic chat with Australia’s very own Chris Sweeney

Chris:  I am Christopher Sweeney from the Dana-Farber Cancer Institute a medical oncologist in Boston.

Nathan:  This study was designed just after TAX327 trial (docetaxal in CRPC) came out. Therefore, why move it forward to cancers that will respond to ADT? We asked Chris why was this study done?

Chris:  Men with metastatic prostate cancer have been treated with hormonal therapy and we know it’s going to last a variable amount of time, and especially those who have a higher burden of disease have a poorer outcome and we thought we need to do better. We’ve got another active agent in a more advanced disease setting, castration resistant prostate cancer; Docetaxel – we said well, if we can use 2 drugs that are active, had single agents and have non overlapping toxicity and attack the AR negative clones that may be present and the AR positive clones we may be able to do it better than just doing it sequentially. So we said, chemohormonal therapy upfront vs. hormones alone – lets see how we go.

Joseph:

• Primary hypothesis- median overall survival would be 33.3% longer- docetaxel added to ADT compared to ADT alone for mHSPC.
• Inclusion
  • Radiologic evidence of metastatic prostate cancer
  • ECOG performance-status score of 0, 1, or 2
  • Prior adjuvant ADT was allowed if the duration of therapy was 24 months or less and progression had occurred more than 12 months after completion of therapy.
• Design
  • Randomized to ADT alone or to combination therapy with ADT plus 6 cycles of docetaxel
  • Daily prednisone was not required- different to STAMPEDE
  • Intermittent hormonal therapy was not allowed- (good considering M1 disease- Hussein paper)
• Outcomes
  • Primary- Overall survival and prostate cancer specific survival
  • Secondary outcomes
    • Disease progression, PSA responses, time to CRPC, and toxicity associated with treatment.

Nathan:

• Designed in 2005, enrolled 790 patients from 2006 to 2012
• This study reports on data censored at December 23, 2013 when we had final outcomes on 53% of the patients.
• Median follow-up was 29 months
• 136 deaths in the ADT-alone group and 101 deaths in the combination group
• Groups were well matched
• Median age around 63/64
• 85% of the patients were white
• Around 2/3rds had ECOG performance-status score of 0
• 2/3rds had high-volume disease
• 2/3rds had a Gleason score of 8 or higher
• 73% of the patients had received no prior local therapy for prostate cancer

Joseph:

• Index pt was a fit white man with high volume, high grade disease, with no previous treatment- important for extrapolations
• Headline result: median overall survival was 13.6 months longer in combination arm with upfront chemo compared to ADT alone (58 months vs. 44.0 months; hazard ratio for death 0.61)
• It was first presented at ASCO in 2014 and there was a lot of discussion about the delay to final publication. We asked Chris why the delay?

Chris:  When you do an industry-sponsored study they’ve got millions of dollars behind it and they’ve got the CROs going into all of the groups and the sites doing the studies and helping clean the database. So this was done on basically a Government co-operative group budget with some limited resources, we had to go back to the sites and update the data. We basically found in the interim analysis that it was so positive and the results were so strong, believable and trustworthy we actually pressure tested in many different ways. Basically the study wasn’t completed so we then had to go and back track and clean the database that it would be suitable for publication. So it was basically interim analysis, results were positive and we just weren’t up to date with the database per closure, that we had a delay in getting all the data updated and then the statisticians finding the time to complete the work.

Nathan: Subgroup analysis- high-volume vs. low-volume disease

• In high-volume- median overall survival that was 17.0 months longer in the combination group than in the ADT-alone group (49 months vs. 32 months; hazard ratio for death, 0.60)
• In low volume- median survival at the time of the analysis had not been reached (but still hazard ratio for death, 0.60)
• Chris, why was this distinction made?

Chris:  The initial phase of the study we opened the study up when the SWOG intermittent vs. continuous metastatic study was ongoing. So there was competing study within the groups. The arrangement was, the patients who needed the most intense therapy we thought would probably be the high volume. So we designed it around high volume and we came up with a definition for high volume that was one that we felt would avoid misclassification. So clearly visceral metastasis – bad so that was an easy one. More bony metastasis is bad but what is more and recognising technician bone scans there’s a lot of false positivity and misreads around DJD. So we recognised 3 or less you do well in the number of bony metastasis from an MD Anderson data set.

Joseph:

• Chris makes a key point- Study design- initially set up not clash with SWOG IAD vs. CAD trial- therefore- high volume only study needing 568 patients
• After completion of enrollment in the NCI-sponsored S9346 trial amended in July 2008 to include patients with low-volume disease and sample size increased to 600 patients
• Then in Dec 2011- the study was increased to 780 patients to reflect new data documenting an increase in median overall survival in men receiving ADT as well as the increased survival in men with low-volume disease. – not included
• Therefore subgroup analysis was performed to separate out different follow-up and expected median survivals as Chris outlines:

Chris:  So we wrote the statistics around the expected outcomes for high volume and low volume with pre specified what we thought the survivals were, and it turns out we were very correct in the long term, our numbers were in a month of the projections, and that allowed us to work out how many patients, and they expected time for follow up. The thing that happened though is that we accrued more high volume patients and we had greater events in the high volume patients as we expected, and so the interim outlook was driven by the high volume patients.

Joseph: So is this difference between high and low volume real or just not enough follow-up yet?

Chris:  There is a difference between high volume and low volume. Low volume patients have a better natural history throughout all the studies over the years. We’ve shown that patients who have a lower burden of disease have a medium overall survival of more than 6 years, where as those who have a higher burden of disease it’s about 3 years. So it’s clear that they have a different natural history when treated with ADT alone, and could it be that they are just a more AR dependent disease and may not need chemotherapy or is it just that we need it longer term follow up for them. We are going to analysis and present the longer term follow up patients of the low volume patients and aim to present that hopefully at the ASLO meeting at 2016 in Copenhagen so stay tuned.

Joseph: Can’t wait. I think this really will be one of the great reveals in modern urology.

Nathan: Secondary outcomes:

• Median time to clinical progression (symptoms /radiologic imaging/clinical deterioration) was 33 months with combination therapy, as compared with 20 months with ADT alone (hazard ratio, 0.61)
• Proportion of patients who had a decrease in the PSA level to less than 0.2 ng per milliliter at 12 months was 28% in the combination group, as compared with 17% in the ADT
• The median time to CRPC was 20 months with combination therapy, as compared with 12 months with ADT alone (hazard ratio for upfront chemo 0.61)
• Toxicity associated with docetaxal- Around 5% will have a grade 3+ AE
• 6% will have febrile neutropenia
• 2% had grade 3 or 4 infection with neutropenia
• Docetaxal well tolerated with 86% of the 390 patients in the combination group who started the assigned therapy completed six cycles of docetaxel therapy

Joseph: Why does it work?

• The hypothesis that a subpopulation of prostate cancer cells may be AR-negative, and thus resistant to ADT from the beginning, was the rationale for combining ADT with docetaxel in men with hormone-naïve metastatic prostate cancer (mHSPC)
• An alternative or additional explanation could lie in different docetaxel pharmacokinetics. The incidence of neutropenic fever in TAX 327 was 2.7 %, whereas the incidence in all three mHSPC studies ranged from 6 to 12 %. These findings may suggest different docetaxel exposure in mCRPC as compared with mHSPC patients.
• One study shown that the clearance of docetaxel is affected by a castrate resistance status. In their study, the clearance of docetaxel was increased by 100 % in castrated as compared to non-castrated men, resulting in a significantly higher area under the curve.

Joseph: Compare other trials

• The magnitude of the OS in the CHAARTED and STAMPEDE trials is remarkable (13.6 and 15 months in the metastatic patient population, respectively)
• In the STAMPEDE trial, 1184 patients with locally advanced and metastatic disease received ADT alone, and 592 received combination therapy. In locally advanced non-metastatic, the median overall survival was extended by 10 mo if ADT was combined with docetaxel, from 67 to 77 months; in the patients with metastatic disease, the median overall survival improved by 22 mo, from 43 to 65 mo.
• A meta-analysis in Lancet Oncology 2015 of the available data, all three trials (CHAARTED, STAMPEDE, GETUG-15) – revealed a robust 9 % absolute OS benefit at 4 years by the use of docetaxel plus ADT in men with mHSPC.

Nathan: Why was the French Genitourinary Tumor Group \ GETUG-15 negative?

• Randomized study involving 380 patients
  • Similar design to that of the current study,
  • Did not detect longer overall survival with combination therapy
  • Median overall survival was longer than CHAARTED- 54.2 months with ADT alone
  • Time to progression was longer, the number of prostate-cancer deaths was smaller, and the number of treatment-related deaths was larger (4 of 195 patients) with early docetaxel therapy than with ADT alone.
  • Chris’ take on the GETUG study:

Chris:  The Getug group did a fantastic job in their updated analysis where they updated the survival but also reclassified patients in exactly the same way as the Chaartered study and that the European Urology paper by Gwinelle Gravis earlier this year and we see that the low volume patients had not a hint or whiff of benefit from early Docetaxel and the high volume patients actually with longer follow up actually went in the same direction as the Stampede and the Chaartered study earlier events, poorer outcomes and maybe the hazard ration was more in favour of early Docetaxel but it was underpowered. One of the questions was why was the Getug study negative and the Chaartered and the Stampede positive. My speculation is that they had accrued all their patients before the approval of the new agent for CRPC. So once the patient got ADT and Docetaxel they had very little access to the other agents, where as those who had ADT plus alone were able to get Docetaxel. So the ADT Docetaxel patients basically had very little therapy for CRPC and that plays out in what these therapies were listed for CRPC. So I think that’s one of the key differences.

Joseph: ?explained by the inclusion of a different M+ patient population and access to the new second-line treatments

Nathan: Limitations of CHAARTED

• Low volume disease
• All trials were in newly diagnosed metastatic prostate cancer; conclusions regarding the use of docetaxel in men previously treated for local disease are also limited. To date, the recommendation of docetaxel plus ADT thus reflects the setting of newly diagnosed metastatic disease.
• One criticism has been that only 62% of men in the standard care arm had received chemo. So does chemo need to be given upfront of do you just need to get it in? We asked Chris what he thought of this criticism:

Chris:  We haven’t finished, a lot of those patients are still on therapy for their CRPC with their abiraterone or their enzalutamide, and they haven’t had Docetaxel yet. And even in the early analysis, 75% of patients who had actually progressed to CRPC actually had got Docetaxel that was associated with the survival data that we’ve presented. 75% of those who were actually candidates for therapy of CRPC because they’d progressed had got Docetaxel, and people were using the denominator of the total patients, but that’s not the correct denominator because it’s only those who had progressed. People were hearing key opinion leaders focus on the total populations denominator and I think misrepresented the truth in that regard.

Nathan: Chris you would be well aware that the new Ezmo and European Urology guidelines have come out, and to quote precisely from them “ADT plus Docetaxel is recommended as first line treatment of metastatic hormone naive disease in men fit enough for chemotherapy”. Specifically, the guidelines do not distinguish between low and high volume disease.

Chris:  If we presume all the events are being driven but the high volume patients, as they are; and I think it’s an unknown entity as to whether the low volume patients do get the benefit and some people would look at it and say well let’s give the benefit of the doubt because when we look at the total of the data in Stampede and the early analysis of the Chaartered looks like there might be a benefit so I think there’s a desire to always do good work and not deny patients a therapy. I think there is a benefit of the doubt proposition for why we should give it to low volume patients but we need to analyse it more closely. So you can be a lumper and put everything into one entity or you could be a splitter, and I think the issue is that we in the US (the Chaartered design) have actually opted to be a bit of a splitter and we’ll see if that gives us more information over time as we said at the ASLO meeting. Where as the MRC have decided to be more inclusive of their approach and I think that’s lead to the guidelines.

Nathan: You would be aware certainly in Australia and Germany with the development of PSMA PET CT, we’re now finding disease where we previously didn’t. In the context of now we are going to get men who previously on conventional imaging were M0, or even low volume disease vs. high volume disease; does that mean that we have to rethink everything or we should be basing our decisions on chemotherapy on conventional imaging alone?

Chris:  I think conventional imaging alone, because if the high volume and low volume story does pan out, and lets just say low volume is actually code for the new work entity of oligometastatic disease; so I think we need to harmonise our definitions of what oligometastatic vs. low volume disease is, I think it’s the same. We need to be careful and there will be stage migration and my biggest concern is we will migrate a patient from M0 who are potentially cured with hormones plus radiation therapy and people notice a 1.2cm retroperitoneal lymph node that’s PSMA positive, who we would have treated with ADT plus radiation with cure of intent and possibly could have; because those patients could possibly be managed with systemic therapy and cured and the local disease managed better and cured with the combined modality. So I’m very concerned that we may be withholding therapy and my approach to the low volume oligometastatic is actually to treat the primary with local therapy and if it’s an isolated bony metastasis radiate that and give hormonal therapy, and do that more in preference to giving chemotherapy in all honesty. I feel like there’s a potential that we may pull off the throttle when we should actually be doubling down on these patients.

Joseph: What a great point. I also believe we are curing people with ADT. It would explain the difference in survival in the radiation trials in the 6-month vs. 3 years adjuvant ADT. After 6 months, there is no more sensitization to radiation- it is all curing micrometastatic disease. Or at least really knocking it on the head.

Nathan: We asked Chris what has been one or two of the feedback issues since the study was published:

Chris:  A lot of people basically yawned for 10 years when we did this study. They said ‘it’s boring and it’s not going to be positive, why are you doing it’? But a lot of people once they saw the data they said ‘that’s so strong we can actually believe it and we’ll get behind it even though we didn’t expect it’. So that was their one thing – it was clearly unexpected.  The other notion is that, a lot of people were saying for 10 years during the study ‘we don’t see metastatic prostate cancer’. And my point was, we are not working at the VA hospitals, you’re not working at the county hospitals, you’re seeing the guy who’s slowly got a rising PSA after their local therapies but, not the 10,000 patients in the US who present with de novo metastatic prostate cancer. Fast forward 10 years, everyone’s saying ‘where were these patients beforehand”?, and the reason being that we didn’t have anything for them. But now we have something for them, people are saying “these patients are coming to of the wood work”. ENZAMET for example is accruing like gangbusters at about 50 patients a month (that’s the study of ADT with or without Enzalutamide and you stratify by whether the physician and patients think they should get Docetaxel) and we should close that study up in early 2017. Australia is leading the accrual on that, it came out of ANZUP, ANZUP has been a fantastic organisation to get that going.

Joseph: Chris, if you could do the study again, what would you do differently?

Chris:  I’ve been extremely fortunate to have been the front man for ECOG in running this and if I had my time over again and I had enough finances to do it I would have powered both the high volume and the low volume enough so that as a prospective well powered sub set, as opposed to, we prospectively defined them but we didn’t power the sub sets for an outcome. That would be the one thing I would have liked to have done in retrospect. The other thing that’s fantastic that I think is going to be the gift that keeps on giving because we are getting the gene expression profiling from as many patients as possible looking for markers of resistance, we’re doing a GWAS analysis on all of the patients, we’re doing serum profiling at multiple different points so we can look at markers of bone turnover, inflammation and a number of other things that could try and find biomarkers. I know what I would have done differently – Updated the case report form to have a bit more granularity about the patients. There are a couple of things that we didn’t capture in the case report form that would allow us to do better secondary analysis, but that’s what we don’t have in there.

Joseph: So what were they?

Chris:  Things like base line alkaline phosphatase but we should be able to do that off the blood that we got off baseline of these patients, looking at bone alkaline phosphatase. We captured high volume and low volume and the way the case report find, we actually don’t know quite yet who actually had lymph node only vs. 3 or less bony metastasis to calve out the lymph node only group. So there are a couple of refinements like that I would have liked to have done.

Nathan: I reckon you’ve nailed the key index patients, a fit 65 year old de novo metastatic disease with good renal function. Who would you be concerned that this data would be interpreted for?

Chris:  In all honesty a push in the envelope a little bit too much on a frailer 72 year old, 78 year old who possibly could have benefited from it but wasn’t chemo fit and maybe had low volume disease and could have done just well with hormones alone. So, that’s where I think with the patient in front of you, you make a clinical judgement, if you know their natural expectancy is many many months and years with ADT alone, and they don’t need the Docetaxel, if you think they are going to die of something else in the meantime; withhold the Docetaxel. But a 78 year old who’s like a fit farmer from Wagga, who’s got 8 bony metastasis and is running around chasing the cows or sheep; why not give him chemotherapy because he’s not going to die of his other disease, he’s gonna die of his prostate cancer.

Joseph: Take home message:

• 6 month improvement in overall survival with upfront docetaxal is unprecedented.
• 39% reduced risk of dying
• Better cancer control
  • With a longer time to the development of castration resistance,
  • A higher rate of decrease of the PSA level to less than 0.2 ng per milliliter at 12 months
  • A lower number of prostate-cancer deaths.

Chris:  So. I just wonder, if you give ADT and Docetaxel up front in a patient with high volume disease you debunk the AR positive and the AR negative disease and potentially make more likely to be sensitive to subsequent therapies because you’ve gotten rid of the AR negative clones is speculation on my behalf. We are trying to do some Chaartered data base mining to see if that’s true and it’s all speculation but that’s why we do research to try and find the answers to these things.

Nathan: Thanks to Chris who was very generous with his time and comments. And thanks for listening and stay tuned for our next podcast where once again we chat to the author of one of the biggest papers in urology. Feedback to talkingurology@gmail.com

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