RTOG 0815

[radoncopotamus]

What are people making of the results presented at ASTRO this year? Do people want to follow the phase III evidence now or stick with retrospective MSKCC data? I don't treat prostate so curious.

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[Palex80]

What are people making of the results presented at ASTRO this year? Do people want to follow the phase III evidence now or stick with retrospective MSKCC data? I don't treat prostate so curious.

I will still advise for 4-6 months of ADT in unfavorable intermediate risk PCA, but will sleep better at night if I cannot persuade the patients to follow my advice.

 

[medgator]

I will still advise for 4-6 months of ADT in unfavorable intermediate risk PCA, but will sleep better at night if I cannot persuade the patients to follow my advice.

I think decreased mets and need for long term adt later is still worth it to some

 

[Ray D. Ayshun]

5 yr OS not statistically different in a patient population we might observe if they had a <5-10 yr expected survival. Otoh, every other disease outcome was far better with adt, right? This changes nothing for me, which is to say, I'll recommend but not lose sleep if they choose not to.

 

[Chartreuse Wombat]

What are people making of the results presented at ASTRO this year? Do people want to follow the phase III evidence now or stick with retrospective MSKCC data? I don't treat prostate so curious.

SHared decision making. Describe the magnitude of the absolute benefit along with the risks and let men and their families decide. A rational human could decide either way

 

[seper]

Are there excessive non-cancer deaths in the hormones arm? Something is suspicious here

 

[Ray D. Ayshun]

Are there excessive non-cancer deaths in the hormones arm? Something is suspicious here

What I see is 119 deaths in RT alone and 100 deaths in RT + ADT. Of those, 10 were cancer related in RT alone and 1 in RT + ADT. So, non-cancer is 109 vs 99 numerically favoring ADT.

 

[Chartreuse Wombat]

What I see is 119 deaths in RT alone and 100 deaths in RT + ADT. Of those, 10 were cancer related in RT alone and 1 in RT + ADT. So, non-cancer is 109 vs 99 numerically favoring ADT.

From the presentation.

5yr non-prostate mortality is 9% in both arms; 8yr non-prostate mortality is 19% RT alone, 16% RT + STAD p=0.5

11/219 (5%) deaths due to prostate cancer; this is likely to increase with time but competing mortality will as well. Remember that the D'Amico trial and RTOG 9408 showed OS benefit (with low dose RT) in the first decade (five years for the D'AMico trial which is likely an overestimate of effect) but this disappeared with longer follow-up in both studies.

Repeat after me...competing comorbidities.

 

[wandering star]

What I see is 119 deaths in RT alone and 100 deaths in RT + ADT. Of those, 10 were cancer related in RT alone and 1 in RT + ADT. So, non-cancer is 109 vs 99 numerically favoring ADT.

I think this is only a one standard deviation difference, so it could just be a play of chance. Given such a low rate of cancer related deaths, there was not really any way that the study could be reasonably powered to show a 5 yr OS benefit. If it were a magic pill that erased cancer completely and we had double the sample size it still would not have been statistically significant in terms of OS. If the selection criteria had skewed towards younger patients unlikely to die of other causes it may have been possible to show OS benefit.

 

[Ray D. Ayshun]

I think this is only a one standard deviation difference, so it could just be a play of chance. Given such a low rate of cancer related deaths, there was not really any way that the study could be reasonably powered to show a 5 yr OS benefit. If it were a magic pill that erased cancer completely and we had double the sample size it still would not have been statistically significant in terms of OS. If the selection criteria had skewed towards younger patients unlikely to die of other causes it may have been possible to show OS benefit.

Right. just answering the question re non-cancer related deaths. OS at 5 yrs is not worth talking about in this population. As far as I can tell, all the other outcomes seem to point to the longer term results looking the way they always have.

 

[Palex80]

If the selection criteria had skewed towards younger patients unlikely to die of other causes it may have been possible to show OS benefit.

Indeed, but probably beyond 5 years.
Median prognosis of metastatic prostate cancer nowadays is around 5 years. Here are the results of the ARCHES trial with ADT+Enzalutamide for mHSPC:

ESMO 2021: Final Overall Survival Analysis From ARCHES: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Enzalutamide + ADT in Men With mHSPC

ESMO 2021 Final analysis of the ARCHES trial of enzalutamide in men with mHSPC, enzalutamide + ADT significantly prolongs survival in men with mHSPC, abiraterone, apalutamide, or docetaxel.

www.urotoday.com

Patients with localized prostate cancer who undergo RT without ADT, go on to develop biochemical progression and ultimately metastatic disease will live longer than that.


One major flaw in RTOG0815, apart from the primary endpoint in my humble opinion, is including all intermediate risk patients. They should have sticked to unfavorable intermediate risk.

 

[medgator]

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One major flaw in RTOG0815, apart from the primary endpoint in my humble opinion, is including all intermediate risk patients. They should have sticked to unfavorable intermediate risk.

The adjuvant taxotere data suffered from the same problem, needed a better selected high risk population to show the benefit

 

[MegaVoltagePhoton]

Wasn’t there another presentation at Astro that basically said adt use helps intermediate? But I don’t think they had info on favorable or unfavorable. Haven’t bothered purchasing the meeting yet … not convinced there was anything major there

 

[Chartreuse Wombat]

Indeed, but probably beyond 5 years.
Median prognosis of metastatic prostate cancer nowadays is around 5 years. Here are the results of the ARCHES trial with ADT+Enzalutamide for mHSPC:

ESMO 2021: Final Overall Survival Analysis From ARCHES: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Enzalutamide + ADT in Men With mHSPC

ESMO 2021 Final analysis of the ARCHES trial of enzalutamide in men with mHSPC, enzalutamide + ADT significantly prolongs survival in men with mHSPC, abiraterone, apalutamide, or docetaxel.

www.urotoday.com

Patients with localized prostate cancer who undergo RT without ADT, go on to develop biochemical progression and ultimately metastatic disease will live longer than that.


One major flaw in RTOG0815, apart from the primary endpoint in my humble opinion, is including all intermediate risk patients. They should have sticked to unfavorable intermediate risk.

UIR was not a thing in 2008 when the study was designed

 

[communitydoc13]

I think I'd go for the short course ADT myself at 68 yo if healthy. Life expectancy 15 years from there and significant risk reduction in terms of indefinite ADT.

This is a useful trial. Modern XRT techniques. I've already used these results for mutual decision making with several patients.

 

[wandering star]

One major flaw in RTOG0815, apart from the primary endpoint in my humble opinion, is including all intermediate risk patients. They should have sticked to unfavorable intermediate risk.

In terms of getting a stronger signal in their primary endpoint, they certainly could have done better by sticking with a higher risk cohort. In terms of trying to counsel prostate cancer patients across the spectrum on when we can de-escalate and avoid ADT, having the spectrum of intermediate risk seems useful.

Sometimes we see these trials with ridiculously aspirational power calculations that have basically no hope of seeing a positive result. In hindsight (esp with advances in other systemic therapy, as you astutely pointed out) RTOG 0815 is one of these trials and it was not possible to get p < 0.05 for 5 yr OS, although longer term followup may work out. In this context I think it's the qualitative lessons that we can learn.

My takeaway from the presentation was that ADT provides pretty uniform risk reduction across the board, whether favorable intermediate or unfavorable intermediate, but your baseline risk is of course higher with unfavorable intermediate. If we had found for example that the recurrences with favorable intermediate just "happened" and ADT had no effect here then we could omit ADT, but that's not what the subgroup analysis showed.

 

[communitydoc13]

ADT provides pretty uniform risk reduction across the board, whether favorable intermediate or unfavorable intermediate, but your baseline risk is of course higher with unfavorable intermediate. If we had found for example that the recurrences with favorable intermediate just "happened" and ADT had no effect here then we could omit ADT, but that's not what the subgroup analysis showed

This is an important observation and I think it holds true for any intervention that is both fairly indiscriminate and effective. (There aren't as many of these as one would think, XRT in breast cancer, ADT in prostate and endocrine therapy in ER+ breast cancer come to mind). In the breast cancer setting, adjuvant XRT uniformly provides a local control benefit, but the absolute benefit is a function of age, cancer biology and receptor status.

These interventions also almost always show some benefit (although not necessarily with regard to survival) with escalation (either dose or target volume for breast and prostate XRT or duration of therapy for ADT or endocrine therapy). The question to me is where we cross the threshold of excessively diminishing returns vs increased cost/toxicity. This is in turn different for each patient.

Kudos to those who ran the trial.

Question? How much does history of significant CAD (either history of MI or PCI) impact your recs for short course ADT in this setting?

 

[ramsesthenice]

Question? How much does history of significant CAD (either history of MI or PCI) impact your recs for short course ADT in this setting?

Almost none. No jokes, if it did, I wouldn't give anyone ADT. Go to Walmart. On a Saturday. You will see around 80% of my patient population.

The question to me is where we cross the threshold of excessively diminishing returns vs increased cost/toxicity. This is in turn different for each patient.

Here it is. I'll be honest, I was a little surprised. I didn't think there was going to be much of any significant effect in the favorable group. However, I have always reasoned there could be and for the last couple years have discussed ADT for these guys in the context that it may help, I can't give them an exact number, and the absolute benefit will probably be small since most people will do well either way. This trial more or less confirmed my suspicions and really won't change my practice. I'll continue to offer but won't lose any sleep when people decline.

 

[Palex80]

Question? How much does history of significant CAD (either history of MI or PCI) impact your recs for short course ADT in this setting?

Is there any data out there suggesting that short-course ADT increases cardiac morbidity? I am only aware of data on long term ADT.

Perhaps RTOG 0815 will shed light into this?
I only read that Grade 3 late AEs were the same in both arms of RTOG0815 (16.2% in Arm 1 and 17.5% in Arm 2 (p=0.27)), but did they break it down to types of late AEs in the presentation?

 

[communitydoc13]

Is there any data out there suggesting that short-course ADT increases cardiac morbidity? I am only aware of data on long term ADT.

Perhaps RTOG 0815 will shed light into this?
I only read that Grade 3 late AEs were the same in both arms of RTOG0815 (16.2% in Arm 1 and 17.5% in Arm 2 (p=0.27)), but did they break it down to types of late AEs in the presentation?

Hormonal Therapy Use for Prostate Cancer and Mortality in Men With Coronary Artery Disease–Induced Congestive Heart Failure or Myocardial Infarction (This was D'amico analysis from years ago)

Cardiovascular Mortality Following Short-term Androgen Deprivation in Clinically Localized Prostate Cancer: An Analysis of RTOG 94-08

Download Citation | Cardiovascular Mortality Following Short-term Androgen Deprivation in Clinically Localized Prostate Cancer: An Analysis of RTOG 94-08 | Background: Androgen deprivation therapy (ADT) is associated with coronary heart disease and diabetes in men with prostate cancer (PCa)...

www.researchgate.net

94-08 analysis negative for adverse events in whole cohort.