When to Add ADT to Early or Late Salvage Radiation - Dan Spratt

August 18, 2021

Daniel Spratt, MD, reviews the data from two trials that demonstrate the selection of patients for the addition of hormone therapy (ADT) to post-prostatectomy radiation therapy. Dr. Spratt discusses two phase three trials that have evaluated hormonal therapy in the postoperative RP setting with a rising PSA. The RTOG 9601 trial and the GETUG-AFU 16 trial are distinct from each other where the RTOG 9601 trial focuses on late salvage radiation therapy, while the GETUG-AFU 16 trial focuses on early salvage radiation therapy. Dr. Spratt goes on to discuss these trials in conjunction with the RAVES and SAKK 09/10 trials. He also states that the standard of care should move to add hormone therapy for men with late salvage radiation therapy. Dr. Spratt discusses how he utilizes Decipher testing for variations in treatment, sometimes independent of PSA levels.


Daniel Spratt, MD, Vincent K. Smith Chair in Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine, UH Cleveland Medical Center

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Daniel Spratt: I'm going to talk a little bit about the data supporting the addition of hormone therapy to postoperative radiation therapy. Really, we have two landmark published phase three randomized trials that have evaluated the benefit of hormonal therapy in this setting. Soon, we hope to see the results of a third randomized trial to be published. And again when that is done we will probably want to get back together and discuss its results. But the two that have been published with now, very long-term follow-up of nine to 12 years, median follow-up is RTOG 9601, which is a trial of a little bit more of a late salvage radiation therapy. It was radiation therapy plus or minus two years of bicalutamide, an antiandrogen.

And the other trial is the GETUG-AFU 16 trial which was more of an early salvage radiation therapy trial with or without six months of a more traditional LHRH agonist. Really, this figure is just a highlight, the red is a more aggressive disease. And so, you can see in 9601, it was a more aggressive population than the GETUG trial. And so as I sort of highlighted, one is a late one and one is an early salvage radiation therapy trial. And when we looked at RTOG 9601, the primary endpoint was overall survival. It improved overall survival by about 5% and it just reached statistical significance. And this helped change the standard of care. And so in 2019, after these sorts of results were live, ASTRO and AUA guidelines stated that clinicians should now offer hormonal therapy with radiation therapy to patients who are candidates for salvage radiation therapy. While this may seem reasonable off of those results, I will sort of dissect this a little more, that should everyone receive hormone therapy. And I would say that I sort of caution in that, AUA and ASTRO as Dr. Ross will sort of talk about, they used to recommend for many, many years that all patients should be recommended adjuvant radiation therapy with adverse pathology. And I think we have now learned potentially that was not right. And I am hoping to avoid history repeating itself.

So, RTOG 9601, as you see the schema here, a key important point of this trial is that it stratified its patients by PSA's of 1.5. Now that is a very high PSA in today's standards to receive salvage radiation therapy, but that was really the era that it was run. And when you look at this and you report it, and this is a secondary ancillary project, secondary analysis of the trial, for the men with PSA's over 1.5, they derived a very, very large improvement in overall survival of 25%. I mean, this is one of the biggest survival benefits you will see.

And now we know based on probably imaging, a lot of these men probably had metastatic disease, but in the men who had lower PSA's, which still isn't even that low, there was absolutely no improvement. And this is 85% of the trial, no improvement at all in overall survival with long-term follow-up. And so what we've shown is that PSA itself, is not only highly prognostic, which we showed you in the study by Ross and others, it is also predictive meaning that men with low PSA's have a significant interaction effect, meaning that they preferentially with low PSA's do not derive as much benefit as those with higher PSA's. And you can see these hazard ratios going from a very large benefit in survival, or metastasis, marching to one, or even crossing one, of not having a benefit in these endpoints of adding hormone therapy. And you can see that trend here. You can see that here going from a reduction of 18% metastasis down to effectively, no improvement in metastasis at low PSAs.

And so pre-salvage radiation PSA is both prognostic and predictive for the benefit of hormone therapy based on this study. As I sort of alluded to, so not only do we know pre-salvage radiation therapy PSA is very prognostic, those with lower PSA's are more likely to be cured of salvage radiation. We now know from PSMA PET imaging, that actually there is a tight correlation that as the PSA goes up, the majority of these patients already have regional if not distant metastatic disease. So this may explain why at high PSA's, hormone therapy provides such a massive survival benefit.

And as many of you know, hormone therapy is not without side effects, and long-term hormone therapy such as Titus bicalutamide actually in this trial increased the risk of other cause mortality by almost twofold. And that was a 9% increased risk in other cause mortality. And this appeared to be driven by increases in cardiac and/or, cardiac and neurologic events, which are known side effects of hormone therapy. And this is in the entire cohort, as well as obviously based on regardless of the PSA subgroup, because a man's PSA, should it drive whether the hormone therapy gives you toxicity and this sort of reassurance, this isn't just some imbalance to toxicities like bladder toxicity, there was no difference between whether the man got hormone therapy or not.

And many will bring up this other trial, the GETUG trial because they will say that it met its primary endpoint, which was an improvement in biochemical control.  But I like to always remind people that, although it initially was powered for PFS, they actually changed the study design to increase its sample size, to be powered for overall survival. So, effectively its primary endpoint was survival. That's what it was powered for with their trial expansion. And just like in RTOG 9601, there is absolutely, with long-term follow-up, no improvement in survival from the addition of more traditional hormone therapy to this early salvage population. And so in the two trials, we have that are published again in almost no setting in oncology, for when there is no improvement in survival, do we really adopt a systemic therapy.

So sometimes what I also like people to look at is, sometimes they will talk about improvements in other endpoints, but the thing that we have to remember is that when you compare in the GETUG trial, the men on the top who got hormone therapy, versus the men who did not get hormone therapy, you will see that there is no tail to this metastasis-free survival curve. It's not like hormone therapy increases the cure rate. It simply delayed the PSA recurrence and the detection of metastasis by almost an identical duration of the initial testosterone suppression from the hormone therapy. And so I always argue that, is this patient benefit, given that all of these patients below this line did not benefit from hormone therapy?  And so you are over-treating many for an unclear benefit for a few.

And now with these trials comparing adjuvant to early salvage, this is the RAVES trial, and this is a trial somewhat like the SAKK trials.  The trial though, really early salvage, everyone at PSA's of about 0.2 almost no man by eight years in the salvage radiation therapy arm, only 3% of them developed a distant metastasis by eight years with salvage radiation alone, which begs the question, how much does hormone therapy benefit in an early salvage radiation therapy cohort? And just as a comparison, favorable intermediate-risk localized disease, which we do not give hormone therapy, actually has a slightly higher risk of metastasis and we happily omit hormone therapy in these men.

And so, of course, the standard of care should be we add hormone therapy for men with late salvage radiation therapy. And one of the goals of this talk is can we do more? People ask me all the time, "Dan, what if they have a high Gleason score or high T stage, can we move beyond just PSA?" And this is data from that RTOG 9601 trial where they then, similar to the SAKK trial, went back and profiled that prostatectomy samples with the decipher assay. And what you see, just like we've seen in the retrospective studies, is that in this fairly aggressive recurrent cohort, low decipher patients, this is death from prostate cancer. Almost none of these men by 12 years have died of prostate cancer.

And when you look at the benefit of hormone therapy in men with early salvage, and in this case, PSAs less than 0.7, the benefit of the hormone therapy is almost non-existent. In these lower Decipher GC risk patients, almost no improvement in metastasis, death from prostate cancer, and they actually had worse overall survival because all you're experiencing, is there is no oncologic benefit, you are just experiencing the harms of the hormone therapy. But in those getting early salvage radiation, some of them, the higher Decipher patients actually derived significant improvements in metastasis and death from prostate cancer and a small improvement in survival.

So in general, and I think everyone's practice is different, so I just show you my practice and I'd love to discuss this with the group. But for men generally, with early salvage radiation therapy, I try to obtain a Decipher on most of these men that I feel are indicated to receive salvage radiation. The lower Decipher, I tend to offer salvage radiation therapy alone. The higher Decipher, even with low PSA's, I tend to recommend hormone therapy. But for high Deciphers and really sort of potentially outside the scope of this talk, especially with the recent FDA approval of PSMA PET, I try to get them a PET scan. And again, based upon what their PET results are, sometimes if it's a negative PET scan, I'll consider Decipher, and that will help me guide whether it's short-term or longer more intensive hormone therapy. So, I think the summary of the talk is really that I think the use of early salvage radiation therapy alone is a preferred treatment for many patients.

Hormone therapy, we have to accept has costs and side effects, and potential long-term morbidity. And so we really should use this just like we do in localized disease to those who will derive meaningful survival benefits. Pretreatment PSA I hope you see now is very prognostic and potentially predictive of the benefit of hormone therapy in this setting and Decipher may really help us identify patients that would derive benefit or the maximal absolute benefit from hormone therapy. And I think we still have a lot of work to really refine this paradigm and where imaging also fits in.