Who Needs Systemic Treatment With Salvage Radiotherapy? APCCC 2022 Presentation - Brandon Mahal

August 11, 2022

At the 2022 Advanced Prostate Cancer Consensus Conference (APCCC) Hybrid Meeting, Brandon Mahal presents on who needs systemic treatment with salvage radiotherapy.


Brandon Mahal, MD, University of Miami School of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL

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Almudena Zapatero: And the second speaker is Dr. Brandon Mahal, also radiation oncologist from Miami. And he's going to talk about who needs systemic treatment and salvage radiotherapy.

Brandon Mahal: All right. Hi, thank you to Silke and Aurelius for inviting me to give this talk. It's a pleasure to be here with my esteemed colleagues on this panel. I'm going to be speaking on who needs systemic treatment with salvage RT. I have no relevant conflicts of interest to disclose. In terms of the overview first, I'll speak about the evidence including what's new. I'll speak about grey zones and how I currently manage patients. And then the final minute of my talk, I'll go over some ongoing trials. To begin, I'll start with discussing three randomized trials. The first is RTOG 96-01, which was really a study of late salvage radiation therapy published in 2017. Study enrolled from 1998 to 2003, salvage radiation therapy plus or minus 24 months of bicalutamide 150. These patients had a PSA of 0.5 to 4.0 and later on in the trial that was modified to include PSAs greater than 0.2, but that was a minority of patients.

So, 44% of patients had a persistent PSA after surgery with a median PSA of 0.6. The study was stratified by the PSA at cutpoint 1.5. With a median follow up of 13 years, there was an overall survival benefit 4% absolute risk number needed to treat was 25, 70% gynecomastia rate with bicalutamide. When looking a little bit closer at stratification by PSA, now this was a post-talk analysis mostly it was only pre-stratified by PSA greater than 1.5. PSA greater than 1.5 showed a significant overall survival benefit. Whereas there was a decrease in that benefit from 0.7 to 1.5 and no benefit seen in the 0.7 group, again, a subgroup analysis. When looking closer at further stratification of this analysis, there was an elegant study done by Dr. Des and Dan Spratt published in 2020. When looking at PSAs further stratified below that 0.6 to 0.7 range, what we saw is that there was an overall survival benefit again, for the PSAs greater than 1.5.

And from 0.6 to 1.5, there was less of a benefit. And then there was no benefit seen from 0.3 to 0.6 and 0.2 to 0.3, there were significant interaction values for this P value 0.02. So, this overall secondary analysis shows that pre-salvage radiation therapy PSA is prognostic and predictive of ADT benefit. When looking closer at some of these toxicity events, men with a PSA less than 0.6, there was no improvement in overall survival, but there was an increase in grade 3 cardiac and neurotoxicity. When looking closer at this particular cohort, again, the secondary analysis showed that 24 months of the bicalutamide 150 increased other-cause mortality with early salvage radiation therapy below 0.6. I'm going to just briefly mention this slide, Dr. Felix Feng is going to get more into genomic classifiers, but another ancillary study this time of 352 patients with analyzable tissue showed that genomic classifiers are prognostic and potentially predictive of ADT response to this study was underpowered to detect a GC ADT interaction. Overall, higher risk genomic scores predicted for a greater benefit from ADT.

But when looking at early salvage radiation therapy patients, there was less of a benefit. For patients with low genomic classifier risk scores, those patients actually had a decrement when treated with ADT. Okay. Switching gears to Casodex just to say one point is that Casodex 150. We don't use it in the US. There were some studies in the metastatic and locally advanced settings where there appeared to be potentially more harm than good. We don't use Casodex 150. We use 50 usually in combination with LHRH agonists. All right. Switching gears again to now a GETUG/AFU-16 study, this was a study of early salvage radiation therapy from 2006 to 2010. Salvage radiation plus or minus six months of GnRH agonist. The PSAs here were 0.2 to 2.0 with a median of 0.3.

Again, compared to that 0.6 in RTOG 96-01. This study was not stratified by PSA. There was a median follow up of 9.3 years. The primary endpoint was progression free survival, but it's important to note that this study was powered for overall survival. Overall, the progression free survival endpoint was defined as PSA nadir plus 0.5 or clinical progression. And that met statistical significance, or was a benefit for progression free survival and possibly metastases free survival. The reason I say possibly is because this upper bound went up to 0.98, and the ice cap surrogate threshold effect upper bound is placed at 0.88. It's something to consider. There was no overall survival benefit in this cohort. Again, this data here that I'm showing is the most recent data from 2019. There was an initial report in 2016. When looking at that 2016 report, there was some stratification post-hoc analysis by PSA at 0.5.

All patients tended a benefit. The patients with PSAs greater than 0.5 appeared to potentially have a trend toward a greater benefit. But again, all patients benefited in the subgroup analysis. This was from the 2016 publication. When looking at toxicity overall, there were no differences in serious acute or late GU, GI, or CV toxicities. There were increases in hot flashes and a slightly higher rate of grade 3 sexual disorders in the arm that received ADT. Okay, so now for the third and final trial, that I'll be discussing the RTOG 0534 SPPORT trial. This was done from 2006 to 2010. This was a trial that had three arms that was salvage bed radiation plus or minus four to six months of short term ADT, which included LHRH agonists and anti-androgen and then plus or minus pelvic lymph node radiation. There was a pelvic bed alone arm, pelvic bed plus short term ADT, and then pelvic bed short term ADT plus pelvic lymph node radiation.

These patients had a PSA of 0.1 to 2.0, median is 0.35, so again, early salvage radiation therapy. This study was stratified at the PSA cutpoint of 1.0, with a median follow up of 8.2 years in primary endpoint of freedom for progression. This in comparison to the GETUG study. This used freedom for progression definition of PSA nadir plus 2.0 where it was nadir plus 0.5 in the GETUG study. In any case, the short term ADT arms tended to benefit more 81% to 87% freedom from progression compared to 71% without ADT. The third arm that included pelvic lymph node radiation was the arm that appeared to be superior to the other arms. And then when looking at the PSA stratified by the median PSA, this is a post-hoc analysis because the study was stratified at 1.0, there appeared to be a benefit to ADT regardless of PSA.

On the left here is PSAs that were lower than 3.5. On the right greater than 0.35. What you see is the curves on the left. The top two curves are the ADT curves. You see, there are superposed. There may or may not be a benefit to pelvic lymph node radiation with the lower PSAs, but certainly appear that there's a freedom from progression benefit, even for ADT, with lower PSAs in the study, again, looking at freedom from progression. When looking at other endpoints, there's potentially a distant mets benefit and a second salvage benefit, but there's no overall survival or metastasis free survival benefit seen in the study. Here on the left, looking at distant mets rate, short term ADT had a lower distance mets rate. Also looking at the right there were lower rates of second salvage ADT rates. I'm not going to summarize the slide for you.

This is for you, if you want to take a picture summarizing the three major studies that I've discussed here. I'll pause here for a second. Okay. Some grey zones. ADT duration zero, four to six months, 24 months. And for whom? What type of ADT we needed to further clarify the benefit of ADT by pre-stratified PSA before salvage radiation therapy, probably Dan Spratt is doing an analysis somewhere. ADT benefit by tumor biology and genomic classifier. Should we be intensifying for systemic therapy for high risk disease? What about the incorporation of advanced imaging? What do I do? This is our risk adapted approach at University of Miami Sylvester Cancer Center. This is adapted from a slide from an expert piece that was put out by Dan Spratt several years ago and updated. This is an oversimplification. And if I had two cents to give you, this is my one penny.

I treat this disease as a continuous disease, but if we were to put buckets to it for lower grade disease and earlier PSAs, then those patients are sometimes patients that can get away with RT alone. And if the grade of disease is higher, short-term ADT, but if the grade of diseases higher, are there other additional risk factors, which we've discussed in the first session, and that Felix Feng will discuss as well with the genomic classifier session. We consider intensifying therapy, including duration and additional therapies. What are some ongoing trials? It's a really active area investigation. RADICALS-HD. This slide was presented by Dr. Toki, which looked at radiation therapy alone six months and 24 months. NRG GU-006 as a biomarker trial, looking at enhanced anti-androgen versus not for more intermediate risk patients.

There's the FORMULA-509 by Paul Nguyen, looking at Abi and prednisone plus enhanced anti-androgen for mostly inter intermediate and high risk patients. And then this slide was shown earlier as well. The DASL-HiCAP study. Thank you to Chris for sending this slide along with Co-Pis Chris Sweeney and Tamim Niazi, looking mostly at high risk localized patients, but 15% of the cohort are post RP patients as well. And so, this is looking at 96 weeks of darolutamide added on top of therapy. And then the RTOG 3506 STEEL study, looking at standard versus enhanced ADT and higher risk patients with a PSA after surgery greater than 0.7. And then the final study is the NRG G002, looking at a high PSA nadir greater than 0.2 after surgery. And this is randomizing to patients with intensification with docetaxel for very high risk disease. All right, thank you. And I'd like to thank my local team back home in Miami. Thank.

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