Rashid Sayyid: Good day everybody, and thanks for becoming a member of us at this time on this UroToday recording. I am Rashid Sayyid, a urological oncology fellow on the College of Toronto, and I am joined at this time by Zach Klaassen, affiliate professor and program director at Wellstar MCG Well being, the place we’ll be going over the 2024 key updates to the NCCN prostate most cancers tips. On this recording, we’ll particularly deal with one of many new sections, which addresses the prevention of symptomatic skeletal-related occasions in sufferers with bone metastatic CRPC.
So we have seen a whole lot of modifications in these latest NCCN tips that had been printed in March. And what’s fascinating from a survivorship standpoint, we have actually had two new sections that had been added that particularly deal with the rules of bone well being in sufferers with prostate most cancers. The primary one is the therapy of associated bone loss, which we’ll be discussing and going over in a later recording. We’ll additionally, on this session, be discussing the part that discusses the prevention of symptomatic skeletal-related occasions in sufferers with bone metastatic CRPC.
And we see right here at this time a superb desk of the abstract of the suggestions by the NCCN, which discusses the optimization of bone well being in all affected person prostate most cancers, particularly these receiving ADT, and in addition stratified by their present bone mineral density. We’ll be going over all of the proof in addition to the suggestions by the NCCN, so as to optimize this side of survivorship for our prostate most cancers sufferers.
And so in mCRPC sufferers with bone metastasis, at present two brokers have been proven to forestall disease-related skeletal problems, particularly denosumab and zoledronic acid. And so they’ve been proven to both forestall or delay the prevalence of those occasions. Specifically, it is a composite end result of fracture, spinal twine compression, or want for surgical procedure or radiotherapy to the bone. And so which one is best? We all know we’ve two brokers which have proven efficacy on this setting, and actually, that provides us many choices, which is nice, however finally, we wish to decide one versus the opposite, relying on the scientific state of affairs.
And so in 2011, we noticed a seminal paper by Dr. Fizazi printed in The Lancet. This was a non-inferiority section three trial that included virtually 2,000 sufferers, particularly with bone metastasis. And so they had been randomized with one in every of two arms, both denosumab, which is given subcutaneously with IV placebo, and these had been administered each 4 weeks, and we’ll discuss why that is related afterward, versus zoledronic acid given at 4 milligrams intravenously with subcu placebo. In order that approach, there was an IV and a subcu injection given for all sufferers so as to improve the blindness.
And on the identical time, along with these brokers, all sufferers had been strongly really useful to obtain each day supplemental calcium, no less than 500 milligrams, and vitamin D, no less than 400 worldwide items. And the first endpoint was time to the skeletal-related occasion. And never solely was denosumab non-inferior to zoledronic acid, however it additionally, as soon as it was confirmed to be non-inferior, was additionally proven to be superior, by bettering the median time to the skeletal-related occasion by virtually three months, from 17 months to twenty.7 months, so a clinically significant distinction once we examine the 2 brokers.
Okay, we appeared on the efficacy outcomes. What in regards to the hostile occasion profile? So once we have a look at the intense hostile occasions, they’re roughly the identical, at about 60%, however there are two particular hostile occasions that had been extra frequent with denosumab which are price highlighting. The primary one is hypocalcemia, and that was virtually double. So we see in denosumab it was 13%, whereas zoledronic acid, 6%. So most likely ought to test a BMP with a calcium degree extra usually in these sufferers. The second factor is osteonecrosis of the jaw. And so though this didn’t meet statistical significance, we see that, in absolute quantities, it was solely a 1% improve increased in denosumab, however it was twofold increased in sufferers receiving denosumab.
So it is necessary in these sufferers, earlier than you begin them on these medication, to perhaps have them see their native dentist, to get a fast test, and guarantee that there are not any contraindications to receiving these medication. Now, one level of rivalry is how usually ought to we give these medication? We noticed on this earlier trial by Fizazi and the remainder of the crew that these medication got each 4 weeks. But in addition, we noticed that the hostile occasions, the intense hostile occasions occurred no less than 60% of the time, and we additionally noticed the hypocalcemia and the osteonecrosis of the jaw.
So if by reducing the frequency that we give it, going from each 4 weeks to each 12 weeks, can we preserve the identical efficacy, whereas lowering the frequency of hostile occasions? And so in 2017, we noticed a vital paper printed in JAMA that was additionally a non-inferiority section three trial, that in contrast two years of zoledronic acid given each 4 weeks, which was the usual of the time, versus each 12 weeks, in virtually 2,000 sufferers who had both metastatic prostate most cancers, breast most cancers, or a number of myeloma.
And the prostate most cancers sufferers accounted for 700, so roughly simply over a 3rd of the cohort. And importantly, we noticed no distinction within the proportion of the skeletal-related occasions, no matter whether or not these had been for each 4 weeks or each 12 weeks. And really, if we simply have a look at it in absolute quantities, it was truly barely decrease within the each 12 week group. What’s necessary is that the pattern was constant throughout all three tumor sorts, together with prostate most cancers. We additionally noticed no distinction within the secondary outcomes of ache scores, efficiency standing scores, the incidence of jaw osteonecrosis, kidney dysfunction, and skeletal morbidity charges. And so, primarily based on these outcomes, the NCCN and lots of different tips at present advocate that each 12 week dosing for zoledronic acid is really useful when indicated for symptomatic skeletal-related occasion discount.
And so what are some necessary issues for the usage of zoledronic acid, denosumab by the NCCN? So the NCCN actually makes some necessary factors about these medication, particularly that utilization of those two brokers for symptomatic skeletal-related occasion discount requires consideration of the diploma of the profit and the chance related to remedy to optimize use dose and schedule. So mainly, when you assume that the upside or the good thing about these medication outweighs the chance, then it is best to positively use them on this setting the place warranted. However it’s additionally necessary to acknowledge that these two medication had been used or examined in an period the place the one therapy possibility for mCRPC sufferers was actually docetaxel.
And we all know that we have had a plethora of brokers authorized within the mCRPC area, particularly the ARPS, corresponding to abi and enzalutamide. We have now different chemotherapy medication, corresponding to cabazi, radium 223, lutetium, by way of radioligand remedy. And so all of those have been independently proven to enhance the skeletal occasions on their very own. And so you’ll assume that by combining these brokers with zoledronic acid and denosumab that you’d additional enhance the bone well being, and there could also be some proof to warrant that. But in addition, it is necessary to understand that they do not at all times act synergistically.
And there is proof that combining radium 223 and abiraterone, each brokers which have been proven to enhance bone well being, truly will increase the frequency of bone fractures. So in the interim, given the proof that we’ve, the NCCN and lots of different platforms do endorse zoledronic acid, with the caveat that as these brokers get examined in additional up to date trials, we might discover modifications and these suggestions might accordingly be affected.
And so primarily based on the present proof, the NCCN says that there is robust proof to help the usage of zoledronic acid each 12 weeks, for the prevention of those skeletal-related occasions in mCRPC sufferers particularly with bone meds. So these aren’t mCRPC sufferers with nodal illness solely or visceral illness, however bone meds particularly. Alternatively, denosumab, in the interim, remains to be really useful each 4 weeks, however there may be ongoing analysis evaluating an each 12-week dosing on the present time. And so in the interim, these are the frequencies.
And it is also necessary to understand that we simply cannot depend on drug remedy. However as we’ll talk about in a later recording, way of life modifications are essential in these sufferers, particularly weight-bearing train, about half-hour at a time, stability coaching, smoking cessation, and limiting alcohol consumption. It is also necessary to understand that, along with these medication, calcium and vitamin D supplementation are essential. So once we discuss calcium supplementation, it is about 1,000 to 1,200 milligrams each day, and this may be from meals alone and/or dietary supplements, in addition to vitamin D supplementation when wanted, for a goal serum degree of 30 to 50 nanograms per ml.
However once more, as we have gone over, it is necessary to notice that a whole lot of the proof on this area comes from older trials on this area. So actually, there’s been a whole lot of new proof that has emerged and has actually make clear these suggestions. And at this level, I will flip it over to Zach to debate a few of the extra up to date nuances, and the way these might be framed within the context of bone well being survivorship for these sufferers.
Zach Klaassen: Rashid, thanks a lot for that nice overview of the NCCN tips. So what I wish to do during the last couple of slides is basically dig into a few of the new information, and actually, these suggestions from the NCCN that Rashid simply went by way of are all primarily based on outdated information, and actually, as he talked about as properly, outdated prostate most cancers therapy regimens and actually poor utilization of docetaxel. So what about extra up to date therapy regimens? How does this mirror our utilization of bone protecting brokers? And what is the information present us?
So let us take a look at the ERA 223 story. This was a trial printed in 2019 by Dr. Matt Smith and colleagues in The Lancet Oncology. This was 806 sufferers that had been randomized, one-to-one to radium 223 plus abiraterone versus abiraterone plus placebo. What’s necessary about this examine, and hold these dates in thoughts, as a result of we’ll have a few dates arising that we’ll refer again to, in November of 2017, the examine was unblinded, as there have been extra fractures and deaths within the radium plus abiraterone group in comparison with the abiraterone plus placebo group. And we are able to see right here these variations in median symptomatic skeletal event-free survival, in addition to fractures, for symptomatic skeletal-free survival radium 223 plus abiraterone, 22.3 months, and longer within the abiraterone plus placebo group at 26 months. Fracture charges, radium 223 plus abiraterone, 29% in comparison with abiraterone plus placebo. So that is what led to a examine being unblinded.
However let’s dig slightly bit additional into what was utilization of bone protecting brokers on this trial. So it is a snapshot of desk one from the intention to deal with inhabitants baseline traits. We will see that within the abi plus radium group, solely 39% of sufferers had been on bone protecting brokers, and solely 42% of sufferers within the abi plus placebo group had been on bone protecting brokers, both denosumab or bisphosphonates. And once we dig into the supplemental tables, we see that that is actually what results in or does not result in fractures.
And so on this first column right here of two rows or two columns, we see the abi plus radium combos, the sufferers that had fractures, 21% utilization of bone protecting brokers, and people who did not have fractures, 48%. So clearly, we see right here that utilization of bone protecting brokers makes a distinction. And we additionally see this within the abiraterone plus placebo group, with fractures, utilizations are very low, at 24%, use of bone well being brokers, as much as 45% of these with out fracture. So there appears to be a sign right here that, with each the intervention and the placebo group, utilization of bone protecting brokers does lower the chance of fracture.
Additionally, digging slightly bit additional, let us take a look at symptomatic skeletal event-free survival with the usage of bone protecting brokers and with out the usage of bone protecting brokers. After we see these two teams, abi plus radium in blue, abi plus placebo in crimson, when bone protecting brokers are used, basically overlapping Kaplan-Meier curves right here, hazard ratio 0.932. After we do not use bone protecting brokers, we do see worse symptomatic skeletal event-free survival for the abi plus radium group, hazard ratio right here, 1.252, not statistically vital however shut, and a rise in fracture price of 25% for that abi plus radium group.
So clearly, the utilization of bone protecting brokers is vital for each teams, however actually importantly on this slide, the take-home message is it mainly brings that threat to even between the 2 teams on this trial. So there have been a number of ramifications from the ERA 223 trial. So within the dialogue, the authors be aware, “The discovering that the usage of bone well being brokers was related to the decreased fracture frequency in each teams on this examine reveals the significance of the usage of these medication to forestall skeletal morbidity in sufferers with metastatic castration-resistant prostate most cancers.” Clearly, of their supplemental, additional digging into the reasoning, it reveals that when these sufferers are on these brokers for each teams, there’s much less bone morbidity.
Equally necessary, and actually for the ramifications for future trials, is what occurred to the PEACE-III trial. And that is the enzalutamide plus or minus radium 223 trial. And as I mentioned earlier than, in November of 2017, the ERA 223 trial was unblinded due to the fracture price. This led to, in March of 2018, primarily based on this ERA 223, the PEACE-III IMDC issued an pressing security letter, after which subsequently, in April of 2018, there was a mandate for bone protecting brokers within the PEACE-III trial. And so it grew to become essential within the medical neighborhood, the funders and the stakeholders on this trial had been actually involved about the opportunity of elevated fractures in enza plus radium 223, primarily based on what was seen within the ERA 223 trial.
And so Dr. Tombola and colleagues at ASCO 2019 did a security evaluation of the subsequent 146 sufferers. And so that is after mandated, the bone protecting agent use elevated from 42.6%, about what was seen within the ERA 223 trial, as much as 86.7% after the mandate was established in April of 2018. And what they discovered on this trial is that mainly the usage of bone protecting brokers fully abolishes the chance of bone fracture. And that is beginning bone protecting agent six weeks earlier than the primary injection of radium 223. We will see right here within the field, just one fracture within the sufferers that obtained bone protecting brokers in both group out of 19 sufferers general that did have a fracture.
A subsequent replace was offered by Dr. Gillison and colleagues at ASCO 2021, so two years later. That is now 267 sufferers. We have seen great uptake in the usage of bone protecting brokers, 96.3% after the mandate was issued in 2018. Once more, the fracture threat reveals that, mainly, it is ameliorating fractures in each teams, with a fracture price of solely 2.6% within the enzalutamide alone group and a pair of.7% within the enzalutamide plus radium 223 group.
So I do know Rashid gave us some glorious NCCN guideline conclusions from what was included within the 2024 replace. These are some extra ideas and a few necessary conclusions. It is necessary to level out that that is the primary time in 2024 that the NCCN prostate most cancers tips have included bone well being and bone protecting brokers of their replace. If we have a look at this determine on the suitable, that is Medicare information, there’s been traditionally very poor utilization of bone protecting brokers in the true world, and as we have seen in these trials as properly.
So on this Medicare examine, if we have a look at 2016, the blue line is any bone protecting agent, roughly round 60%. And so we have seen it within the replace of the PEACE-III trial in 2021, this quantity was as much as 96%. However actually, no less than from this older information, taking a look at the true world utilization, that is about what we’d anticipate. Not excellent utilization, roughly 60% of sufferers getting bone protecting brokers. And so the brand new inclusion of bone well being within the tips is well timed. It is also a name to motion, and it additionally is smart that that is included now, given the seemingly presentation of the PEACE-III information both in late 2024 or in early 2025. So we thanks very a lot on your consideration. We hope you loved this NCCN replace for UroToday on the prostate most cancers tips, trying on the prevention of skeletal-related occasions in mCRPC sufferers.
