Rashid Sayyid: Hey, everybody. And thanks for becoming a member of us in the present day on this particular NCCN recording of the 2024 key updates to the most recent tips the place we’ll be discussing the M1 CRPC tips updates. I am Rashid Sayyid, a urologic oncology fellow on the College of Toronto, and I am delighted to be joined in the present day by Zach Klaassen, affiliate professor and program director at WellStar MCG Well being. There have been quite a lot of adjustments in these newest set of tips and here is a little bit of an overview of the important thing factors that we’ll be touching upon.
To start with, we’ll give our listeners a fast overview of the present brokers which might be FDA accepted for the therapy of mCRPC sufferers. We’ll discuss in regards to the present administration algorithm of mCRPC sufferers. We’ll have some key factors that we frequently neglect about. We’ll discuss in regards to the therapy choices for mCRPC sufferers, primarily these with adenocarcinoma based mostly on the prior therapies obtained. We’ll dive into the 2024 updates to those tips. After which we’ll talk about additionally, importantly, the proof that informs these 2024 updates.
Right here we have seen the schematic, all of the brokers which have been FDA accepted for the therapy of mCRPC sufferers. Presently, we’re sitting at round 16 approvals with the vast majority of these coming from 2010 onwards. Most not too long ago, we have seen in 2023 actually the emergence of the PARP inhibitor, ARPI mixtures with niraparib and enza, olaparib and abi, and talazoparib and enzalutamide for sufferers with both BRCA 1/2 mutations or homologous recombination restore mutations.
Right here we see in 2024 the present administration algorithm for sufferers with M1 CRPC. And it is actually vital to notice that development to castrate-resistant illness would not simply imply a PSA development. It might be PSA, which means biochemical, it might be medical when it comes to ache, for instance, or radiographic. So it is actually vital to think about all these three points. And what’s actually vital once we take into consideration CRPC is, to begin with, to verify that sufferers are literally castrates. After we discuss castrate resistance, actually we wish testosterone ranges lower than 50. So it is essential within the clinic to make it possible for sufferers, A, are literally receiving it, after which B, confirming that their testosterone is sufficiently suppressed. And what’s vital as effectively is to at all times stage these sufferers. The NCCN talks about imaging research constructive for metastases. So which means a CT chest, stomach, pelvis, or in lieu of CT stomach pelvis, you may think about an MRI with and with out distinction as effectively.
Listed below are the completely different choices that now we have after we verify a analysis of CRPC. Biopsying the metastatic lesion. So along with confirming that you’ve got metastasis, the opposite door that it opens up is testing, somatic testing, for homologous recombination restore mutations or the microsatellite instability mismatch restore deficiency and tumor mutational burden, particularly if these haven’t been beforehand performed on the first specimen. What this does is, it actually opens up quite a few therapy choices for our sufferers that in any other case sufferers wouldn’t have been eligible for. And you do not have to biopsy each affected person suspected of mCRPC, however doing so does open up this chance.
Then the opposite factor we’d like to consider is that, along with the widespread adenocarcinoma, these sufferers, significantly the closely pretreated sufferers which have superior stage illness, can have small cell or neuroendocrine prostate most cancers. And actually there are some medical indicators in addition to genetic adjustments that actually ought to alert the treating doctor that such a element could also be current. Whenever you see a affected person with cumbersome illness, however on the identical time low PSA or if they’ve a excessive carcinoembryonic antigen or an LDH degree, these are some telltale indicators that the affected person could have both pure small cell neuroendocrine or could have a mixture of adenocarcinoma in addition to this neuroendocrine. And actually that adjustments the therapy paradigm. So we’ll discuss that some extra, nevertheless it’s essential to grasp why the NCCN talks about doubtlessly biopsying metastatic lesions.
What’s vital in all of the sufferers, no matter the underlying pathology, is to proceed the ADT with a purpose to preserve the castrate ranges of serum testosterone, once more, outlined as lower than 50. However we’ll see with the newer present testing kits that lower than 20 actually is the goal and has been proven in lots of research to be related to higher outcomes. It is essential for all these sufferers, along with specializing in the therapy of prostate most cancers, to consider the supportive therapy choices. So you need to at all times hold at the back of your thoughts the bone well being. So bone anti-resorptive remedy, denosumab, which stays a class one or most well-liked routine, or you should use zoledronic acid as effectively if bone metastases are current, which invariably they’re in sufferers with mCRPC. Additionally, if sufferers are having painful bone metastasis, then think about palliated radiotherapy and at all times greatest supportive care as indicated.
So going again to the entire biopsy difficulty, if sufferers haven’t been biopsied, the NCCN tells us that it is okay to think about these sufferers as having a default adenocarcinoma and treating them based mostly on that. And we’ll talk about the completely different therapy choices within the subsequent few slides. However once we discuss in regards to the small cell neuroendocrine, you may see right here that the choices are actually fairly completely different in comparison with what we’re used to in classically adenocarcinoma. And I will spotlight one therapy modality that actually has emerged most likely as the very best of all the present choices, which is the mix of cabazitaxel carboplatin whereby in 2020 we noticed a part one-two trial of 160 mCRPC sufferers. And these sufferers weren’t solely a small cell or neuroendocrine prostate most cancers, nevertheless it might have been adeno or have a mixture of each. The truth is, we noticed that over half of them had components of each. So one thing essential to bear in mind.
And these sufferers had been closely pretreated. So a couple of third had docetaxel earlier than and virtually all of them had an ARPI earlier than, a novel hormonal remedy, abi or enza. And these sufferers had been randomized to obtain both cabazitaxel alone or cabazi plus carboplatin and had been adopted for about two and a half years. And we see that this mix, so including carboplatin to cabazitaxel, improved metastasis-free survival from 4 and a half to 7.3 months, which looks like a minimal change, however once more, it actually highlights the poor prognosis these sufferers have and the aggressive nature of this variant. So once more, one thing to bear in mind when treating these sufferers.
Right here we see a really busy slide that discusses the completely different systemic remedy choices for sufferers with M1 CRPC, particularly the adenocarcinoma subtype. And the NCCN does a very nice job of breaking down the therapy choices by the prior remedy obtained. We’ll go over these individually, briefly highlighting the popular regimens and the rising ones as effectively.
If we begin with sufferers who obtained no prior docetaxel or no prior ARPI, the “first-line” remedy choices, the popular regimens stay these which have been accepted for some time now. So abiraterone, docetaxel, and enzalutamide, and now we have the research right here that led to those approvals. However it’s additionally vital to remember that not too long ago we have seen, as I discussed earlier than, the mix of the ARPI and the PARP inhibitors for sufferers with BRCA or HRR mutation that actually have emerged as class one suggestions helpful in sure circumstances.
Subsequent, once we talk about sufferers who’ve obtained the prior novel hormonal remedy corresponding to abi or enza, however no docetaxel, actually the constant theme right here is sufferers have seen a sure drug attempt to use a unique drug with a unique mechanism of motion with a purpose to not fall prey to the identical mechanisms of resistance. So in the event that they’ve obtained a previous novel hormonal remedy, attempt docetaxel. And completely different choices that we have seen emerge and we’ll talk about, and these are the adjustments or a number of the adjustments that we have seen in these tips, is now that olaparib for affected person BRCA mutation based mostly on the profound trial and rucaparib as effectively for these with BRCA mutations with class one based mostly on the 2023 TRITON3 trial have emerged as most well-liked regimens for therapy of those sufferers who’ve progressed earlier than on a novel hormonal remedy. Once more, this highlights the significance of early genetic testing in these sufferers with a purpose to open up these essential and fairly efficacious therapy choices.
Subsequent, if sufferers have progressed on prior docetaxel and haven’t any prior novel hormonal remedy, so clearly abi and enza are choices, but additionally we’d like to consider tropic, which was printed in 2010 and actually has proven the advantage of cabazitaxel within the post-docetaxel setting for these sufferers.
And now if sufferers have progressed on each a docetaxel and a novel hormonal remedy, we all know based mostly on the CARD information printed in 2019, the cabazitaxel is a most well-liked routine. And the docetaxel re-challenge can also be affordable. And that is significantly of relevance if sufferers have progressed on docetaxel within the hormone-sensitive setting. And that is one thing that is vital as we see these brokers being shifted additional and additional up the therapy paradigm. After we come to deal with them afterward, many of those sufferers are going to have seen many of those brokers earlier than, and it is actually vital to grasp the worth of those brokers utilized in a re-challenge setting. Though this isn’t a most well-liked routine however helpful in sure circumstances, it is vital to remember that lutetium is a really engaging choice particularly for sufferers with PSMA constructive metastasis as a class one suggestion. And that is why it is thought-about helpful in sure circumstances as a result of we wish to make sure that these sufferers are eligible based mostly on the PSMA findings. And we all know that there are completely different standards, significantly when it comes to incorporating FDT PET as we noticed within the remedy trial.
Now, let’s go over a number of the adjustments that we have seen. Right here we’ll spotlight in packing containers of various colours. What are a number of the adjustments that we have seen to those NCCN suggestions? To start with, we see that pembrolizumab actually has emerged as helpful in sure circumstances for sufferers particularly with microsatellite instability excessive or DNA mismatch restore mutations for sufferers throughout actually the therapy spectrum. So these have actually seen no docetaxel or novel hormonal remedy earlier than. These have progressed on a previous dose however no NHT, and those that have progressed on an NHT with no doses. So basically anyone who’s both not progressed or progressed on one of many two brokers. And we have seen that for sufferers that progressed on each even earlier than, pembro has been indicated for some time. Actually this selection has emerged in all of the completely different pre-treatment classes. So essential information we’ll discuss as effectively, Zach will, in regards to the proof that actually informs these adjustments within the tips.
Subsequent, if we particularly deal with sufferers who’ve progressed on a previous novel hormonal remedy, as I discussed earlier than, now olaparib and rucaparib are each thought-about class one suggestions for sufferers with BRCA mutation. So very, very, essential for our sufferers. There are some minor adjustments within the helpful in choose circumstances that will or is probably not of quite a lot of relevance, nevertheless it’s vital to spotlight them nonetheless. So once we discuss a routine that is modified, olaparib for HRR mutations aside from BRCA 1/2 is now not thought-about a class one suggestion. So a little bit of a semantic change, nevertheless it’s vital to notice, significantly once we take into consideration the proof that informs this. After which the routine eliminated is rucaparib for BRCA mutation, and that is as a result of now it is thought-about a most well-liked routine and never simply helpful in choose circumstances.
After which an important change is that going from enza to abi or abi to enza is basically now not advisable by these tips. As I discussed earlier than, a typical theme is when sufferers have progressed on a selected drug, we actually wish to problem them with an agent with an alternate mechanism of motion with a purpose to overcome these resistance mechanisms. So though we all know from Dr. Kimchi’s group within the publication in 2019 that sufferers who go from abi to enza at a couple of 36% PSA response and conversely from enza to abi a bit worse, or truly considerably worse, about 4 to eight%, actually the NCCN would not assume that this actually warrants a problem with these medication, significantly as we see so many various choices emerge. So that is now not advisable, going from abi to enza or enza to abi no matter the therapy obtained earlier than. At this level, let’s discuss in regards to the proof that has knowledgeable these adjustments. Zach will go over the present proof beginning with pembrolizumab for sufferers with MSI excessive or DMMR mutations.
Zachary Klaassen: Rashid, thanks a lot for that nice overview and actually highlighting these adjustments in the latest NCCN tips. What we’ll do over the following few slides is simply undergo a number of the proof that led to a few of these key adjustments. In order Rashid talked about, pembrolizumab actually has emerged, and this story actually begins in Could of 2017 when the FDA accepted pembro for sufferers with unresectable or metastatic MSI excessive or DMMR stable tumors who progressed on prior therapy and had no passable different therapy choices. And that is based mostly on the outcomes of 5 research, 149 sufferers, and actually agnostic approval. This was in colorectal non-colorectal sufferers. As you may see right here, too, these sufferers within the research had been mCRPC, total response price was 40%. And among the many mCRPC sufferers, one affected person had a partial response and one had steady illness better than 9 months.
After we dig a little bit deeper taking a look at pembro particularly for mCRPC, one research checked out pembro plus enzalutamide evaluated in 10 mCRPC sufferers. These sufferers had non-visceral metastases and illness development with prior enzalutamide. Of word, 5 of those 10 sufferers additionally obtained extra abiraterone, and there was close to full response PSA response in three out of those 10 sufferers. Two out of three had radiographic measurable illness and achieved a partial response, and one out of two sufferers with measurable illness had an MSI excessive tumor. Amongst these different seven sufferers, three had steady illness and 4 had no perceived medical profit.
Wanting once more at a number of different research. These are some early trials. KEYNOTE-028, part 1B trial of pembro in 23 sufferers with superior prostate most cancers. 74% of those had been closely pretreated, greater than two or extra prior therapies for metastatic illness. The target response price was 17%. These had been all partial responses. And steady illness was famous in 35% of sufferers. Within the KEYNOTE-199 trial, this was a part two trial of pembro and 258 mCRPC sufferers pretreated with both docetaxel or better than or equal to 1 novel hormonal remedy. Sadly, the target response price for these was comparatively low. Cohort one, which is PDL constructive, 5%. Cohort two, which is PDL adverse, was solely 3%.
The NCCN assertion for pembro relies on the obtainable information. The panel helps the usage of pembrolizumab in sufferers with MSI excessive or DMMR metastatic CRPC whose illness has progressed by means of docetaxel and a novel hormonal remedy. As we all know from earlier research, the prevalence of MMR deficiency in metastatic CRPC is estimated at 2% to five%. And testing for MSI excessive or DMMR may be carried out utilizing DNA testing or immunohistochemistry. Notably, if a tumor is MSI excessive or DMMR, the panel recommends referral for genetic counseling for consideration of germline testing for Lynch syndrome.
Now, once we look a little bit bit additional on the pembrolizumab story, in June 2020, the FDA granted accelerated approval for pembro’s use in sufferers with unresected or metastatic sufferers with a excessive tumor mutational burden. So that is one other indication that was accepted in 2020. That is amongst all stable tumors which have progressed following prior therapy and who haven’t any passable therapy choices. The part two KEYNOTE-158 trial included 790 sufferers. You may see the forms of cancers right here. Notably, no prostate most cancers sufferers, however we do see an goal response price of 29% within the tumor mutational burden excessive sufferers. The NCCN assertion based mostly on this KEYNOTE-158 trial is that, though there have been no sufferers with prostate most cancers on this research, the panel concludes that pembrolizumab is an choice for sufferers with mCRPC, prior docetaxel novel hormonal remedy, and a tumor mutational burden better than 10 mutations per megabase based mostly on extrapolation from different tumor varieties. So these are a number of of the vital updates. After all, this can be a small inhabitants amongst mCRPC sufferers, however notable within the NCCN updates for 2024.
So now let’s swap gears to speak about olaparib and rucaparib as most well-liked regimens following prior novel hormonal remedy, however no prior docetaxel for BRCA mutations. And this actually begins with olaparib within the PROfound trial. PROfound, as we all know, is a part three RCT of 380 CM CRPC sufferers with development on enzalutamide or abiraterone. These sufferers had been then randomized two to 1 to olaparib or the doctor selection of enzalutamide or abiraterone. What’s vital right here is there’s two separate cohorts. Cohort A had no less than one alteration in BRCA1, BRCA2, or ATM; and cohort B had alterations in another of 12’s pre-specified genes. As we will see on the Kaplan-Meier curves on the fitting, the first endpoint was imaging-based progression-free survival amongst cohort A sufferers. This was a median progression-free survival of seven.4 versus 3.6 months favoring the olaparib-treated arm. Hazard ratio statistically important at 0.34. And the secondary consequence on the time of the first evaluation was total survival 18.5 versus 15.1 months favoring olaparib.
After we have a look at a subsequent publication that appeared on the total survival profit in cohort A particularly, so that is simply the sufferers with BRCA 1/2 or ATM mutations, on the left we see the general survival in cohort A hazard ratio was 0.69, 19.1 months median survival for olaparib versus 14.7 months within the management arm. And once they did a crossover adjusted evaluation, that is adjusting for sufferers that obtained subsequent therapies, this total survival profit elevated to a hazard ratio of 0.42 favoring the olaparib arm in comparison with the management arm.
Why are BRCA 1/2 mutations solely advisable for olaparib? And actually the profit right here is just not seen in ATM. And so we see that on this subgroup evaluation of imaging-based progression-free survival, we see that the profit for BRCA actually is pushed by BRCA2, hazard ratio of 0.21, very tight confidence interval. We additionally see a hazard ratio of 0.41 for BRCA1. The statistical significance is possibly topic right here with the vast confidence interval. However actually the take-home right here is that ATM reveals no profit, hazard ratio of 1.04, confidence interval of 0.61 to 1.87.
Let’s swap gears to speak about rucaparib. That is based mostly on the TRITON3 trial, which was printed in 2023. And that is taking a look at rucaparib after development on an ARPI. Once more, a part three trial of 405 mCRPC sufferers with BRCA1/2 or ATM mutations, once more, randomized two to 1 to rucaparib or the doctor selection of docetaxel or the alternate ARPI. The Kaplan-Meier curves on the fitting present the first and secondary outcomes. That is imaging-based progression-free survival. For the BRCA subgroup, that is on the high Kaplan-Meier curve, we see imaging-based PFS of 11.2 months versus 6.4 months favoring the rucaparib arm, hazard ratio of 0.50. And the intention to deal with inhabitants, once more favoring rucaparib as we see on this Kaplan-Meier curve, per imaging-based progression-free survival median of 10.2 months versus 6.4 months with a hazard ratio of 0.61. Once more, we see no profit within the ATM group, basically overlapping Kaplan-Meier curve hazard ratio of 0.95.
After we have a look at the general survival information, the maturity on the preliminary publication was fairly low, nonetheless at 54% to 59%. Within the BRCA subgroup on the high right here we see 24.3 months versus 20.8 months, hazard ratio of 0.81 within the BRCA subgroup. And once more, no shock, zero profit for total survival within the ATM subgroup with a hazard ratio of 1.20 and practically similar median total survival.
To summarize this replace of the NCCN, particularly for mCRPC sufferers, this replace reveals that pembrolizumab for MSI excessive DMMR tumors was added as helpful in sure circumstances for sufferers with no prior docetaxel and no prior NHT. These sufferers with development on prior docetaxel and no prior novel hormonal remedy, in addition to for development on prior novel hormonal remedy and no prior docetaxel. And these had been added as a class 2B suggestion.
After we look particularly on the development on prior NHT and no prior docetaxel, most well-liked regimens had been added for olaparib for BRCA mutation class one, in addition to rucaparib for BRCA mutation, additionally a class one. As Rashid talked about already, helpful in sure circumstances, the routine has been modified to now not have olaparib for HRR mutations aside from BRCA1/2, so it is now not a class one suggestion. And the routine was eliminated for rucaparib for BRCA mutation. Different advisable regimens eliminated: abiraterone, abiraterone plus dexamethasone in addition to enzalutamide. So that is the ARPI swap, which is now not advisable. And eventually, development on prior docetaxel and prior novel hormonal remedy, regimens eliminated, once more, highlighting that the ARPI swap to abiraterone or enzalutamide is now not advisable. We thanks very a lot to your consideration and we hope you loved this NCCN replace of the mCRPC therapy tips.
