The Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute presents a succinct summary of all the prostate cancer clinical updates you need to know from ESMO 2024.
Thank you everyone for joining us for the Ge Oncology Asmo conference highlights. My name is Vincent Xu at Dana Farber Cancer Institute and in our Medical Oncology, Geo oncology review, I'm joined by our three panelists, Doctor T Choudary, Doctor Joaquim Belmont and Doctor Tony Shri. And we'll be giving updates today on prostate cancer, bladder cancer and kidney cancer. So ill get started. We're gonna start this session of the emo review with our prostate cancer updates. It was really an action packed uh conference for GEO cancer in general and also for prostate cancer. Specifically looking at prostate cancer. We have several practice changing new trials. First, we know that Enzalutamide plus radium +223 improves overall survival in metastatic castro resistant prostate cancer and is a new standard of care in this setting. We learned that deride plus AD T is superior to AD T in hormone sensitive prostate cancer and therefore, deride joins our other A RS sides of this setting, including Aber aro utom and apalutamide. We also have data showing that transdermal estradiol is non inferior to traditional AD T and is a new alternative way to administer AD T with A different toxicity profile and we have several other interesting updates to share. Let's start with, I think what is arguably the biggest prostate trial from this uh from this year's as well. Piece three. This is a randomized multi center open label phase three trial comparing enzalutamide versus a combination of radium 223 and enzalutamide uh in asymptomatic or mildly symptomatic patients with bone metastases and castration resistant prostate cancer. We know from prior trials that enzalutamide and other A RPIS improve progression free survival and overall survival in CR PC. We also know from prior trials that radium 223 improves overall survival in MC R PC. This trial piece three investigated whether the combination improves outcomes compared to enzalutamide alone. The patients were enrolled with MC R PC and bone metastases and no known visceral metastases. Patients were randomized to either enzalutamide standard of care or radium plus enzalutamide bone protecting agents. Mostly denosumab, but including zoledronate were mandatory and this was added in a protocol amendment after the 1st 119 patients, I want to point out that this trial was largely done in the uh in the setting of A RPIS, not yet widely used in the hormone sensitive setting. So looking at the baseline characteristics, only 2% of patients received prior aaton and 30% of patients received prior dose Taxol. Otherwise, this is AC R PC patient population and about half of patients uh had less than 10 metastases in the bone and the other 42% had more. The primary endpoint was radiographic progression free survival. Enzalutamide plus radium was superior to enzalutamide in this setting with a hazard ratio of 0.69 and a highly significant log rank P value improvement with the combination arm was seen across all subgroups with enzalutamide plus radium. Um being better compared to enzalutamide. Similar findings were seen for overall survival. Again, the combination arm with radium plus Enza was superior with a hazard ratio of 0.69. And this actually did meet the statistical threshold for the P value of being statistically significant. Looking at the other uh key end points, there was no difference in time to pain progression or symptomatic skeletal events in the two arms. And this is a little bit reassuring because in the prior studies, the combination of radium plus AONE was felt to be associated with a high rate of bone fractures from prostate cancer. And so it looks like the bone protective agents are really um helping to prevent that. In this trial, radium was generally well tolerated. And most of the increased AES from the Enza plus radium arm were in fact, cytopenia consistent with the prior radium data. In summary piece, three shows that enzalutamide plus radium improves RPFS and OS in bone predominant MC R PC. On the one hand, this is practice changing data and patients who have not previously had an A RSI and have CR PC certainly should be considered for Enza plus radium. However, this trial was designed quite a while ago and took a while to enroll. And in the time since this trial was designed, most patients are now receiving a RSI S in the hormone sensitive setting. So the underlying patient population for this trial is getting smaller and smaller patients on the trial must receive bone protective agents and so must be emphasized that all patients should be getting denosumab or zoledronate. This trial really leaves open the question of whether this approach is appropriate in patients who got a lateral in the hormone sensitive setting. So patients who are getting aaton either on high risk prostate cancer per stampede or in the metastatic hormone sensitive setting and have progression. We don't really know whether those patients are gonna be beneficiaries of combination therapy with UTOM plus radio since only 2% of the patients on this trial fell into that category. Next, we have a second, potentially practice changing trial. This is the efficacy and safety of deride plus AD T in patients with metastatic hormone sensitive prostate cancer error note, we already know from the era sense randomized trial that combination therapy with the triplet DOCEtaxel AD T and Dalam is superior to DOCEtaxel plus AD T. However, we don't have data yet from a large randomized trial for whether Dalam plus AD T without dosel is better than AD T alone. This trial seeks to fulfill that knowledge gap patients were enrolled with first line hormone sensitive prostate cancer, metastatic and randomized 2 to 1 to deride plus A T versus placebo plus A T. The primary endpoint was radiographic progression free survival. The baseline characteristics are notable for this being an international trial. This trial largely accrued in countries where first line A RSI was not widely available. Hence, randomizing patients to placebo plus AD T, which would not be considered a standard of care. Today, in the United States, there was a large representation of Asian and Black patients and 71% of the patients had the noble metastases and 71% of patients as well had high volume disease. This trial met its primary end point. Dalam significantly reduced the risk of RPFS by 46% with a 24 month RPFS of 70% versus 52% has a ratio of 0.54 at a significant P value. What was really quite impressive was the toxicity from this trial and deride consistent with prior trials was a very well tolerated drug. And I want to point out especially that fatigue, the incidence of fatigue was actually lower in the combination arm compared to the placebo arm. Similarly, treatment emergent adverse events leading to this continuation of the drug was actually more common for placebo compared to deral. Again, pointing out that deride is quite tolerated. Their UDOM also showed a benefit across secondary endpoints and this included time to ps a progression, time to castration, resistance time to initiation of subsequent therapy, as well as time to pain and progression. In summary error note shows that deride plus AD T improved radiographic progression free survival and secondary endpoints compared to AD T alone. The overall survival from this data uh remains immature. This data supports the use of diamide plus ad T as a potential option in the first line hormone sensitive setting. And given that we know that deride has less cns penetration compared to other A RSI S like for example, enzalutamide. This could be an option for patients who don't tolerate enzalutamide or apalutamide. Next, we have another phase three trial. This trial investigated the use of transdermal estradiol versus conventional L hr H agonist for androgen suppression in non metastatic prostate cancer. We know from prior studies that transdermal estrogen can be a way to lower testosterone. The potential advantage of transdermal estrogen is that it avoids some of the common side effects of L hr H agonist. For example, with transdermal estrogen, there is lower risk of osteoporosis, fewer metabolic side effects and less incidence of hot flashes. However, this trial investigated whether efficacy is comparable for transdermal estrogen compared to L hr H agonists such as Lupron and this was a non inferiority. MFS endpoint. This trial met its MFS primary endpoint hazard ratio was 0.96 not different between the two arms uh numerically in favor of estrogen and metastasis's free survival was similar between the two Arps. Overall survival was also essentially the same between the two arms. The hazard ratio was numerically 0.89 in favor of estrogen castration rates defined by low testosterone were similar hot flashes, not surprisingly were less common among patients receiving estrogen. However, also not surprisingly, gynecomastia was much more common in patients receiving transdermal estrogen. In summary, this phase three trial met its noninferiority endpoint for MFS and supports the use of transdermal estrogen in M zero prostate cancer as an alternative to conventional L hr H agonist. The selection of one versus the other is gonna come down to side effects for most patients, transdermal estrogen is a good option for patients who have intolerable hot flashes concerns about bone density or metabolic toxicity. However, there is a significantly higher risk of gynecomastia and patients need to be counseled about this. We have some more interesting data in prostate cancer. This with a pure immunotherapy regimen. In this trial, patients were evaluated and treated with nivolumab plus eliab. In molecularly selected patients with CR PC. The inspire study enrolled patients who were selected for several biomarkers that were thought to potentially enrich for response to immunotherapy. This included CR PC patients who are mmr deficient or M si high with high TMB with BIC CD K 12 loss or BRC A two mutated patients were treated with I bel followed by naval A maintenance and the primary end point was disease control rate. The efficacy endpoint was notable for really a quite nice response rate in the Mmr deficient subgroup response rates were less impressive in the other uh categories such as TMB, high CD K, 12 bic loss or BRC A two mutated. There was a 75% response rate in the deficient mmr population. There were no CRS uh but there was a high pr rate and a disease control rate of 81%. The median PFS among Mmr deficient patients was 33 months, which is really quite impressive for MC R PC. Looking at the efficacy, endpoints clearly PFS and OS were much better in the Mmr deficient patients compared to the other subgroups. The PS A 90 response rate was 86%. Um in Mmr deficient patients again much less in the other cohorts. How does this compare with other data? We know from prior real world data that patients with Mmr deficiency can respond to PD one inhibitors with response rates in the 55 to 60% range. Um In this nice slide from Doctor Sweeney's discussion in summary, IPIL had a high response rate in patients with Mmr deficient MC R PC. 75% overall response rate, 86% PS A 90 rate and a medium pfs of 33 months responses were much more limited in the TMB high CD K 12 by loss and BRC A subgroups. This data supports the use of IIL in patients with mmr deficiency. However, it remains unclear in the lack of a comparator arm, whether IVO is better than PD one inhibitors alone, which also have activity in this setting. Next, we have a new radio yy based therapy. This is the splash trial which investigated 177 luteum PNT 2002 in PS MA positive MC R PC in patients who have progressed on prior androgen receptor pathway inhibitors. This is a new radio liga. However, structurally, I would argue that it has more similarities than differences compared to lutetium pluvial PS ma 617, which is the molecule that we're all familiar with at is FDA approved. These molecules have an identical PS MA binding mo and there are some biochemical differences with a bit more polar molecule for this new molecule and additional IODIDE that could allow for dual labeling in the splash study design. Patients who had progressed on A RP I with CR PC were randomized to this new luteum conjugate versus the alternative A RP I. So the control arm here was a hormone switch. Patients were allowed to cross over after read graphic progression to the treatment arm. In the primary analysis, radiographic PFS was superior for the radio ligand compared to alternative A RP I with a hazard ratio of 0.71 and A P value of less than 0.01 at the intention of treat analysis. The first interim Os showed no significant difference with a hazard ratio of 1.1 and a P value of 0.6. Uh Keeping in mind that crossover was allowed. This study is interesting in the context of PS MA four. There is a similar patient population in PS MA four. The radiographic PFS hazard ratio is 0.71 here versus 0.4 for PS MA four. However, this had a longer interval between doses uh with eight weeks between doses of this radio liga and a fewer number of total uh dose intensity. So it remains to be seen where this radio L gun will fit relative to the existing approval for Ishia PS MA 617. Next, we have some updated data including the overall survival analysis and the final results from contact two. Contact two was a randomized trial that investigated cabozantinib plus a tazo lium among patients with MC R PC. Compared to hormone switch. We know from prior uh reports that contact two was positive for its PFS primary endpoint. In this report, we have the final analysis of the other primary end point which is OS PFS continues to be superior in the I TT population with a hazard ratio of 0.65. Uh and performing particularly well among patients with liver metastases with a hazard ratio of 0.4. However, overall survival was not significantly different. It remains to be seen a little bit where Kozan by the Tas Aiza fits in in the CR PC landscape with the lack of an os benefit and it's not entirely clear as well. Um whether this is mostly from Kabal Zany and whether Taz Ali really adds much to this combination. Next, we have a very interesting study from Stampede where patients were adding Metformin to AD T among patients with metastatic hormone sensitive prostate cancer. We're all familiar with the Stampede platform. This part of Stampede is investigating patients with metastatic hormone sensitive prostate cancer, no treatment for diabetes, normal hemoglobin A one C randomized to either standard of care or standard of care plus Metformin. And it's important to point out that at the time this trial was designed, most patients in the standard of care arm received AD T plus Dota. In other words, first line A RSI S were not yet common. At the time the study was accruing. The primary endpoint was overall survival and secondary endpoints are are as shown. This study did not meet its primary endpoint. Overall survival was not significantly better in the Metformin plus standard of care arm with a hazard ratio of 0.91. However, looking at the subgroup analysis, there was better overall survival among patients with high volume disease with a hazard ratio of 0.79 and A P value of uh 0.006. This is intriguing data. The overall study was negative. This subgroup was not a prep powered subgroup although it was a preplanned subgroup. And it's interesting hypothesis generating data. I don't think this data is strong enough to recommend giving Metformin to all our patients who don't have diabetes. But it certainly, I think supports the use of Metformin in patients who have an indication for Metformin, knowing that there might be some signal for longer overall survival in the high volume patients also remains to be seen how this data extrapolates to the current era where most patients are getting a RSI S as a bonus. We have a bit of data that's not actually from ESMO, but came out between ESMO right now. But I think it's important that practice informing, we often get asked from patients about trying to decide between protons versus IM RT. Um We have this data that was presented from Doctor Facio and colleagues at Astral. In this trial. Patients were randomized to either proton beam therapy or IM RT. There were no significant differences in cancer control or health related quality of life, whether it was bowel or urinary or sexual function between the two arms. So I think this is useful data for counseling our patients who are considering these two different radiation modalities. And with that, I'm gonna pass the baton over to Doctor Choudhry to give some insights into this data. Well, uh you already gave excellent insights along the way. So um now I have to remember what all the studies were. So just starting with piece three. I was surprised by this result because there was really absolutely no signal for benefit from radium 223 when combined with Aber Aone and the R A 223 study. In fact, the overall survival was worse. And so the fact that the overall sur was improved by seven point something months is just something that we don't see in the CR PC space. And so, um as you mentioned, this did included a very small minority of patients who progressed on prior aone. But if you have a patient who you think is a candidate for um a hormone switch kind of anyway, which is something that we sometimes do in practice for the people who don't have visceral mets or um bulky disease. Um It's hard to um make very strong arguments as to why you shouldn't give the radium 223 with the olamide because it's a relatively well tolerated drug. The myeloid suppression was sort of modest, which is what we see in our standard practice. And there are additional studies that suggest that giving radium prior to luteum doesn't seem to um increase the likelihood of myelin suppression with the luteum. So it's a safe well tolerated drug. And I think that it really does change my um practice pattern in those patients where I'm considering an A RP I switch. Uh The AONO trial was uh again, just consistent with uh the other trials that were done in the space with titan and arches, it doesn't yet meet uh an overall survival endpoint, but the tolerability is favorable. And we know when comparison comparing um aramis, which is the trial in nonmetastatic cr PC to prosper and spartan um that the survival was the same in those particular settings. So I think that it's not um very unreasonable to consider um deride in this particular setting. And uh even without the OS data quite yet, um knowing that it's a very well tolerated drug uh looking at uh the transfer estrogen, it's not something that I've tried yet. I think certainly the gynecomastia is a concern and certainly a concern for many of my patients when they start. Ad T but I think that the other favorable end points like the um osteoporosis, um less osteoporosis, less hot flashes is compelling. So it really is dependent on what the patient's particular perspectives and uh desires are. Um splash, I feel like didn't really add much in terms of the um PS ma int the activity seemed maybe not quite as good as the uh Pluto the um 17 lutricia, 177 PS ma 617. So, um we'll see if it uh gets granted an approval based on this data, but it's hard to make any arguments of why we would choose this over Plato um based on the data that we see the Cabo Tizo study. Uh It's and also a splash, the Comparator arm was kind of a suboptimal comparator. Um They seem to show some benefit in the patients with liver metastases um compared to the A RP I switch, but we know that A RP I switch has essentially no activity in patients with liver metastases. So again, it's just hard to know what to make of that and how to use that data moving forward. And in terms of the uh protons not being better than photons. I think that's reassuring to all of us uh who would say, tell people that in clinic but not really know for sure until we had this randomized data. So congratulations to the authors um for putting that all together and uh getting the data that the elderly needed. Did I miss anything that did you have for the patient that have bone metastases deriving benefit from Anza? Would you add radio? That's what you have. So I've done that and I feel like that has been helpful in terms of time to chemotherapy and more to treatment because it, and radium is generally well tolerated. I would say that this data does not give any rationale for uh doing that for our patients. So I would say that what I used to do is switch to Enza and add the radium at the time of rising PS A. But I would argue that this data makes it much more compelling to add the radium at the same time as you switch to Enza, um Carrie asked the question, are you concerned about radium limiting lutetium later in the patient's course. So again, um there was a trial, um there was a name like Rau or something where they compared the patients who got luteum, um whether or not they had prior radium and there just didn't seem to be a difference in the rates of myelin suppression and granted it might be a selected population of uh patients who, um, were able to get both. Um, but at the same time, I haven't seen big problems in my patients either oftentimes because at the time that they're switching from the Alvarado intens salut amide, um, they're relatively, uh, their bone marrow is relatively intact and I just don't see in my patients a ton of myelosuppression and in the trial again, the, the rates weren't anything too outrageous. Thank you, Doctor Cry for those, uh, for those, for those insights.
