So next is uh Doctor Anari. Uh she's our prostate cancer guru. Uh She sees patients both at Fox Chase and East Norton. And uh she's gonna talk about uh updates and prostate cancer, advanced prostate cancer over the last year or two. All right. So today we're gonna talk about um updates really of FDA approvals over the last year. I have no disclosures. Um So we're gonna review all the data um for these approvals. So, first of all, we're gonna start by talking about parts and you can't talk about parp inhibitors without talking about genetic testing. Um The reason why we test is 12% of the time regardless of family history, someone's gonna have a germline genetic mutation that made them more likely to get prostate cancer. This is prognostic. We know that people with BRC A mutations are going to have uh poorer outcomes, they present with more advanced disease at younger ages. It's predictive also because of uh parp inhibitor eligibility helps guide family member testing. Um and screening for other malignancies. I think about testing in men with um high risk, very high risk prostate cancer, but also especially in the metastatic setting when it really impacts our treatment decision making. Something else to consider is that aside from germline genetic testing, we should also be thinking about somatic testing, especially because um these DNA damage repair mutations can develop over time at the time of progression. Um So getting somatic testing is also important along the way. So before 2023 and 2020 we had the approvals of root cap rib and olaparib, olaparib had a more um broad label. It was open to all Hr R or homologous recombination repair gene mutated hormone resistant prostate cancer. Um and it was available prechemotherapy. So I'm gonna talk about the triton three study first, um which looked at Ru Capri versus physicians choice, which notably was either chemotherapy or um a novel hormonal agent like Abby Aone or enzalutamide. Uh This was a phase three trial looking at hormone resistant prostate cancer patients with a BRC A 12 or ATM mutation. They were randomized 2 to 1 to receive Ru Kib versus again, physicians choice. And the primary endpoint was radiographic progression free survival and then secondary endpoint was overall survival. Important to note this trial allowed for a crossover to rue Capri. So these are the baseline um characteristics. I think what's important to note here. Uh One, this was largely a study of uh Caucasian men, African American men were largely underrepresented. Uh The breakdown of mutations BRC A two was the most common at around 65%. And then ATM and then BRC A, one mutations were represented uh about 20 to 23% of men had, had dose of Taxol in the hormone sensitive setting. And then on the trial physicians, choice over half of the people um and the control group were in uh were given dosa. So this study met its uh primary end point of improvement in radiographic progression free survival in the BRC A subgroup. Uh medium progression free survival is 11.2 months in the P inhibitor versus the control group, which was 6.4 months in the intent to treat population, which was BRC A 12. And ATM, you can see a very similar um uh median RPFS amongst RU Capra versus physicians choice. When you look at the ATM subgroup, you can see that the uh benefit really is not there in the root kib group. The hazard ratio is 0.95. And when you look at that compared to the BRC A subgroup, um you can tell that the BRC A subgroup is really what's driving the, the benefit here, they also broke it down by which group uh which uh treatment they got in the subgroup. So either dosa Taxol on the left or a second generation novel hormonal agent on the right. And you can see here that the benefit remained uh that root cap rib, um improved radiographic progression free survival in both. Um in terms of overall survival. Uh The data was not mature. Um But they, the authors note that there is a trend towards overall survival benefit. Um But this was not statistically significant. I think safety when talking about parp inhibitors is probably the most important thing to consider. Um The parp inhibitor subgroup had more dose interruptions, had more discontinuations, had more dose reductions than the uh physicians choice of chemo or novel hormonal agent. And notably about 30% of people in the recap arm required at least one blood transfusion uh while on trial. So here the conclusions are, this study did meet its primary end point of improving radiographic progression free survival. Um The benefit was really driven by the BRC A altered patients. Um What I think is also important from this study is this was the first demonstration of A P inhibitor, improving progression free survival over taxing chemotherapy. Um And again, anemia was one of the most significant side effects that we saw. Next. We're gonna go over um three phase three trials um that looked at first line parp inhibitors with an A R inhibitor again in hormone in the hormone resistant space. Um This led to three approvals this year. The magnitude trial led to the approval of Nera with Aber um propelled, led to a Laib plus AONE being approved. And the telop pro two study uh also led to Tali and Enzalutamide being approved. There's some rationale for cot targeting of uh androgen receptor signaling and P inhibitors. It's felt that there's some synergy between the two medications. So, first we're gonna talk about the propelled trial that was a phase three trial um in first line hormone resistant prostate cancer. Notably, there was no prior Aaron and this trial was not for men who had progressed on a novel hormonal agent. They had to have stopped it for over a year prior to starting. Um, DOCEtaxel was allowed in the hormone sensitive space and men were randomized 1 to 1 to get aone with olaparib versus aone uh plus placebo and primary end point for all of these studies, you'll see is radiographic progression free survival with OS uh or overall survival being a secondary end point. And the propelled trial met its primary endpoint of improvement in radiographic progression free survival. Um with an 8.2 month overall improvement in the Aber aeron Alaa group versus Aber Aon plus placebo. The final OS. Um there was about a 7.4 month overall improvement with the combination arm being 42.1 months of median OS versus uh 34.7 months in the Aber Ader and placebo arm. I think we need to break this down a little bit more to see who was benefiting. And you can see here we'll go, I'll show you the Kaplan Meier curves, but it's really the hormone or I'm sorry, the homologous recombination repair mutated patients. Um And BRC A mutated patients have benefited the most. So here you can see on the top is overall survival and those with any um HR R mutation. And you can see here, the blue line up top is Aber aone plus a lap rib. The OS, the median O SS was not reached as opposed to Aber with placebo was 28.5 months. And then in those without the HR mutation, uh the curves really don't split very much. This is the most impressive uh subgroup to me is if you look at the top, that's the BRC A mutated subgroup. And here you can see the curves uh split apart and stay apart. And the hazard ratio here was 0.29. Um in the non BRC mutated subgroup, the hazard ratio is only 0.91. And you can see those, those curves are really hugging. Again, you're gonna hear this throughout this talk, but the most common adverse effect really is anemia. Um that makes the aero plus a laper group stand out. Uh 16.1% had grade three anemia, meaning a hemoglobin of eight or less. Well on trial. And notably, this trial had the highest incidence of pulmonary embolism is around 7% in the combination arm versus uh 2% in the apparat arm. So here you can see that there is an overall survival trend. Um It improved OS by 7.4 months. The largest uh benefit really was seen in these BRC A mutated patients. Um One of the limitations of this study is it didn't enroll people that had uh previous uh novel hormonal agent pre MC R PC. Um And this led to the FDA approval in the BRC A mutated hormone resistant prostate cancer patient population. Next, we're gonna go into data behind uh Talas Opera with Enzalutamide. This is the Tip pro two study um at the ASCO meeting, they went through uh data for the hr deficient population which we'll delve into now. So a little bit about this study again, first line MC R PC men were randomized to receive either talli opera with Enzalutamide or Placebo with Enzalutamide. Um What's important to note here is that they were allowed prior Aber Aone or dosa Taxol uh to be given previously primary and point the same radiographic progression free survival. Right now, we're gonna talk about really cohort two. That's the hr mutated uh patient population. Um The all comers cohort one had been uh previously reported out uh here, what's important to know uh The baseline characteristics were pretty balanced. Um You know, they said that prior aone was allowed only 8% of men um had prior AONE in each group and about a third of patients had prior dose of Taxol. And here you can see this is a breakdown of what gene alterations they looked at BRCABRC A two is the most common followed by ATM CD K 12 check two BRC A one and then a slew of others. And you can see here that in the hr deficient uh population, the study also met its primary end point of radiographic progression free survival uh with a hazard ratio of 0.45. Um When you look at the breakdown of who benefited in the subgroups, um you can see that regardless of prior Avara dosa Taxol, the hazard ratio also hovered right around um the uh all comers group. So it was 0.43 versus 0.46. And really the BRC A alteration. Yes, first, no, those who had a BRC A uh mutation uh benefited the most with the hazard ratio of 0.2. Um in the non BRC A altered patients. Uh The benefit was a little bit more modest of the hazard ratio of 0.68. Um This slide really, it's, it's a little bit busy. But what this shows you is that the BRC A patients uh benefited patients with pal B two and CD K 12 also seemed to benefit whereas patients with ATM and CHECK two really did not have as much of a benefit here. Um They reported out on overall survival again, uh it's not mature, but the, the authors say that there is a trend towards overall survival, the breakdown in the hr deficient group. So this cohort two was actually pretty similar to cohort one, in terms of response rates, response rates were a little bit higher in this group. It was 67% in the all comers or cohort one. it was 60%. Um, so not a large difference there but seemed to have higher response rates. If they had an hr mutation, I'm sounding like a little bit of a broken record, but most common side effect here really was anemia. Um, the pe side effects here were actually pretty balanced in the two groups. Um and fatigue was common among both. So here, uh the conclusions of Telop pro two where it met its primary end point of RPFS, the benefit was greatest in PR C A altered patients. Um And what's important to note here is that patients who received prior aone or dosa Taxol uh tended to have a similar benefit. We're gonna touch very briefly on the magnitude trial. Um This is what got the FDA approval for nap and A atone and BRC A mutated patients. So there was an update also at ESMO 2023. Not as exciting as what ben pre uh presented in bladder cancer, but this was a trial looking at first line hormone resistant prostate cancer. Uh men were allowed prior toxin based chemotherapy prior A R pathway inhibitor in either the M zero CR PC space or castrate sensitive space. Um and they were also allowed to start on trial after they had been on AONE for four months to allow for genetic testing results to come in. Um They really reported out on the HR R mutated patient group because cohort two, which was hr negative um and closed early for futility. So this trial um met its uh primary endpoint of radiographic progression free survival benefit. Um That benefit was more pronounced as you can imagine in the BRC A mutated group. And then the overall survival again, there was a trend towards overall survival, but this was not statistically significant. So the conclusions here is that OS was favored, um there were no new safety signals, we didn't go into all of that, but it's very similar to what had been presented for the other part, inhibitor combinations. And this led to the approval of neurapain Alvarado on predniSONE and BRC A mutated hormone resistant prostate cancer. We're gonna switch gears a little bit and talk about the embark trial. Last. Uh This was a phase three trial that looked at enzalutamide and the biochemically recurrent uh prostate cancer space. So it's important that we have some new data in this space because there's really no level one evidence um for how we manage the biochemical recurrent setting. Um There was a trial long ago looking at intermittent ad T versus continuous AD T and intermittent ad T was non inferior, had better um quality of life outcomes. So that's what we often use. I think it's also important to note that in this space that this space is really shrinking. We have PS ma pet scans. We're catching much more metastatic disease than we ever did before with conventional imaging. So this is the study schema for the embark trial. So patients that were eligible for this trial had a PS A doubling time of nine months or less. Um there if they had radical prostatectomy in the past PS A had to be at least one if they had prior definitive radiation therapy, then the PS A had to be two above the nar um CT and bone scan had to be negative. PS ma pe T scans were not used in this trial. They were allowed prior hormonal therapy in different settings, whether it was the salvage or definitive setting. Um but it had to be uh completed at least nine months prior to joining the trial. These men uh were randomized either enzalutamide with Lupper Light or AD T placebo with AD T or enzalutamide monotherapy. At 36 weeks, the PS A was assessed and then they were allowed to stop therapy. If at that point, the PS A was undetectable, which they defined as less than 0.2. If it was not less than 0.2 then men remained on treatment. And the primary end point here was metastasis free survival comparing the 1st and 2nd arms, which is enzalutamide plus AD T versus AD T alone. And then secondary endpoint was metastasis free survival in the enzo monotherapy versus AD T. Uh This treatment is what we largely talked about um on the prior side. So, study population highlights very similarly to the other studies. Median age was just about 70. Majority of the men were caucasian. Uh median PS A doubling time was five months. Uh It was balanced in both, in that 20%. Each arm had a PS A doubling time of less than or equal to three months. Median PS A was 5.2. 30% of the patients had received prior AD T and about 50% had had uh both prior radical prostatectomy and radiation therapy. So this study had a five year metastasis, free survival um benefit. And you can see here in the Enzalutamide containing arms. So the five year mfs for AD T and Enzalutamide was 87%. Um for Enzalutamide was 80% and for AD T was 71.4%. The top Kaplan Meier Curves is AD T Enza versus AD T alone. And you can see there was a statistically significant benefit with a hazard ratio of 0.42. Um And then on the bottom Kaplan Meier Curves, it's enzalutamide monotherapy versus AD T I mean, you can see also a statistically significant benefit here with a hazard ratio of 0.63. Uh This trial, um some of the secondary endpoints were freedom from PS A progression at five years. You can see the greatest benefit was in AD T plus Enzalutamide at 97% but Enzalutamide was also about 89% versus AD T alone, which was 70%. Um I want to bring your attention to five year overall survival. You can see that what I highlight here is the this patient population does remarkably well really regardless of which treatment you ultimately decide to put them on. Um And right about 90% of all of these men are alive at five years. I think adverse events is something really important to note when thinking about these treatment options. Um, hot flashes were much more common in any of the arms that contained ad T. Um but the enzalutamide monotherapy in particular had increased gynecomastia, nipple pain, breast tenderness. Um What's not noted here when you look at some of the surveys of quality of life data, um it seemed to favor enzalutamide monotherapy for sexual function. This is the data for 36 weeks. Um 90.9% of men in the combination arm had an undetectable PS A. Um 86% of men in the enzalutamide monotherapy and undetectable PS A and in the looper Light alone arm, it was about 68%. And as you would expect that the median duration of treatment suspension, meaning off of therapy was highest in the combination arm and shortest in the enzalutamide monotherapy arm. That's mainly because in enzalutamide monotherapy, you're not su suppressing the testosterone, you're just blocking it. So as soon as you take away that agent testosterone is in the body to fuel those prostate cancer cells. This here is just another um figure to show in the green above is enzalutamide monotherapy and these are testosterone levels. Um and you can see that the testosterone levels were clearly higher in the enzalutamide arm monotherapy arm. So, conclusions from this trial, metastasis free uh survival was significantly improved in the combination arm but also in the enzalutamide monotherapy arm. Um monotherapy, also the enzalutamide monotherapy also improved time to ps A progression and time to first um chemotherapy. So just a few weeks ago, the FDA approved enzalutamide with or without ad T for high risk men with biochemical recurrence. So I think take home points from all of these talks over the last year. You know, how does this change what we do in clinic tomorrow? I think it's clear that all men with advanced prostate cancer need to have genetic testing, both germline and somatic testing. Um There's clearly a radiographic progression free survival benefit and people with hormone resistant prostate cancer who get parp inhibitor with a novel hormonal agent. Um My take home message here is that the biggest benefit is in this BRC A mutated men um followed by other hr mutations, then all comers than men without these mutations. Um I think when thinking about who's eligible for these, I think this population is also shrinking. The field is evolving so quickly that with the advent of triple therapy and most men getting um a novel hormonal agent in the hormone sensitive space. And now we have enzalutamide in the um in the biochemically recurrent space. I just think that the field is moving faster than these studies can ultimately be reported out. So I think it's gonna be a special patient who's gonna be eligible for this. Um Either someone who got AD T plus dosa Taxol from the old charted data um or someone who's on AD T alone for whatever reason. I think also in the biochemical recurrent setting, I think we have a much bigger discussion now to have with our patients now that we have enzalutamide available. I think what we found is that in the field in general, moving our most effective treatments up earlier in the disease course um has been shown to improve outcomes. Um And I think this is just another example of, of that. Thank you.