Understanding the PNT2002 Phase 3 SPLASH Trial Control Arm


Webinar hosted on August 18th, 2022 - Download Slides

Sherin Al-Safadi - Vice President, Medical Affairs (POINT Biopharma)
Good morning, good afternoon, and good evening everyone, my name is Sherin Al-Safadi and I'm Vice President of Medical Affairs at POINT Biopharma, and on behalf of the entire team at POINT, we're excited to welcome you today to our third educational webinar entitled Understanding the PNT2002 Phase 3 SPLASH Trial Control Arm. POINT is a public company, it's listed as PNT on the NASDAQ and as such, we have on this slide our legal customary forward looking statements as well as our medical ones.

So radioligand therapy is currently tracking to become the next revolutionary pillar of treatment in oncology, and at POINT we are very excited to be able to be leading the discovery and development of radiopharmaceuticals - next-generation radiopharmaceuticals - to be able to really advance this treatment to the forefront of oncology. And we're doing so in several ways.

We have currently an industry leading pipeline, so our SPLASH trial is currently in phase 3 and it's looking at our PNT2002 program in the advanced prostate cancer space. And we recently announced the launch of our FRONTIER study, which is our phase 1 study that’s evaluating our PNT2004 program, which is a pan-cancer program looking at a FAP-alpha inhibitor.

We own 100% of our manufacturing infrastructure, and that speaks volumes about our capabilities and competencies of being able to supply the rest of the world, North America and Europe, in a timely and efficient way. We have a highly experienced team, so our team brings collectively decades of experience in the radiopharmaceutical world from a drug manufacturing standpoint and a drug development standpoint, and we've come together to be able to hopefully achieve POINT's vision, which is to transform the lives of patients and their caregivers and loved ones and families that have been impacted or will be impacted by cancer.

So today's webinar is going to focus on three topics. We’re going to first provide an overview of the SPLASH trial design, including the lead-in phase, and then talk to you a little bit about hormone switches, why we've allowed for hormones switches, what is a hormone switch, or an ARPI switch, ARPI being an androgen receptor pathway inhibitor.

And then talk a little bit about control arm benchmarks. So why they're used in oncology, which control arm benchmarks we've selected, PROfound and IMbassador250 specifically, and a little bit more detail around the trial design for these control arm benchmarks.

And finally talk a little bit about what's happening in the real-world clinical setting. How are mCRPC patients currently being treated? What are these treatment patterns? What do they look like, and what are some sequencing considerations? This is a highly fragmented landscape, with alternating mechanisms of action that are currently approved. How are we taking these therapies and sequencing them in the most efficient way in order to ensure optimal outcomes for mCRPC patients?

I'm delighted to welcome our speakers today, our two guest speakers Dr. Kim Chi and Dr. Oliver Sartor, who are no strangers to the world of oncology. Dr. Kim Chi is currently serving as Vice President and Chief Medical Officer of the British Columbia Cancer Agency, or BCCA, out of Vancouver, Canada. And Dr. Oliver Sartor who is a Professor of Medicine and the Medical Director at the Tulane Cancer Center, the University of Tulane School of Medicine in New Orleans.

Dr. Chi is going to walk us through more details around the phase 3 SPLASH trial, but I'd like to redirect your attention to our lead-in cohort and provide you with an update here. So, if you recall the dosimetry findings for this 27-patient lead-in cohort were previously published this year, around the February timeframe, at the mid-winter SNMMI meeting. And I'm excited on behalf of POINT and the team, the entire team at POINT that's been involved, to announce that we are now going to be presenting the efficacy and the safety data from this 27-patient lead-in, albeit a limited follow up time due to requirements around submitting the data. So we're looking forward to presenting this at ESMO 2022 which we'll be taking place in Paris the second week of September.

We hope that you'll leave today's webinar with a better understanding of the rationale behind ARPI switches that commonly happen in the mCRPC space, and more depth and context around our control arm benchmark studies PROfound and IMbassador250. And hopefully that provides you with more clarity around what radiographic progression-free survival, or rPFS, looks like for mCRPC patients that undergo ARPI switches.

And last but not least, before I pass it on to Dr. Chi, we'd like to invite you to join us at our poster presentation. So this will take place on September 11th in person at ESMO in Paris. Otherwise, if you're unable to join in person, we encourage you to look up our e-poster, the number is 1400P, for you to get a better look at the efficacy and safety data from our lead-in cohort. So thank you very much, without further ado, I'll now pass it on to Dr. Chi, who's going to take you through the next portion of this webinar.

Dr. Kim Chi - Vice President and Chief Medical Officer (British Columbia Cancer Agency)
Hello, I am Dr. Kim Chi, I'm a medical oncologist with over twenty years of experience, specializing in the treatment and research of prostate cancer, and I'm pleased to be able to discuss today the study design of the SPLASH study.

As clinicians, beyond the usual staging systems, which characterize the extent of disease such as localized versus metastatic, we think of prostate cancer as a series of disease states. Prostate cancer is dependent on androgens, the main form of androgens being testosterone. Castration therapy, which is the suppression of testosterone in the body either by surgical or medical means, is the initial management of advanced prostate cancer. Virtually all patients will respond to the initial castration therapy, however, with time, the disease becomes resistant, and this is what we call castration resistant prostate cancer. This can occur within a few months, or within a few years, but ultimately the cancer will progress.

The treatment algorithm for advanced prostate cancer has rapidly evolved over the last decade. This figure is from our current treatment algorithm adopted in my province of British Columbia, Canada, and I show this not for the details, but to highlight that the use of next generation AR pathway inhibitors, or ARPIs, such as abiraterone acetate, enzalutamide, apalutamide, and darolutamide, figure promptly as the first line treatment of the disease for both castration sensitive, as well as castration resistant disease. Subsequent therapy options include chemotherapy with docetaxel and cabazitaxel, and the radioligand therapy radium-223.

However, despite evidence of improved survival with these next lines of therapy, they are only used in a minority of patients. This is population-based pharmacy data from my province of British Columbia, which has a single-payer, government-funded health system, where we can track all patients with cancer and their treatments. Looking over the past two-year period with the denominator of roughly 1,000 patients, although the vast majority of patients received a next-generation ARPI, only a minority of patients received subsequent therapy. The reason being is that patients with advanced prostate cancer are usually older and have comorbid illnesses, and there's a lack of perceived benefit from these more toxic therapy.

Hence, a common practice has been to switch AR pathway inhibitors after progression. There have been a number of retrospective studies demonstrating responses to this kind of therapeutic switch, but our group is the first to perform a prospective study, which was published in Lancet Oncology last year. What we showed is we looked at abiraterone versus enzalutamide, and then, at progression, patients were crossed over to receive the alternate therapy.

With first line treatment with either abiraterone or enzalutamide, there was a higher response rate with enzalutamide, although this was not that statistically significant and there was no difference in time to progression. However, what we did see with a ARPI switch is that patients who had received abiraterone and then subsequently received enzalutamide had a 34% PSA response rate; that is a 50% decline in the PSA from baseline.

Whereas for patients that received abiraterone as second line therapy, the response rate was only 4.3% percent, although a larger proportion of patients had more stable disease or had some decline in their PSA. This translated to a longer time to PSA progression with the second line enzalutamide of 3.5 months versus 1.7 months for second line abiraterone.

Putting it together, there was a difference between the sequence of abiraterone followed by enzalutamide, versus enzalutamide followed by abiraterone, and there was actually a trend for a little bit of longer overall survival for the abiraterone to enzalutamide switch.

This kind of data demonstrates, yes indeed, there are responses to second line AR pathway inhibitors, although they tend to be of brief duration. Nevertheless though, for patients that are relatively asymptomatic, or asymptomatic, and do not want to or are not candidates for a second line therapy, that switching AR pathway inhibitors can have some benefit of response to them.

Now, fortunately, we're continuing to make progress in treatment for metastatic, castration resistant prostate cancer and, as everyone knows, lutetium-177 PSMA-617 has demonstrated improved imaging-based progression-free survival, and overall survival patients in the VISION study, which recruited patients that had prior AR pathway inhibitor, as well as taxane chemotherapy. Many patients having had four lines of therapy.

So that does establish lutetium-177 PSMA-617 as a standard of care therapy for those patients at the right end of the spectrum, at the late stage of the disease. But clearly, we need something earlier than that for patients that had just failed AR pathway inhibitor, because many patients only receive the AR pathway inhibitors as their line of treatment for prostate cancer, and there is therefore a very big need for effective and tolerable options earlier in the disease course.

177-lutetium PNT2002 is a PSMA-targeted small molecule radioligand, it has been administered to over 600 patients in a variety of doses based on currently published reports, and responses have been shown with a PSA decline of greater than 50 % being observed in 35% - 65% of patients. In these studies, 177-lutetium PNT2002 has been well tolerated, with the most common observed adverse events to be mild and transient, including the expected side effects of xerostomia, fatigue, and myelosuppression.

In the phase 3 SPLASH trial, we're evaluating lutetium-177 PNT2002 in this phase 3 trial in patients that have only received AR pathway inhibitor. After a lead-in cohort, patients are randomized two to one to receive either lutetium-177 PNT2002, or the alternate hormone therapies of abiraterone or enzalutamide. Primary endpoint is radiographic progression, and then patients who have received the control arm treatment can go on to receive experimental arm treatment with the 177-lutetium PNT2002.

The key eligibility criteria are listed here. Males greater than 18 years of age that have progressive metastatic CRPC are eligible, they have to have disease progression based on rising PSA, soft tissue progression, or bone progression. They can only have prior treatment with one AR pathway inhibitor, but this could be either in the CSPC or CRPC setting, and they have to have a PSMA-PET scan that is positive as per central review. ECOG performance test has to be zero or one.

Exclusion criteria are that they cannot have had any prior cytotoxic chemotherapy for CRPC, they are allowed to have chemotherapy for CSPC, but the last dose has to be greater than one year prior to consent, and this is because docetaxel chemotherapy has been approved or is commonly used for patients with metastatic castration sensitive prostate cancer and usually given for six cycles, and this can be also given in combination with an AR pathway inhibitor.

Liver metastases, greater than one centimeter, are also excluded. A superscan on bone scan is excluded, patients that have CNS metastases are also excluded, and there cannot be any contra-indications to the use of a planned AR pathway inhibitor therapy.

The primary endpoint is radiologic or imaging-based progression-free survival, as assessed by blinded independent central review, using the RECIST criteria and the Prostate Cancer Working Group 3 criteria. This is standard for phase 3 trials and is an accepted FDA endpoint. It is an event-driven analysis, powered at 90% to test the alternative hypothesis of a hazard ratio of less than 0.66, at an alpha of 0.025.

A two to one randomization will be employed with a total of 260 patients in the experimental arm, and 130 patients in the control arm. The two to one randomization makes it very attractive for patients to accrue, as well as the crossover design. A sample size estimation is based on the primary endpoint of radiographic progression-free survival, otherwise also known as imaging-based progression-free survival, in total 257 radiographic progression-free survival events are required and provides a 90% power to test the alternative hypothesis of a hazard ratio of less than 0.66, at an alpha of 0.025. A hazard ratio corresponds to improvement in the median progression-free survival from 5 months for the control arm to 7.6 months with lutetium-177 PNT2002.

Typical secondary endpoints are included, including objective response rate, duration of response, overall survival, PSA response, biochemical (or PSA) progression-free survival, safety and tolerability.

The control arm assumptions are based on two phase 3 trials, the PROfound study and the IMbassador250 study. The PROfound study was the phase 3 study of olaparib versus enzalutamide or abiraterone acetate in men with mCRPC, and the IMbassador250 study was a study of atezolizumab in combination with enzalutamide in patients with mCRPC.

First, the olaparib study, which is the PROfound study, patients had mCRPC and had to have progressed on prior next-generation hormone therapy, that is abiraterone or enzalutamide, and they could have also had prior taxane chemotherapy. And they were randomized in two cohorts, either olaparib or physician’s choice of treatment based on usually a switch over to either enzalutamide or abiraterone. Note however, that patients could have received multiple lines of therapy with an AR pathway inhibitor as well as chemotherapy.

In fact, if we look at this, most patients had received either enzalutamide or abiraterone only, and about half the patients, or two thirds of patients, had received a prior taxane chemotherapy, including up to two lines of prior taxane chemotherapy. For the primary endpoint of imaging-based progression-free survival, looking at the entire cohort, the median time to progression-free survival in the control arm, that is the subsequent AR pathway inhibitor, was 3.5 months.

Now, it's important to note that this included patients with one or two lines of chemotherapy, so to understand how this compares and for a population like the SPLASH population which will be chemotherapy-naive, we have to delve down into the data a little bit. This is the data for patients with ATM mutation by prior taxane, and this is where we can get the hints of what the imaging-based progression-free survival for patients that are taxane-naive. Now, it's relatively small numbers, but, as you can see here, for both the patients on olaparib, as well as the control arm with no prior taxane, the median imaging-based progression-free survival was in the 5 months range, 5.3 months for olaparib, 5.7 months for control.

Moving on to the other study, IMbassador250, again, these were patients with mCRPC, they could only have progressed on abiraterone, but they could have also had prior taxane chemotherapy. They were then randomized to either atezolizumab plus enzalutamide, or enzalutamide, so basically, the AR pathway inhibitor switch.

These are the baseline characteristics just to show that again about half the patients had prior taxane chemotherapy.

The primary endpoint was overall survival, and there was no benefit, in fact there was a bit of a trend for worsening survival with atezolizumab plus enzalutamide, but this was not statistically significant.

But looking at the secondary endpoint of radiographic progression-free survival by taxane chemotherapy, for the patients that had no prior docetaxel and received enzalutamide, the median time to radiographic progression-free survival was 4.8 months. For the atezolizumab plus enzalutamide, this was 4.3 months. This is again, for patients without prior docetaxel, which would be very similar to the patient population being enrolled on to the SPLASH trial.

Looking at that enzalutamide activity after abiraterone, so again these are patients very similar to our study that we had done looking at the sequence in the switch, you see a time to PSA progression of about 3 months, which is very similar to what we had showed, but again, we do see responses, so this is why the switch does occur, because for patients that are asymptomatic and either don't have other treatment options or don't want those other treatment options such as chemotherapy or radium-223, it is a reasonable and a common practice for clinicians to prescribe a second line AR pathway inhibitor.

So, to summarize, there is a need for tolerable and effective therapies post AR pathway inhibitors in taxane-naive patients with metastatic CRPC. AR pathway inhibitors are the primary first line therapy for advanced prostate cancer and widely used. Use of subsequent chemotherapy and radium-223 is historically much lower across jurisdictions. Despite the lack of evidence of a benefit, switching an AR pathway inhibitor is commonly performed. There are responses described in prospective studies with a median radiographic progression-free survival in taxane-naive populations being about four to five months, which is what we have established in the SPLASH study for the control arm. Treatment is well tolerated and is reasonable in patients who were asymptomatic without significant visceral metastasis and are not taxane chemotherapy candidates. The SPLASH study design addresses this important clinical need. Thank you for your attention.

Dr. Oliver Sartor - Professor of Medicine and the Medical Director at the Tulane Cancer Center (University of Tulane School of Medicine)
Hi I'm Dr. Oliver Sartor, I'm the Medical Director for the Tulane Cancer Center, and I'm going to give a little broad overview about metastatic castrate-resistant prostate cancer, with emphasis on current treatment patterns in the real-world clinical settings. I think this will be a little bit interesting for those who may not be very familiar with the space, and, if I'm going to be starting to talk about prostate cancer, I'm going to use this slide as a very broad overview.

First of all, we're going to divide the prostate cancer patients into two broad categories, the castrate sensitive or the castrate resistant, and then in truth, we divide these further into those with non-metastatic disease and those with metastatic disease. I won't really talk a lot about localized therapy and typically, we use radiation, radical prostatectomy, and if those patients are cured then they never go on to additional treatments. But for those individuals who are initially diagnosed with overt metastatic disease, today we use androgen deprivation therapy, and these would be things like leuprolide and Trelstar, etc. etc. plus a novel hormone. And we use things like abiraterone, apalutamide, enzalutamide, or maybe we'll use docetaxel and darolutamide, which has been very newly FDA approved. But the bottom line is we're using these novel hormones early for those with metastatic castrate-sensitive disease.

Now, if you fail your initial therapies say, radical prostatectomy or radiation, ended up with a rising PSA, many of these patients will be treated with androgen deprivation before they have metastatic disease, but they're going to inevitably fail. And when they do, they have what we call non-metastatic CRPC, and here we now have enzalutamide, darolutamide, and apalutamide all FDA approved. So, whichever way you look at it, these novel hormonal therapies are now going earlier than they used to be. In the old days they were approved in the metastatic CRPC, but that's changing. Now what's really changing overall, is metastatic CRPC, that's castrate resistant prostate cancer. It used to be we kind of had the pre-chemo and the post-chemo sort of trials, but now we're evolving into this new space, of kind of the post-abi/enza sort of setting, and that has real implications. I might also add that there are genetically selected cancers, that we treat in a very specific way, things like rucaparib, olaparib, and pembrolizumab, and don't forget the new kid on the block, and that's PSMA-617 lutetium-177 or Pluvicto.

Now, if we look at the life prolonging trials, for metastatic CRPC, I have them all listed here, and I'm going to draw some real distinctions. First of all, in the top of the slide, we see these frontline metastatic CRPC patients. This goes way back to 2004 and that's when the TAX 327 trial was reported in New England Journal of Medicine. And what they found way back then, is that median survival was about 16 months with improvement to 19.2 with docetaxel. But that is 18 years ago, and so much has changed in the interim. The more modern trials for metastatic CRPC involve either abiraterone or enzalutamide in the frontline setting, and here you can see patients are living two and a half to three years, so it's a very different group of patients that are being treated when you move from abiraterone / enzalutamide back to the old days of the TAX 327 and docetaxel. Sort of the next wave of trials were those that were post-docetaxel metastatic CRPC, and one of the things I want to underscore here is: if you look at abiraterone, say in Cougar 301, or enzalutamide with the AFFIRM trial, these are post-docetaxel. Look at the differences that you see. So if you are looking say in PREVAIL or Cougar 302, you're talking about overall survival is almost three years. If you're coming in the post-docetaxel space, for -301 and AFFIRM, you're seeing survivals of 15.8 and 18.4 months. Very, very different. You have to be incredibly cautious when you’re looking at post-trial comparison and cross-trial comparisons, because it turns out that the preceding treatments are incredibly important for what you will find and cross-trial comparisons you have to be extremely cautious with.

Now, I'm going to come down in some of the more modern era in the post-abi or post-enza space, and this was the PROfound trial which was reported in New England Journal, and was an olaparib, or PARP inhibitor trial, and now you can begin to see that about 19.1 months is what you might see in this highly selected patients with mutated homologous recombination repair defects.

In the third line setting, we have CARD and VISION. Well CARD, it really is a third line trial, because these patients were post-abi, or enza, and docetaxel, and you can see how the cabazitaxel performed. Whereas the VISION trial, which is the PSMA-617 lutetium-177 or Pluvicto, this was not really a third line trial, it was really a fourth and fifth line trial. About 40% of patients had also received cabazitaxel, and about 50% of the patients had received both abiraterone and enzalutamide. And here you can see the control arm was about 11.3 months, the Pluvicto arm was about 15.3 months, but this is a very different group of patients than the metastatic CRPC that we started out in 2004, so be careful about cross-trial comparisons.

Okay, going forward. If we look at the NCCN guidelines today for those with prior novel hormonal therapies, and that's the abiraterone, enzalutamide, apalutamide, darolutamide pre-treated patients, and no prior docetaxel, the preferred regimens are either docetaxel or sipuleucel-T. If we look at those agents or combinations that are appropriate under certain circumstances, we see things like cabazitaxel/carboplatin, olaparib, pembrolizumab, radium, rucaparib, and then other recommended regimens might include abiraterone, enzalutamide, or some alteration thereof.

If we begin now to look at what I call the real-world data, and this was published a couple of years ago, looking at metastatic CRPC, and I'm the second author on this particular manuscript I might add, we looked at a flatiron database. The Flatiron database is derived from large group practices throughout the United States. Well, first of all, what was rather interesting, is that a lot of patients were not necessarily receiving life-prolonging therapies. 77% of the patients did, but when you get to second line it was only 49%, third line it was 43%, and a lot of patients died without even getting additional lines of therapy. This was a little bit surprising. By the way with the adoption of the hormones in a little more depth now, this number of untreated patients is actually declining.

So what do practitioners in the United States choose as their first line therapy? And you can see on the upper left here, abiraterone and enzalutamide are chosen. If you combine those two together, you can have about 55% of patients are being treated with abiraterone / enzalutamide, those are the most popular choices. If you go to the second line setting it's a little bit interesting, now you see enzalutamide and abiraterone, little bit of a reverse in the order, but still being used in about 54% of patients. Docetaxel is only used in 14%, when you get to third line therapy, docetaxel is around 24%, enzalutamide and abiraterone are still popular but they drop down to 16% and 14% respectively. The bottom line is docetaxel is not used in a lot of patients. When we look overall, docetaxel is probably around 50% of patients in the United States get docetaxel before they die.

Now, if we look at the selection of patients, it's also important to understand precision medicine. There are homologous recombination repair genes when mutated can be treated with PARP inhibitors, olaparib or rucaparib. There are mismatch repair genes, when mutated, but this is only around 3% or 4% of patients, these can be treated with pembrolizumab. One of the problems with genetic testing is it's not done in a large number of patients. I was going to simply say that the adoption of precision medicine remains uneven across practitioners in the United States.

So how does radioligand therapy fit into this? I'm going to say, first of all, that docetaxel chemotherapy is often avoided, and that sipuleucel-T and radium are rarely used. One of the reasons for that is that PSA doesn't go down with sipuleucel-T or radium, men want to see their PSA go down. So people want to avoid chemotherapy, and they want see their PSA go down, and they're not getting that with docetaxel, sipuleucel-T and radium.

And then you look at precision medicine as a whole, and it's under-delivering. Genetic testing is still relatively under-utilized in prostate cancer, and by the way, the PARP inhibitors are broadly approved, but the truth is, they're active in the BRCA mutations and maybe PALB2, but a lot of the other homologous recombination repair mutations, they're not particularly active, things like ATM and CDK12. I see radioligand therapy moving rapidly into this post-abi, post-enza, post-darolutamide, post-apalutamide space. Patients do not want to be treated with a chemo, they want to see their PSAs go down, and I think radioligand therapy is going to be very rapidly adopted here.

In summary, metastatic CRPC, most patients today in the real world get repeated hormonal therapies, that is exactly what you see in the control arm in the SPLASH trial. I think avoidance of chemotherapy is typical with advanced prostate cancer, these are older castrated men, they're not ideal chemotherapy candidates, and they don't want chemotherapy. So, if you want to be able to provide a feasible option and avoid chemotherapy and get a PSA response, you got to use radioligand therapy, and I think it's going to be rapidly adopted in this space.

One more thing I would like to draw your attention to, and that is you can get some initial data from SPLASH in a 27-patient lead-in cohort, and that's going to be presented at ESMO 2022 in an e-poster, 1400P. Now hopefully you'll get to go to Paris and enjoy yourself, but if not, you can get this preliminary data from the SPLASH trial, and I think I'll simply say it's provocative. So, with that, I'll wrap up, and we can continue the discussion as a group, if you like. Thank you very much.