Activity Transcript

Module 1: Novel Molecular Targets for the Treatment of Metastatic Hormone-Sensitive and Castration-Resistant Prostate Cancer

Niven Mehra, MD, PhD: Hello everyone, I'm Niven Mehra. I'm a medical oncologist from the Radboud University Medical Center in Nijmegen, the Netherlands. Welcome to the first module of this program titled "Depicting the Next Clinical Phase in Metastatic Hormone-Sensitive and Castration-Resistant Prostate Cancer."

In this module, I will discuss novel molecular targets for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC) and unique pathways that lead to mCRPC and mHSPC progression. I will give an introduction on targeting cell cycle progression through the cyclin-dependent kinase 4 and 6 (CDK 4/6)-cyclin D pathway that controls the G1-to-S transition. Also, I will be touching upon the phosphoinositide 3-kinase/protein kinase B/mechanistic [mammalian] target of rapamycin (PI3K/AKT/mTOR) pathway, which is the most apparent pathway in cancer. Also, cell surface antigens, such as prostate-specific membrane antigen (PSMA) and prostate stem cell cancer antigen (PSCA), can be used by bispecific antibodies, antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR) T-cell strategies to also target prostate cancer. Lastly, I will touch upon dual blockade of inhibitory checkpoints. 

So even though we made great progress in the treatment of prostate cancer, metastatic prostate cancer remains lethal, and hormone-sensitive prostate cancer strategies are predominantly still focused on targeting the androgen receptor or using taxane chemotherapy. However, in-line with our knowledge that prostate cancer is a heterogeneous disease, clinical responses to these therapies are also heterogeneous, and our tumor molecular landscape has been unraveled by next-generation sequencing (NGS) efforts, DNA methylation, RNA pathology, and proteomics. With this knowledge of prognostic and predictive molecular mutations and tumor suppressor genes and oncogenes, which are involved in various cell cycle and signal transduction pathways, we can make headway to the future. 

Hyperproliferation is a hallmark of cancer development. The cell cycle can be divided into 4 ordered phases: the growth, or gap 1 (G1); the DNA synthesis phase (S); rapid growth, or gap 2 (G2); and the mitosis (M). All these cell cycle divisions are precisely controlled by molecules such as CDKs, and key regulatory checkpoints in G1 and G2 phase determine whether cells can enter the S or the M phase. The CDK 4/6 checkpoints, which are 2 serine/threonine kinases, are crucial for the transition from G1 to S phase. Cyclin 4/6 is activated by active cyclin D, and the cyclin D-CDK 4/6 complexes phosphorylate and inactivate the retinoblastoma (RB) tumor suppressor gene. RB proteins bind transcription factors. But on phosphorylation and inactivation, E2F's binding affinity [is] reduced with transactivation of E2F transcription factors, which recruit RNA polymerases and cyclins, which lead to G1-to-S phase transition.

Receptor tyrosine kinases (RTKs) and PI3K signaling activate the PI3 kinase/AKT/mTOR pathway. In prostate cancer, the most common driver of PI3K activation is phosphatase and tensin homolog (PTEN) inactivation, found in 20% to 35% of prostate cancer patients, but also, less commonly, PIK3CA and AKT alterations. PTEN is a dual-specificity phosphatase which converts phosphatidylinositol (3,4,5)-trisphosphate (PIP3) into phosphatidylinositol (4,5)-bisphosphate (PIP2) and directly antagonizes class I PI3K, which converts PIP2 to PIP3. PIP3 is a second messenger which leads to recruitment of 3-phosphoinositide-dependent kinase 1 (PDK1), which phosphorylates its target, AKT, and phosphorylated AKT subsequently regulates several downstream signaling cascades, including mTOR.

Other ways to target prostate cancer are through using cell surface antigens, such as PSMA or PSCA. These are transmembrane receptors, which are found on the prostate cancer surface. You can directly antagonize these antigens by antibodies, but most commonly, we are now using antibodies, dual-specific antibodies, or bispecifics, or ADCs, or CAR Ts to deliver a payload or T-cells to the prostate cancer cells.

Bispecific T-cell engagers, or BiTEs, are bispecific antibodies targeting a tumor specific antigen on the prostate cancer cell, such as PSMA or PSCA, but also recruit T-cells against the tumor cells. To reduce degradation of these antibodies, fragment crystallizable (Fc) receptor parts are modulated by DNA recombinant technology, and toxicity is based on, of course, the pharmacokinetic (PK) profile, but also on off-target expression, so on healthy cells.

Let's talk a bit more about PSMA. PSMA, of course, is the most used cell surface antigen, which can be targeted by PSMA-617, which is a small-molecule inhibitor and is bound to lutetium. In the VISION study, we have seen that this leads to clinical responses and overall survival (OS) benefits. When PSMA-617 is bound to the receptor, it's internalized and the β radiation damages DNA and results in cell deaths. The γ particles, which are also emitted, allow for imaging during therapy. But also, PSMA can be used for, as I said, ADC delivery or CAR T.

PSCA is an upcoming cell surface antigen found predominantly on prostate cancer cells. It's under the control of the antigen receptor, so by binding the ligand, testosterone, PSCA is upregulated and transported to the cell surface. PSCA can be targeted directly, which gives an antitumor effect; nevertheless, more effect is seen when we use PSCA to co-target the cells with CAR T, so bringing T-cells to attack the cancer cells or deliver a payload such as chemotherapy. PSCA is highly expressed on prostate cancer cells but can also be expressed on bladder and neuroendocrine gastrointestinal (GI) tract. Multiple phase 1 and phase 2 trials are using PSCA to deliver BiTEs, ADCs, and CAR Ts.

Lastly, lymphocyte-activation protein 3 (LAG3) is a cell surface molecule expressed on activated T-cells, natural killer  cells, and B-cells, and plays an important role in activation of these lymphocyte subsets. In addition to the interaction between LAG3 and its ligand major histocompatibility complex (MHC) II, it's thought to play a role in modulating tumor cells. Preclinical data has documented a role in LAG3 in T-cell exhaustion, and by blocking LAG3-class II interactions, especially in combination with anti-programmed cell death protein 1 (anti-PD-1), is being used in numerous clinical trials in cancer patients.

Thank you for participating in this module, and please continue to the next module in which Dr Scott Tagawa will discuss ongoing recent data for these novel treatment options for mCRPC and mHSPC.

Module 2: Backing Up Innovations With Clinical Context: What New Data Do You Need to Be Aware Of?

Scott T. Tagawa, MD, MS: Hi, I'm Scott Tagawa, a professor of medicine and urology at Weill Cornell Medicine in New York, New York. Welcome to this program entitled "Backing Up Innovations With Clinical Context: What New Data Do You Need to Be Aware of?" In this module, I will discuss ongoing and recent data for novel therapeutic options in the treatment of mCRPC and HSPC.

You've already been introduced in the prior section to bispecifics. One of the targets of bispecifics in the setting of prostate cancer is PSMA. This is an approved diagnostic and therapeutic target with multiple drugs in development, including targeted radionuclides beyond the approved lutetium-177 (¹⁷⁷Lu)-PSMA-617 ADCs as well as immune therapeutics. These include bispecifics or CAR T-cells. There are multiple PSMA x cluster of differentiation 3 (CD3) bispecifics that have presented data, and some have been published.

Those include drugs including JNJ 01, AMG 212 and 160, HPN424, as well as CC-1, which had 2 presentations at American Society of Clinical Oncology (ASCO) 2023. There's also at least 1 PSMA × CD28 bispecific of interest. Essentially, all the data has been in pretreated mCRPC patients and at a high level, what they've shown is that there's a subset with prostate-specific antigen (PSA) decline. There are some immune-related adverse events (irAEs), including cytokine release syndrome (CRS), and different strategies have been employed with step-up dosing condition infusion, subcutaneous administration, as well as the use of premedications to ameliorate some of these toxicities.

CC-1 is 1 of these bispecifics with PSMA and CD3 that has been studied in early phase trials in mCRPC.

With some updated data, there was a phase 1 dose escalation phase, and that's been presented at prior meetings, and a dose expansion at the recommended phase 2 dose (RP2D), and that was updated at ASCO 2023. The primary outcome of the phase 1 was safety with secondary outcomes of additional safety plus PSA decline.

There was some CRS and associated adverse events (AEs) with that, as well as some AEs that were associated with the use of anti-interleukin-6 (anti-IL-6). But what was of note at the RP2D -- so, that expansion cohort that was presented at ASCO 2023 -- is that all patients except for 1 had some PSA decline. That's of interest because it's only been a subset before in some of the other ones. It's still early, but it's of interest. When we think of immunotherapy in general for patients with prostate cancer, is pretreated mCRPC the right setting, where the immune system may not be as active and there may be more resistance mechanisms?

Interestingly, there was a trial in progress presented with this drug that is targeting very early prostate cancer, so biochemical recurrent prostate cancer with a slow PSA doubling time, a doubling time of greater than 12 months, and no adverse disease risk factors. This is a fairly aggressive move, but is this going to be the setting if we can do it safely that there's going to be some cure? I think that is of interest and we'll see. They're using step up dosing, twice-weekly administration in a typical dose-escalation study, the primary endpoint of establishing a RP2D with secondary endpoints of PSA50 (> 50% decline in PSA) decline.

CDK 4/6 was introduced as a target in the prior section. I think some of you or all of you are aware of the drug abemaciclib. This is being studied in prostate cancer with some data as a single agent in what's called the CYCLONE 1 study, where there was overall some disease control, mostly stabilization, with what was called tolerable adverse events. I think that we all need to understand how to monitor and provide supportive care, but patients with pretreated mCRPC were able to tolerate the drug.

And this drug has moved forward in combination in the CYCLONE 2 and CYCLONE 3 studies. CYCLONE 3 is a study that has been presented before, at least in terms of study design, a 3-part study, but really a phase 2/3 study and to jump ahead, mCRPC in combination with abiraterone and prednisone, naive to prior androgen receptor pathway inhibitors (ARPIs). Phase 2 has been completed, has been reviewed by the data safety monitoring board (DSMB), and has moved on to phase 3, so that's an ongoing study, and we're hopeful for positive results there.

CYCLONE 3, the study design was presented at a trial-in-progress poster at ASCO 2023, which is moving a step earlier into the frontline setting of the mHSPC population. This is enrolling a patient population with high-risk features, randomizing to androgen deprivation therapy (ADT) abiraterone and prednisone with placebo or ADT abiraterone, prednisone with abemaciclib with a primary endpoint of radiographic progression-free survival (rPFS), and that's an ongoing study.

Coming back to PSMA, I mentioned that as a target, there's a number of developments for targeted radionuclides. There's a number of rational combos that are out there, androgen receptor (AR), immune checkpoint inhibitors, chemotherapy, PSMA and PSMA combinations, but one of the combinations of interest are poly (ADP-ribose) polymerase (PARP) inhibitors. If we can damage DNA with the β-emitter ¹⁷⁷Lu, can we prevent DNA from being repaired with a PARP inhibitor? This was designed to come in with a PARP inhibitor regimen on an intermittent basis, not to be necessarily so active on its own in terms of olaparib, but to improve the efficacy of ¹⁷⁷Lu-PSMA 617. The phase 1 dose escalation was presented as an oral presentation by Shahneen Sandhu, and a tolerable regimen was derived. And I look forward to seeing further follow-up and expansion into phase 2.

A separate poster presentation was some level of circulating tumor cell (CTC) profiling in patients on that study called LuPARP. I think there's a lot of rich potential for analyzing CTCs. This was mostly on enumeration, where the majority at baseline had detectable CTCs. On those CTCs, there was a PSMA that was detected in the majority, but not all, as we expect based on prior studies even in a patient population that's already been selected by a PSMA positron emission tomography (PET). In terms of enumeration, there was decline following therapy, so that's of interest.

Sticking with the theme of cell surface targeting and shifting back to immunotherapy, there was an interesting study presented by Tanya Dorff in the poster discussion session of a PSCA CAR T-cell phase 1 study. There was some hemorrhagic cystitis that may have been due to the cyclophosphamide, so as they adjusted that, they came up with what appeared to be a more tolerable regimen. There was some disease control that was there. I think we all want to see, broadly speaking, the development of CAR T cells for solid tumors in general. I think it's more difficult with solid tumors than it is with liquid tumors. Prostate cancer is a disease that has some unique cell surface targets, and I look forward to further development of this as well as other CAR T-cells for prostate cancer.

Thank you for participating in this module. Please continue on to the next module in which Drs Elena Castro and Nivan Mehra discuss stratifying, selecting, and sequencing emerging therapies for advanced prostate cancer.

Module 3: Saying Goodbye to the One-Size-Fits-All Model: How Can We Stratify, Select, and Sequence Into the Future?

Elena Castro, MD, PhD: Hello, my name is Elena Castro. I'm a consultant medical oncologist at Hospital Universitario 12 de Octubre in Madrid, Spain. Welcome to module 3, "Say Goodbye to the One-Size-Fits-All Model: How Can We Stratify, Select, and Sequence Into the Future?" Joining me today is Dr Niven Mehra, who is a medical oncologist at Radboud University Medical Center in Nijmegen, the Netherlands. Welcome, Niven.

Dr Mehra: Hi, Elena.

Dr Castro: In this module, we will discuss the clinical relevance of some emerging therapies, the need for molecular biomarkers to stratify and select treatment options, and how to sequence emerging therapies with the established options to ensure the maximum benefit.

Niven, regarding the patients' stratifications, we have been using clinical variables for years and we thought we were doing our best. Then we learned that there are some molecular biomarkers, such as p53 mutations or RB1 loss or PTEN loss, etc, etc, that are associated with patients' outcomes. But still, we have not integrated those clinical variables and those molecular biomarkers. We don't have any nomogram or anything like that integrates both. How do you do that? What do you think?

Dr Mehra: Yes, Elena, that's an excellent question. I think we are moving towards integration of clinical variables in the nomograms which we have and adding into that very prognostic biomarkers such as TP53 or even BRCA, and also following these patients from diagnosis until death so we know in which line these biomarkers are prognostic or predictive.

With the developments we are having in artificial intelligence (AI), I think this is also going to help us making good integration of not only selected biomarkers, but the whole molecular picture. Because we went from not using any NGS, to BRCA testing, and now many institutes are doing broad testing and we are still using only a fraction of the information for our modeling. I think in the next years we will see stratification based on these profiles for standard of therapies, but also, excitingly, for the new therapies which we'll be discussing today.

Dr Castro: We are starting to see some studies that are incorporating AI, algorithms, and digital pathology to improve patients' stratifications. The data that have been presented is mostly in localized disease. Do you think this will also have a role in advanced prostate cancer?

Dr Mehra: Yes, for sure. I think it holds a role, of course, in localized disease because we have this information present, but the number of institutes which do biopsies in the castration-resistant setting is so small, so we need to work together on this to get the large data sets. But I am convinced that digital pathology holds a future also in CRPC, also for imaging radiomics. I think in all settings it will have some kind of a prognostic or predictive characteristic. For PSMA therapy, of course, we really know that using a supervisor approach, looking at PSMA avidity, can stratify patients. But if we are still not using all the characteristics which you extract from a PSMA positron emission tomography (PET) scan or a computed tomography (CT) scan or bone scan. So, I'm also very excited in all settings that this will really pave the way to more personalized treatments.

Dr Castro: Niven, I know that you have an excellent access to genomic profiling of prostate cancer tumors. Could you tell me how that changed your patient management? Whether you are able to offer targeted therapies to most of your patients? What are the newest targeted therapies that you are developing in your institution and how is this changing patient management?

Dr Mehra: I'm very lucky to be working in a large academic institution. For us, access to large panels (even whole-genome sequencing, RNA sequencing) is present even though budgets are being restricted. We are providing our frontline mCRPC patients large sequencing panels. We are not only using this information to identify patients with BRCA. So we know upfront before starting a first line what the path will be for this patient, because I think it's important that you can plan ahead and not when you progress and you're clinically progressing, you need to make split decisions and you want to then not wait for 2 months before you get your results back from your sequencing. Knowing this upfront really helps us.

Not only for BRCA patients, but we are identifying patients with microsatellite instability (MSI), we're identifying patients with neuroendocrine features or small-cell features by biopsying these patients. At this point, I think for about 20% of our patients, we really change management by using DNA sequencing, and these 20% of patients are mainly the poor prognostic patients. So, knowing that you are treating a patient on the first-line enzalutamide, and they progress in the second line, we can enter these patients in immunotherapy trials if they're CDK12-mutant or they have MSI or high tumor mutational burden (TMB). That's about 10% of the patients. And we can enter these patients also in DNA damage repair trials with PARP combinations, but also the new agents coming like ataxia telangiectasia and Rad3 related (ATR) and ataxia telangiectasia mutated (ATM) inhibitors.

So, I think the 20% which we can, at this point, identify and change management, this percentage will change in the next years when we have novel targets. It's a real exciting time for me as a precision medicine oncologist.

Dr Castro: Niven, what do you think will be needed for us as a community to be able to really move from that 1-treatment-fits-all to really personalized medicine?

Dr Mehra: As we touched upon, I think access for DNA sequencing and broad sequencing, that's something which is a problem in many countries, but I think access would be one. Second, you need access to precision medicine trials. I know that, of course, we have a lot of pharma trials, which are in different institutes, but I think there needs to be an effort in also when we identify our patients that we also work together in getting these patients into these trials.

Also, there are some global efforts in setting up basket trials, which can be small cohorts of patients who have been agnostic for tumor types, where, based on specific alterations, patients can be entered. In the Netherlands, we have this Drug Rediscovery Protocol, which is a real exciting protocol, where patients can be entered based on molecular aberrations with drugs which are already registered for other indications. Meaning that you can move faster forward to precision medicine trials, and reimbursement, also.

I think that these are very exciting things, but also, we should not forget, we have our standard of care (SoC) therapies also, which are very important and very effective drugs. So, 1 of the key things is also, for our patient well-being, is that we try to sequence novel trials with also SoC therapies. And that's also something we need to improve on probably.

Dr Castro: Niven, thank you for this great discussion and thank you all for participating in this module. Please continue on to the next module in which Dr Scott Tagawa and I will discuss a multidisciplinary approach to the use of emerging treatment options.

Module 4: Challenges in Integration: How Can We Collaboratively Incorporate Targeted Therapy to Push the Needle?

Dr Castro: Hi, I am Elena Castro. I'm a consultant medical oncologist at Hospital Universitario 12 de Octubre in Madrid, Spain. Welcome to module 4, "Challenges in Integration: How Can We Collaboratively Incorporate New Targets to Push the Needle in the Clinical Care of mCRPC and mHSPC." Joining me today is Dr Scott Tagawa, who is professor of medicine and urology at Weill Cornell Medicine in New York City. Hi, Scott.

Dr Tagawa: Hi. Great to be here.

Dr Castro: In this module, we will discuss future use of emergent therapies in clinical practice, which members of our multidisciplinary team should be involved in clinical decision-making, and effective and efficient collaboration between clinicians with the use of emerging therapies. Scott, tell me how are you implementing these new therapies in the care of your patients?

Dr Tagawa: Broadly speaking, I think that for us in the clinic, in terms of medical oncology, it's nice that we have more than just docetaxel. We have a lot of different types of therapies and many of these, nowadays, partly because we have choices and partly because we have other tools, whether they're genomic or imaging or other, we have different tools for patient selection. So that I could say that's very nice.

The newest type of a therapy that we now have in the clinic is a type of targeted radioligand, ¹⁷⁷Lu-PSMA-617. It's the second radioisotope that we've had for prostate cancer, so it's not totally new. That other one, to remind people, did have a bone scan as a biomarker.

But there are a couple of different aspects, I think, that are now becoming prime-time to add to members of the multidisciplinary team. That includes someone specialized in imaging interpretation -- nuclear medicine is kind of the most specialist, but some radiologists are highly skilled in assessing PET scans. And then the general, what I call the primary care people for patients with metastatic prostate cancer, oncologists -- neurologists typically don't have the licenses to administer these therapies, so now we're increasingly bringing in nuclear medicine or radiation oncology. I think that is an important aspect to have and to have that as a team, because there are parts that are not just patient selection, not just the administration of the compound. It is following the patient on therapy, deciding what other medicines are going to be given at the same time, assessing, and dealing with toxicities, assessing when someone should be getting the next cycle or not. I think those require, really, a back and forth between all the different members of the team.

Dr Castro: We are going to need larger and larger rooms to accommodate all the people that are involved every time we discuss a clinical case. From a practical point of view, when a patient with advanced disease comes to your clinic or your department, how do you usually, do you assess the presence of targets for which we have targeted therapies? Do you do a PSMA PET at the same time to decide between potential therapies? What do you usually do?

Dr Tagawa: Definitely in the setting of, what I would call, in the VISION setting, post-androgen receptor (post-AR) pathway inhibitor, post-taxane chemotherapy, so kind of on label for ¹⁷⁷Lu-PSMA-617. Sometimes those patients have few other choices or no other choices. They may not be a candidate for a clinical trial, they may have had both taxanes and not be candidates for the other types of therapy. So that is a little bit of an easier decision where I will interpret, with nuclear medicine, the PSMA PET with a very low bar. Any uptake, or even very little uptake with no other choices, I would give that a try. Because in my viewpoint there, while there are clearly AEs that can happen, overall, it's tolerated relatively well and there might be a benefit. So it's a lower bar.

As we're moving further upstream, trials such as PSMAfore in the chemo-naive setting where there are other choices, that's where I think that we want to be a little bit stricter in terms of the interpretation of the PET scans. But as we think about how strict do we need to be -- of having every single lesion be very hot or bright on the scan -- I think it depends. Clearly, we have drugs that only hit certain compartments, such as radium, where we know that low-volume lymph nodes are OK even though the targeted when we're targeting the major compartment and there's still a survival advantage.

So, I think we need to take into account, what are the other choices in that particular situation? What are the goals that we have with the patient and their family? And then that also helps us pick therapy. Are we going to be very strict about PSMA PET and look at if we have the tools available, maximum standard uptake value (SUVmax), SUVmean, etc, or is it just visual uptake in most of the lesions? Things like that.

Dr Castro: Who would you say is the best candidate of the best patient for treatment with lutetium? Did you take into consideration the SUV? Did you take into consideration other variables? Is there a way? How can we predict which is the patient that is going to get the best results from this therapy?

Dr Tagawa: I'm going to answer that in a couple of ways. One thing to note there is kind of a retrospective nomogram out there that was pooling of the data, looking at a number of different factors, including imaging. And at ASCO 2023, Ken Herrmann presented the nomogram from the VISION prospective study. They're a little bit overlapping, but those take into account clinical factors as well as imaging factors. We don't yet have genomic factors in these nomograms. But those can be helpful whether depending on what endpoint we're looking at, OS, PFS, or response. Imaging is part of all of those nomograms. So the brighter that is by whatever tool that we're looking at, SUVmax or SUVmean, those are both independently important in terms of the nomogram. Lymphocyte count stood out for all these, lactate dehydrogenase (LDH), not surprising. Things that we've known for a while.

But what's important to note, particularly for a VISION population that doesn't necessarily have a lot of other therapies, once they qualified for the study, regardless of what their SUVmean was or their SUVmax was, every patient did better with ¹⁷⁷Lu-PSMA-617 vs control. So I think, again, it goes back to what are the other choices that are there? But in terms of directly answering your question for optimal, "Well, who is the most optimal?" Part of that is going to be the brightest, most homogeneous uptake on the PET scan.

Dr Castro: Continuing with that, I think at ASCO there were also some data presented regarding the radiation to other organs and safety. I don't know if you would like to comment on that as well.

Dr Tagawa: Yes, you're talking about the dosimetry. At ASCO 2023, there was a focus on tumor dosimetry. The overall dosimetry was there, and I know it's been accepted, I can't actually remember if it was fully published yet, but that manuscript looking at normal organ dosimetry has been accepted. That was a subset in Germany of the overall VISION trial. It's nothing surprising compared to what we've seen before in terms of organ exposure as one would expect based upon PSMA expression and urinary excretion. So, not so much there.

I will quickly mention, just for drug development, that it doesn't look like external beam normal organ limits apply directly to radionuclide therapy. But in terms of tumor dosimetry, what we'd really like to see is the next step in terms of, like we're used to with external beam, if we get more to the tumors, do the patients do better in terms of responses? And that's a work in progress. So, at a high level, what we know about in this patient population, again, not that there's no AEs, but generally speaking, most patients will tolerate this drug given at 7.4 gigabecquerel (GBq) per dose with the possibility of dose reduction times 4 with the possibility of 2 additional ones if they're still responding and not having high-level toxicity. We know that, overall, the patient population will tolerate that, and most will benefit from that.

Dr Castro: Thank you, Scott, for this great discussion. I've learned a lot from you, and thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has been edited for brevity and clarity.