Hello everyone, and welcome to this KCast program entitled, “Treatment Options in Metastatic Castration-Resistant Prostate Cancer: A Year in Review.” I’m Neal Shore. I’m the medical director of the Carolina Urologic Research Center and also work with Atlantic Urology Clinics in South Carolina.

Our discussion today is going to focus on current standards in mCRPC [metastatic castration-resistant prostate cancer], and I’ll focus discussion on the recent data that have been presented at ASCO [the American Society of Clinical Oncology Virtual Scientific Program] 2020 and ESMO [the European Society for Medical Oncology Virtual Congress] 2020 from the PROfound trial. Let’s begin.

One of the first tasks is to set the landscape of mCRPC. We’ve made a lot of progress since 2010. We now have 9 survival-prolonging, FDA-approved agents, which is rather remarkable. Yet patients with mCRPC still suffer from this disease, and it is a terminal disease. Interestingly, many patients will have a cardiovascular mortality that might surpass their prostate cancer–specific mortality, but we still have made great advances.

In terms of following and evaluating these patients, I typically talk with my patients about the importance of 3 aspects. The first is symptomatic performance, including changes in symptomatology, which requires a detailed examination and history. The second part is imaging. The frequency of imaging is predicated upon the assessment of the patient’s biology and their symptoms. That includes traditional, conventional imaging, CT scan, and bone scan. The other thing that’s sweeping across the globe in various regions is the augmentation of next-generation imaging, and particularly PET PSMA [positron emission tomography prostate-specific membrane antigen] scans.

The first 2 aspects are imaging and symptom assessment. Third are laboratory tests and laboratory assessment. It’s not just PSA [prostate-specific antigen], although PSA is obviously very important. It includes the complete blood count, the CMP, or comprehensive metabolic panel, and other biomarkers, as well. LDH [lactate dehydrogenase] and other markers, such as CTCs [circulating tumor cells], chromogranin A, may also be used.

When I consider factors in treatment, that includes everything that we just talked about. But we also now have other biomarkers, such as the recent recognition of DNA repair damage gene alterations and what some would call homologous recombinant repair gene mutations. Those allows us to offer PARP inhibitor therapy.

We also have other findings we’re discovering in gene alterations, or what is sometimes described as comprehensive genomic profiling, and the ability to enroll patients into clinical trials. For example, patients may have next-generation sequencing 

How do we make these treatment selections? Of course, prior lines of therapy come into play. There have been a lot of recent data demonstrating that sequencing AR [androgen receptor] pathway inhibitors is not an optimal strategy, and that happens quite frequently, for understandable reasons. They are oral medications with good tolerability. But we now have radiopharmaceuticals, taxanes, PARP inhibitors, and immunotherapy in the US. Those allow us to give more thoughtful consideration to optimizing care. Data clearly suggest that the more therapies a patient can receive in a timely way, the better their long-term survival.

These are all of the factors that weigh into sequencing appropriately. Again, those are the patient’s biology, the phenotype of the disease, what prior therapies they’ve had, and appropriate monitoring, including lab work, symptomatology, and timely imaging.

Overview of Metastatic Castration-Resistant Prostate Cancer

One of the things that has really changed in the United States in 2020 has been the FDA approval in May of 2 PARP inhibitors for patients with mCRPC [metastatic castration-resistant prostate cancer]. There have been additional PARP inhibitor approvals by EMA [the European Medicines Agency] and throughout the world, and others in further regulatory review. The importance here is testing. Genetic and molecular tests are now available to us, and they include patients who have alterations that may have been inherited from their mother and father. This is under the umbrella of germline testing.

 mutation inherited from a parent, this will pervade all cells. The germline mutations are easy to obtain. They require a simple blood test or saliva through buccal mucosa. This can be extremely helpful. Having said that, if we just stopped with anoetic germline mutation assessment, we would miss another 50% of patients in the mCRPC landscape who might have an 

 mutation. We’ve now found this in multiple studies, including the PROfound trial, which I will also review.

For my patients who present with metastatic disease, I’m very cognizant of, and I like what’s evolved in the NCCN [National Comprehensive Cancer Network] guidelines. For metastatic disease, they recommend germline testing in everyone. There is certainly consideration for somatic testing, as well.

Personally, I like to do both. I like to get as much information as possible. I recognize that accessibility of tests is important and can be a rate-limiting factor. But as I’ve already stated, if you stopped at just germline testing alone, you might miss another 50% of patients who have 

 mutations in the mCRPC population. This has been well described, not only by the PROfound trial, but by studies and publications by Colin Pritchard, [MD, PhD,] and Elena Castro, [MD]. This was a really important aspect.

Additionally, sometimes we’ll find other somatic mutations that are potentially actionable for clinical trial work or for other indications, in addition to 

 mutations that could be found within germline testing.

The world has changed rather significantly for all of our colleagues who take care of patients with advanced prostate cancer, including medical oncologists and urologists. In the United States, the FDA has approved a 14-gene 

 mutation panel. The most prominent driver here is the 

. This has been demonstrated to have real value in PARP inhibition, not just in prostate cancer, but also in ovarian, breast, and pancreatic cancer.

It’s important to test, because if you’re not testing, you’re not finding the results that could arguably enhance your patient-physician chair discussion and improve your armamentarium. You won’t have as many options on the shelf as patients progress through their already approved lines of advanced prostate cancer treatment.

The optimal time for testing is for patients who are newly diagnosed with high-grade disease or have a family history of significance. I would encourage our listeners to look at what has been listed as significant. One or more cancers, including prostate, breast, ovarian, colorectal, and pancreatic cancer, especially if a family member was 60 or younger, is significant. Additionally, any high-grade disease is significant. I check for germline mutations in all of these patients. That’s in the nonmetastatic population.

In the metastatic, it’s important to move forward with somatic testing and get tissue right away. The tissue testing is important because it is the most valuable and accurate. Sometimes, tissue testing isn’t available. The tumor tissue may have degraded, or it may not be accessible through a supply chain issue. Then, we have the ability to do what’s described as liquid somatic testing, circulating tumor DNA, or cell-free DNA. This could be very valuable, as well.

The other option for getting somatic tumor tissue testing would be to do metastases-directed biopsies of large lymph nodes and liver lesions. Mediastinal nodes are very accessible by our interventional radiology colleagues. Bone lesions can be obtained, particularly large bone metastatic lesions in pelvic bones, ischium, and femur. Ribs and spinal metastases are a bit more challenging. That also may be useful if you just have spine and rib lesions, where liquid somatic testing could be of value, as well.

The most important thing is that it’s not about consideration; you must test. Based upon the PROfound trial, which is a phase 3 trial with 2 publications in 

, and the TRITON2 paper, we now have 2 distinct PARP inhibitors in the United States that one could avail themselves of for their patients who are navigating the mCRPC landscape.

Genetic Testing in Metastatic Castration-Resistant Prostate Cancer

How do I have a conversation with my patients regarding the importance of getting tested? That is a really good question because, historically, we have not done genomic profiling, and certainly not in urologic oncology. Our medical oncology colleagues have been doing this for some time, as it relates to breast, ovarian, and most recently, pancreatic cancer. But all of us now need to have a conversation and be able to articulate the importance ofgenomic profiling for patients with advanced prostate cancer. I explain to my patients that their disease is advanced, or their disease may even be newly diagnosed, high-grade localized. Or they have high-grade localized disease, or sometimes, low-grade localized disease, but a really significant family history.

My conversation hits on several points. I first explain that if we’re able to demonstrate through either somatic testing, or germline testing, or both—I typically get both. I get them as early as possible, because I want to make sure we don’t lose control of the archival tissue that you can get from a prostate biopsy or a prostatectomy specimen. If I can do that, I want to be able to interrogate the tissue before there are any issues of decay or tumor DNA degradation, which sometimes can happen. That said, if I can’t get that, we can do now liquid-based testing. There are liquid-based tests that have been approved by the FDA that further allow us to recognize somatic alterations. Those are blood-based tests. That’s what liquid means.

I explain this to patients in a much more simplistic way, saying, “We’re going to review your archived tissue to see if there are gene alterations. While we’re doing that, we now have approved therapies that I have in my toolbox to treat this cancer if you fall into that 25%.” Additionally, if they happen to have a germline alteration, then it predisposes them potentially to other malignancies. Equally importantly, I explain that it could affect their own family members, particularly their children, nieces, nephews, and siblings. Those relatives may want to also get tested. If they are positive, they may want to consider earlier screening to avoid demonstrating disease that’s advanced and could have potentially been picked up when it was localized. That includes various syndromes such as hereditary breast and ovarian cancer syndromes and Lynch syndrome.

In addition to picking up alterations that can lead to oral medications, there are also some alterations that demonstrate the ability to use checkpoint inhibitors. Those include immunotherapies. I review it with my patients in those very simplistic terms. Ninety nine percent of my patients will say, “Please move forward as long as there’s not some accessibility or cost factor.” They really understand that it enhances their optionality for treatment to help them individually, and may also help their children, nieces, nephews, and siblings.

 is the chief driver of a very significant percentage of the 

. These are all important gene alterations. Sometimes, we may see a demonstration of what’s described as a variant of uncertain significance. That isn’t necessarily actionable at this time. But there are ongoing biorepositories and additional clinical studies that could give us helpful clinical information in the future.

I explain that to patients. I say, “The majority of the time when we’re doing the somatic testing, we may not find something that’s going to help you right now. In 25% of patients, we do, but for the remaining patients who don’t have an actionable approved therapeutic right now, we may have clinical trials that they could benefit from.” This is extremely important. Clinical trials are part of the recommendation of all the major guideline organizations. Going forward, there are alterations of uncertain significance that could change over time. There are FDA-approved indications for not only PARP inhibition, but also with MSI [microsatellite instability]-high or TMB [tumor mutational burden]-high disease. We have checkpoint inhibitors, as well, in addition to clinical studies.

Genetic Testing: A Conversation with Your Patient

Now let’s talk about PARP inhibition in mCRPC [metastatic castration-resistant prostate cancer].

One of the things that we’ve seen over the course of our investigations is that about 10% of patients who have metastatic castration-sensitive prostate cancer will have an 

 mutation. When you get to the mCRPC population, that can increase to about 25% of patients. Therefore, it’s not an insignificant number of patients who could benefit, especially with the recent approval of both olaparib and rucaparib for patients with mCRPC in the United States and other countries around the world, depending upon their regulatory authority review.

It’s important to recognize this, that one wants to now enter the arena of precision, or real personalized therapy. By way of using either a germline test, somatic tissue, or somatic liquid, if you find an 

 mutation, patients can now potentially benefit from this when they have mCRPC.

There are some variations on who can benefit, as it relates to the approval in the United States for olaparib. It is approved for patients with mCRPC, 

 mutation based on a 14-gene panel, as long as the patient has progressed after receiving a prior novel hormonal agent [NHA]. Those NHAs include abiraterone and enzalutamide.

One can make an argument that if they have progressed through nmCRPC [nonmetastatic CRPC] on recently approved darolutamide or apalutamide, that makes good clinical sense as well.

For rucaparib, it’s a little bit different. On their label, patients have to have proceeded through progression of a novel hormonal agent, as well as a taxane, and be mCRPC. It’s approved for patients with gene alterations of 

, not the full 14-gene panel. Nonetheless, these are both dramatic advances in 2020.

This has ushered in the area we’ve often talked about, how can we better tailor therapy? How can we personalize therapy? How can we be more precise in our decision-making?

I should note that these therapies should not obviate or negate the ability to use other mCRPC-approved treatments at an appropriate time, whether it’s a radiopharmaceutical, a taxane-based therapy, or a clinical trial.

Newly Approved Agents for Metastatic Castration-Resistant Prostate Cancer

Let’s take a deeper look at the PROfound data. I had the great honor to participate in this study and be part of the steering committee, but it was brilliantly led by Johann de Bono [MD, MSc, PhD, FRCP,] and Maha Hussain [MD, FACP, FASCO].

Within a 1-year period, we met our primary end point of radiographic progression-free survival [rPFS]. That led to publication in 

. We saw patients who had been heavily pretreated, all had received novel hormonal agents, and about two-thirds had received a taxane therapy. A significant portion of those patients had received taxanes, and oftentimes, several taxane therapies.

These patients had extensive bone disease and a high percentage also had visceral metastases. Fortunately, we were able to demonstrate in this study that patients had clearly met an rPFS of a nearly 4-month benefit, particularly in what was described as cohort A. Cohort A was the group of patients who had either 

I want to quickly review the clinical trial design of PROfound, because sometimes it can be a bit confusing, but frankly, it doesn’t need to be that way. It’s fair to say that this was an mCRPC [metastatic castration-resistant prostate cancer] population. They had to have had a qualifying 

 mutation of 15 genes that were prespecified. That was largely because of great work that had been done in earlier trials known as TOPARP-A and TOPARP-B. We divided patients if they had 1 of these 15 gene alterations and had mCRPC, progressing on a novel hormonal agent. They could have also had a prior taxane.

. There were 245 patients. Cohort B included the other 12 gene alterations in the panel. The patients were randomized 2:1 in either cohort A or cohort B. They would receive 300 mg of olaparib, which is 2 tablets twice a day, vs a control. In the control group, if they had had abiraterone, they’d get enzalutamide. If they had previously been on enzalutamide, they’d get abiraterone.

Similarly, in cohort B, with the other 12 alterations, the same randomization was used. The primary end point was rPFS. If indeed this was met, we would look at the objective response rates from a hierarchical standpoint analysis, which was done with a blinded independent central review. Subsequently, rPFS was analyzed for cohorts A and B. We then looked at other aspects, such as time to pain progression. Very interestingly, we also looked at overall survival in cohort A.

Moving to the punchline, I’ve already mentioned we had a statistically significant benefit in cohort A for rPFS. We also saw improvement for cohort B. For cohorts A and B, we had statistically significant rPFS benefit, which led to FDA approval for that 14-gene panel. One particular gene alteration, 

Several months later, we also had an opportunity to look at the overall survival. Those data were very nicely presented by Joaquin Mateo [MD, PhD,] at ESMO [the European Society for Medical Oncology Virtual Congress 2020], demonstrating the survival benefit with a hazard ratio in the cohort A group of 0.69. In comparison to the control physician choice of either abiraterone or enzalutamide, it was a benefit of nearly 5 months. This is a remarkable finding, especially given that about 80% of the patients crossed over in the physician choice arm.

When we looked at that crossover rate and then we reevaluated the overall survival benefit, the hazard ratio dropped from 0.69 to 0.42, which we were incredibly pleased to see. Therefore, this is a rather compelling aspect of the PROfound trial. It demonstrated for the patients with 

 mutations, particularly in cohort A, an rPFS benefit, and now a rather significant overall survival benefit.

This is an oral medication. It’s given twice a day, and for urologists who are focusing on advanced prostate cancer treatments and have advanced prostate cancer clinics, this is a really welcome offering. It’s also welcomed by our medical oncology and radiation oncology colleagues. This will improve patients’ requirement for other antineoplastic therapies. We also demonstrated a reduction in pain progression and a rather significant improvement in objective response rates.

This was one of the most landmark papers and trials of 2020. In terms of some safety and adverse event issues, there are some unique aspects to the class of PARP inhibition medications. There can be some myelosuppression. One needs to monitor hemoglobin, platelet, and white blood cell counts. The transfusion requirement in the trial was low, more so than one might see in the continuation of sequencing an ARPI, or an androgen receptor pathway inhibitor. But the degree of transfusion requirement is not what you typically would see with patients with high-volume disease requiring taxane-based treatments.

This is a rather important advancement, not just for the recent FDA approval, but globally, for all of our colleagues who treat mCRPC.

A Look at the PROfound Trial

We’ve known for quite some time that PARP inhibitors and their mechanism of action as a class have clearly benefitted patients with advanced breast, ovarian, and most recently, for pancreatic cancer. But for the purposes of our conversation today, we now have demonstrated in the phase 3 PROfound trial, the only phase 3 trial completed and published to date, that if you have an 

 mutation, there is a clear radiographic progression-free survival benefit [rPFS] and an objective response rate benefit for patients with 14 of the 15 gene alterations. But it was predominantly driven by the cohort A with alterations in 

 mutation will always benefit. We need to better understand the association between biallelic, monoallelic, and other resistance patterns to PARP inhibitors. But what’s particularly compelling are the Kaplan-Meier curves and overall survival [OS] benefit that we published in 

. This is attributable to wonderful leadership from both Maha Hussain [MD, FACP, FASCO,] and Johann de Bono [MD, MSc, PhD, FRCP]. We need to learn more about PARP resistance. We need to learn more about the low-level prevalence single-gene alterations, and that’s always a very important topic. But if a patient has one of these gene alterations or the 

 mutations that we described and reviewed in the PROfound trial, it’s so important that you test. Test to see if these patients have this alteration. You can potentially have an open discussion to see if that’s of benefit for them prior to or after receiving other mCRPC [metastatic castration-resistant prostate cancer] treatments. The nice thing about the PROfound trial and the approval is that patients with mCRPC, whether they received abiraterone or enzalutamide in the mCSPC [metastatic castration-sensitive prostate cancer] space or in the mCRPC space, can potentially benefit from olaparib.

When we looked at the safety and tolerability after we demonstrated rPFS and OS data for patients who have 

, and benefitted from the use of olaparib, it’s important to recognize that these patients had very high tumor burden. They had previously undergone many other lines of therapy. Two-thirds of our patients had also received taxane therapy, and a third of that two-thirds had received multiple lines of taxane-based therapy. When we look at the benefit in cohort A, it’s very clear from an rPFS and OS standpoint. These patients had a lot of lines of treatment, heavy tumor burden, and yet the overall safety and adverse events profile was entirely consistent with what we’ve seen with other PARP inhibitor experiences in other tumor lines. You want to look for myelosuppression. Yes, there can be some mild to moderate GI [gastrointestinal] issues, but overall, they’re very manageable.

Our medical oncology colleagues have seen this when they’ve used PARP inhibitors in nonprostate advanced disease states. For our urology oncology colleagues, they will embrace the use of this oral twice daily medication and feel excited about having the testing. When you have positive results, it expands your treatment armamentarium and options for your patients with mCRPC. For all of us who do clinical trials, it’s a very fertile area for combinations and ultimately for using PARP inhibitors more proximally in the prostate cancer journey.

The Role of PARP Inhibitors in Prostate Cancer

One of the things I’m particularly interested in as the clinical trial landscape evolves, and I do a lot of clinical trials, is how can we best combine PARP inhibitors with other therapies? There are many trials right now combining PARP inhibitors with drugs such as abiraterone, AR [androgen receptor] inhibitors, enzalutamide, and radiopharmaceuticals such as radium-223. This is a really interesting aspect. Can we ultimately move the PARP inhibitor class up into mCSPC [metastatic castration-resistant prostate cancer]? Those trials will be ongoing as well, and therefore we continue to make strides for these patients who ultimately will succumb to a terminal disease.

What about the impact of COVID-19 [coronavirus disease 2019] in mCRPC? What a remarkably unusual and anxiety-provoking year for all patients with cancer, and sometimes we see these surges, which can certainly stymie our ability to get access to patients and vice versa. This is something that we all share globally in how we navigate this. There’s no doubt that this has led to a tremendous amount of anxiety and fear for patients. That goes for all patients with terminal cancers, but particularly the ones I’m seeing in GU [genitourinary] oncology are patients with mCRPC. The ability to have an oral therapy during the pandemic is of obvious benefit, because patients don’t have to come in and be exposed in the clinic for an intravenous, subcutaneous, or even an IM [intramuscular] application. This protects patients. This also protects our health care teams. This is somewhat of a truism across the board. Our typical patients with mCRPC are elderly, immunocompromised, and have other comorbidities. The risk of these patients getting SARS-CoV-2 would be devastating. Having the ability to continue to offer outpatient treatment via oral therapy is a real advantage.

We have done a lot of telemedicine, and sometimes it’s still clearly important to do a physical examination, but we are improving our ability to get outpatient blood drawing and urine monitoring for infection, to limit the extent and requirement of outpatient imaging. That said, telemedicine has been a real silver lining to reassure patients and their caregivers. We are still monitoring them to see how they are doing and continue that full-throated discussion we describe as the patient-physician shared decision-making. It’s absolutely essential. For health care providers, it’s improved our ability to articulate and communicate better. I find that I’m seeing patients more frequently through telehealth than I would be previously when asking them to come in to the clinic, even in the pre-pandemic era. There’s a lot of arduousness. This has actually been, in some remarkable ways, very beneficial to patients with advanced mCRPC.

They’re able to continue to get family support at home through telehealth and telemedicine. It’s challenging now when positivity rates for SARS-CoV-2 are high. We limit, depending upon your clinic or hospital system, the ability of caregivers to come in, especially if they’re hospitalized. Telehealth allows that level of family support because there can be as many people in the room that are as safe as possible. It’s a trying time. With the development of vaccines, we all look forward to getting this pandemic under better control.

But having oral therapies, such as PARP inhibitors, makes a significant difference to patients who have appropriate 

. We see throughout that the prevalence of these other single-gene alterations is low, but we will continue to aggregate and learn more from other trials. In addition to PROfound and TRITON2, there is an upcoming readout on TRITON3. There are other PARP inhibitor trials going on with other drugs that will perhaps help us get a better understanding of these other single-gene alterations that don’t have the same prevalence as the 

It’s important to always continue to support our patients with nutrition and exercise regimens, and reassure them that we have so many different options for them. But I would add and conclude that it’s important to test. If you haven’t tested, then you can’t really know if someone can benefit from the new advancements of PARP inhibitor therapy, specifically for olaparib with the 14-gene panel.

I hope that you found this helpful. I enjoyed the opportunity to speak with you, and I’m glad that you can have an opportunity to review the numerous KCast prostate program segments. I wish you great success in taking care of your patients with advanced prostate cancer. Thank you very much.

COVID-19 and Treating Metastatic Castration-Resistant Prostate Cancer

Treatment Options in Metastatic Castration-Resistant Prostate Cancer: A Year In Review

Dr. Neal Shore reviews treatment options in metastatic castration-resistant prostate cancer available in 2020.

Treatment Options in Metastatic Castration-Resistant Prostate Cancer: A Year In Review

EP 1: Overview of Metastatic Castration-Resistant Prostate Cancer

EP 2: Genetic Testing in Metastatic Castration-Resistant Prostate Cancer

EP 3: Genetic Testing: A Conversation with Your Patient

EP 4: Newly Approved Agents for Metastatic Castration-Resistant Prostate Cancer

EP 5: A Look at the PROfound Trial

EP 6: The Role of PARP Inhibitors in Prostate Cancer

EP 7: COVID-19 and Treating Metastatic Castration-Resistant Prostate Cancer