Treatment Options in Metastatic Castration-Resistant Prostate Cancer: A Year In Review - Episode 4

Newly Approved Agents for Metastatic Castration-Resistant Prostate Cancer

December 20, 2020
Urology Times staff

Neal Shore, MD: 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 HRR 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 HRR 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, HRR 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 BRCA1/2, 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.


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 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, and I’ll focus discussion on the recent data that’s been presented at ASCO 2020 and ESMO 2020 from the PROfound Trial. So let’s begin.

One of the things to first sort of table set for is the landscape of mCRPC. We’ve made a lot of progress since 2010. We now have nine (9) survival prolonging approved agents by the FDA, which I think is rather remarkable. Yet still 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 these patients, evaluating these patients, I typically talk about, with my patients, the importance of sort of a three-legged stool approach or three aspects, and that is of course symptomatic performance, changes in symptomatology, which requires a detailed exam and history. Additionally, the second part would be imaging. And the frequency of imaging is predicated upon the assessment of the patient’s biology and their symptoms. And that includes traditional conventional imaging, CT Scan, bone scan. And the other thing that’s really, we’ll sweeping across the globe in various regions, is the augmentation of next generation imaging, and particularly PET PSMA scans.

So imaging in conjunction with symptoms, and third is labs, laboratory assessment, and it’s not just PSA but PSA is obviously very important, but it includes the complete blood count of the CMP – Complete Metabolic Profile – and other factors as well, other biomarkers. LDH, sometimes other markers such as CTCs, Chromogranin A, etcetera.

As it relates to the factors that I consider in treatment, it’s everything that we just talked about but also now we have other biomarkers, such as the recent recognition of DNA repair damage gene alterations, or what some would call also homologous recombinant repair gene mutations. And that allows us to offer PARP inhibitor therapy.

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

And how do we make these treatment selections? Of course, prior lines of therapy come into play. There’s been a lot of recent data over the last few years demonstrating that sequencing AR pathway inhibitors is really not an optimal strategy, and that happens quite frequently, for understandable reasons: oral medication, overall good tolerability. But we certainly now have radiopharmaceuticals, taxanes, PARP inhibitors, immunotherapy in the US, which allows us to really give a more thoughtful consideration of optimizing care. And of course the more therapies a patient can receive in a timely way, data clearly suggest will improve their long-term survival.

So these are all of the factors that I think weigh into sequencing appropriately, the patient’s biology, the phenotype of the disease, what prior therapies they’ve had, and it’s important to do an appropriate monitoring – lab work, symptomatology, and timely imaging.

Now one of the things that I think has really changed in 2020 has been, at least in the US, is the FDA approval in May of 2020 of two PARP inhibitors for mCRPC patients. Now there have been additional PARP inhibitor approvals by EMA and throughout the world, and still with further regulatory review. And the importance here is testing. Genetic and molecular tests are now available to us, and they include patients who have alterations that they may have inherited from their mother and father, and this is under the umbrella of germline testing.

If there is a significant HRR mutation inherited from a parent, this will then pervade all cells. But the germline mutations, which are easy to obtain – a simple blood test or saliva through buccal mucosa, or even a blood test. And so this can be extremely helpful. Having said that, if we just stopped with anetic(?) germline mutation assessment, we would miss another 50% of patients who would be in the mCRPC landscape who might have an HRR mutation. We found this now in multiple studies inclusive of the PFOfound Trial which I will also review.

So for my patients who present with metastatic disease I’m very cognizant and I like what’s evolved in the NCCN Guidelines. For metastatic disease they recommend germline testing in everyone, and 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 to getting tests is important and can be a rate-limiting factor. But as I’ve already stated, if you stopped at just germline alone, you might miss another 50% of patients who have HRR mutations in(?) the mCRPC population. And this has been well described by not only the PFOfound Trial but by studies and publications by Colin Pritchard, Elaine Castro. So I think this was a really important aspect.

Additionally, sometimes we’ll find other somatic mutations that are actionable potentially for clinical trial work or for other indications in addition to HRR mutations that could be found within germline.

So the world has changed rather significantly for all of our colleagues who take care of patients with advanced prostate cancer, inclusive of neurologists, medical oncologists, and urologists. In the US the FDA has approved a 14 HRR mutation gene panel. The most prominent driver here is the BRCA gene, or BRCA2. And this now has been demonstrated to have real value in PARP inhibition, not just in prostate cancer but also in ovarian cancer, breast cancer, and pancreatic cancer.

So 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, your, your armamentarium, your toolbox, to offer patients. Or what some would describe to 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, I think for patients who are newly-diagnosed with high-grade disease or have a family history of significance, and I would encourage our listeners to look at what has been listed as what is significant. Certainly one or more cancers, consistent of prostate cancer, breast cancer, ovarian cancer, colorectal cancer, pancreatic cancer, especially if one of those family members was 60 or under that age. But additionally really any high-grade disease. I check germline in all of these patients. That’s in the nonmetastatic population.

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

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

So I think the most important thing is it’s not about consideration, it’s about that you must test. Because based upon the PROfound Trial, the recent, which is a phase 3 trial with two New England Journal publications, and the TRITON2 paper, we now have, at least in the US, two distinct PARP inhibitors that one could avail themselves for a consideration with their patients who are navigating the mCRPC landscape. Now let’s talk about PARP inhibition in mCRPC.

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

And I think it’s important to recognize this that one wants to now enter the arena of precision, or real true personalized therapy. So by way of using either a germline test or somatic tissue or somatic liquid, if you find an HRR mutation, now patients can potentially benefit from this when they have mCRPC.

Now there are some variations on who can benefit as it relates to the approval in the US for olaparib. It is approved for mCRPC, HRR mutation patients, a 14-gene panel, as long as the patient has progressed of having received a prior novel hormonal agent and is mCRPC. And those NHAs include abiraterone, enzalutamide.

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

For rucaparib, it’s a little bit different. Patients on their label approval have to have proceeded through progression of a novel hormonal agent, as well as a taxane, and be mCRPC, and it’s approved for patients with gene alterations of BRCA2 and 1, not the full 14-gene panel. But nonetheless, these are both really dramatic advances in 2020.

So this has really ushered in the arena, the area of what we’ve often, and for a long time have said, how can we better taylor 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 point in them, whether it’s a radiopharmaceutical or a taxane-based therapy, or for that matter, clinical trials.

Let’s take a deeper overlook right now at the PROfound data. I had the great honor to participate in this study and be part of the Steering Committee, but it was really brilliantly led by Johann de Bono and Maha Hussain.

And what we were able to demonstrate within a one-year period was meeting our primary endpoint initially of radiographic progression-free survival. And that led to a New England Journal publication. What we were able to see in patients who had been heavily pretreated, all had received novel hormonal agents, and about two-thirds had received a taxane therapy upwards of a significant portion of those patients who had received taxanes it was oftentimes several taxane therapies.

These patients had extensive bone disease and a high percentage also had visceral metastases. And fortunately what we were able to demonstrate in this study was that patients had clearly met an RPFS of a nearly four-month benefit, particularly in what was described as Cohort A. Cohort A was the group of patients who had either BRCA2 or 1, or ATM.

Just to quickly review the clinical trial design of PROfound, because sometimes it can be a little bit confusing, but frankly it really doesn’t need to be that way. I think it’s fair to say that this was an mCRPC population. They had to have had a qualifying HRR mutation of 15 genes that were prespecified of these 15 gene alterations. Largely because of great work that had been previously done in earlier trials known as TOPARP-A and TOPARP-B. We divided patients then if they had one of these 15 gene alterations and had mCRPC progressing on a novel hormonal agent, they could have also had a prior taxane.

Cohort A was B1, B2, or ATM. Now there was 245 patients. Cohort B was all the other, the other 12 gene alterations in the panel. And the patients were randomized in either Cohort A or Cohort B to a 2-to-1. So they would receive olaparib, 300 milligrams, which is two tablets twice a day, versus a control. And the control was if they had had ABI, they’d get ENZA. If they had ENZA, they’d get ABI.

Similarly in Cohort B, with the other 12 genes, alterations and the same randomization. And the primary endpoint was rPFS. And if indeed this was met, that we would look at from a hierarchical standpoint analysis the objective response rates, which were done with a live and independent central review. And then subsequently rPFS for Cohort A and B; and then looking at other aspects such as time-to-pain progression. And then very interestingly, overall survival in Cohort A.

So moving to the punchline, obviously I’ve already mentioned we had a statistically significant benefit in Cohort A for rPFS, and we saw also improvement for Cohort B. But also for Cohort A and B we had statistically significant rPFS benefit, which led to the FDA approval for that 14-gene panel. One particular gene alteration – PPP2R2A – was removed.

Several months later we also then had an opportunity to look at the overall survival, and that data was very nicely presented by Joaquin Mateo at ESMO this year, 2020, demonstrating the survival benefit with a hazard ratio in the Cohort A group of .69. So in comparison to the control physician choice of either ABI or ENZA, it was a benefit of nearly five months. And this is really a remarkable finding, especially given the fact that about 80% of the patients crossed over in that, in the physician choice arm.

So when we looked at that crossover rate and then we reevaluated the overall survival benefit, the hazard ratio dropped from .69 to .42, which we were incredibly pleased to see. And, therefore, I think this is a rather compelling aspect of the PROfound Trial demonstrating for the patients with HR mutations, particularly in Cohort A, rPFS benefit, and now a rather significant overall survival benefit.

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

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

I think this is a rather important advancement, not just for the FDA recent approval but globally for all of our colleagues who treat mCRPC. 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. And so there are many trials that are out there right now combining PARP inhibitors with drugs such as abiraterone, drugs such as AR inhibitors, enzalutamide, additionally combining PARP inhibitors with radiopharmaceuticals, such as Radium-223. I think this is a really interesting aspect. Of course, can we ultimately move the PARP inhibitor class up into mCSPC. Those trials will be ongoing as well, and so therefore we continue to make strides for these patients who ultimately will succumb to a terminal disease.

Now, what about the impact of COVID 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 for them to get access to us. This is really 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, all patients with terminal cancers, but in particularly the ones that I’m seeing in GU oncology, our mCRPC patients. I think 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 application, or subQ, or even an IM application. This protects patients. This also protects our healthcare teams. So this is sort of somewhat of a truism across the board. Our elderly patients who just typically mCRPC patients, they have immunocompromise, they have other comorbidities, and the risk of these patients getting SARS-CoV-2 would be devastating. So having the ability to continue to offer outpatient treatment oral therapy I think is a real advantage.

We have done a lot of telehealth or telemedicine, and sometimes it’s still clearly important to do a physical exam, but we are improving our ability to get outpatient blood drawing, outpatient urine monitoring for infection, and sort of limiting the number and requirement of outpatient imaging. That said, I think telehealth and telemedicine has been a real silver lining to reassuring patients, their caregivers, and monitoring them to how they are doing and continue that full-throated discussion of what we describe as the patient-physician shared decision making. And it’s absolutely essential. I think for healthcare providers, it’s improved our ability to articulate and communicate better. What I find is I’m actually seeing patients more frequently through telehealth than I would be previously asking them to come in to the clinic, even in the era of non-pandemic, because there’s a lot of arduousness associated oftentimes with that travel, and showing up, and logging in or registering at the clinic. So I actually think that this has actually been, in some remarkable ways, very beneficial to advanced mCRPC patients.

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 and we limit, depending upon your clinic, your hospital system, the ability of caregivers to come in, especially if they’re hospitalized. And telehealth allows that level of family support because there can be as many people in the room in their pod that is safe as possible. It’s a trying time. Certainly with the development of vaccines, we all look forward to getting this pandemic under better control.

But having oral therapies, such as PARP inhibitors, I think make a really significant difference to patients who are appropriate, who have appropriate HRR mutations, largely led by BRCA2. But we see throughout, the prevalence of these other single-gene alterations is low, but I think if we continue to aggregate, we continue to learn more from other trials, in addition to PROfound, TRITON2, upcoming readout on TRITON3. There are other PARP inhibitor trials that are going on with other PARPs that will really help us perhaps get a better understanding of these other single-gene alterations don’t have the same prevalence as the BRCA gene alterations.

I think it’s important to always continue to support our patients with nutrition and exercise regimens, and reassure them that we do 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 really 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 really enjoyed the opportunity to speak with you and that you can have an opportunity to review the newest KCast Prostate Program segments, and I wish you great success in taking care of your patients with advanced prostate cancer. Thank you very much.

Excellent. Thank you so much. That was perfect. As we were going through, there was a couple questions maybe I’d like to ask you per section, not every section but a little bit, maybe you could add a sentence or so. For section I, I know you already did speak a lot on this, but how do you tell your patients to get tested? Is there a certain way that you say it or just straight up, “I think you should get tested.”
 What is your approach there. And then within that, the mutations beyond BRCA, how has that changed your treatment? Can you maybe speak to those?

The first question is how do I discuss with patients getting tested?

Yes, exactly, please.

And the second question was how do I talk to patients beyond BRCA2.

Yes, please.

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

So my conversation hits on several points, first explaining that if we’re able to demonstrate through either somatic testing, or germline testing, or both, which I typically get both. And I get them as early as possible because I want to make sure we don’t lose control of the tissue, 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’s 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 and there are liquid-based tests that have been approved by the FDA that further allow us to recognize somatic alterations that are blood-based tests. That’s really what liquid means.

Now, I explain this to patients in a much more simplistic way saying we’re just going to review your archived tissue to see if there are gene alterations. While we’re doing that, we now have approved therapies that if you fall into that 25%, I have that in my toolbox, in my war chest to treat this cancer. Now, additionally upon that, if they happen to have a germline alteration, then it predisposes them potentially to other malignancies. And also, equally importantly, I explain that it could affect their own family members, particularly their children, nieces, nephews, and siblings and how they may want to also then get tested. And if they were 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. And that includes various syndromes such as hereditary breast, ovarian cancer syndromes, Lynch syndrome.

So, in addition to picking up alterations that can lead to oral medications, there’s also some alterations that demonstrate the ability to use checkpoint inhibitors, immunotherapies. And I review it with my patients in really those sort of very simplistic terms, and 99% of my patients will say, please move forward as long as there’s not some accessibility or cost factor. They really understand it enhances their optionality for treatment to help them individually and may also help their children, their nieces, nephews, and their siblings.

Regarding patients who are not BRCA2, and BRCA2 is the chief driver of the; very significant, highest percentage of the HRR mutations are in BRCA2. But we also see mutations and the PALB1, 2, CHEK1, CHEK2, CDK12, and these are all important alterations, these gene alterations. Sometimes we may see a demonstration of what’s described as a variant of uncertain significance, and so that isn’t necessarily actionable at the current time. But there are ongoing biorepositories and additional clinical studies which could give us additional helpful clinical information in the future.

I explain that to patients, and I say, well, the majority of the time that we’re going to be doing the somatic testing, we may not find something that’s going to help you right now. But certainly in 25% of patients we do, but the remaining patients who don’t have an actionable approved therapeutic right now, we may have clinical trials that they could benefit from. I think this is extremely important. And clinical trials are part of the recommendation of all the major guideline organizations. And then going forward there are alterations of uncertain significance which could change over time. So the alterations that we find now, there are FDA approved indications for not only PARP inhibition but also with MSI-high or TMB-high mutational burdens. We have checkpoint inhibitors as well, in addition to clinical studies.

Thank you. One more or two more little things here if we can add kind of around the PROfound data. Could you maybe discuss the importance of having pre-chemo patients included in the trial? I don’t know, you did say something a little bit about the time to use olaparib. Is there anything you want to add? And then can you specify the three tumors that you can use olaparib in? Ii know you just in this segment kind of said some more, but just to summarize it here.

We’ve known for quite some time that PARP inhibitors and their mechanism of action as a class have been clearly of benefit for patients with advanced breast cancer, and ovarian cancer, and now most recently for pancreatic cancer. But, for purposes of our conversation today, we now can demonstrate that if you have an HRR mutation, as demonstrated in the phase 3 PROfound Trial, the only phase 3 trial completed and published to date, we saw a clear survival benefit, a radiographic progression-free survival benefit, an objective response rate benefit for patients with the 14 or the 15 gene alterations. But it was predominantly driven by the Cohort A of BRCA2, 1, and ATM.

Not everyone who has an HRR mutation will always benefit. We need to better understand the association between biallelic and monoallelic and other resistance patterns to PARP inhibitors. But what’s particularly compelling is the Kaplan-Meier curves and the overall survival benefit that we published now in New England Journal. I think that this really is attributable to wonderful leadership and recognizing that from both Maha Hussain and Johann de Bono. 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 you have one of these gene alterations or the HRR mutations that we described and we reviewed in the PROfound Trial, it’s so important that you test to see if these patients have this alteration and can potentially have an open discussion and to see if that’s of benefit for them prior to or after receiving other mCRPC treatments. The nice thing about the PROfound Trial and the approval is that mCRPC patients, whether they receive ABI or ENZA now in the mCSPC space or in the mCRPC space, can potentially benefit from olaparib.

Thank you. Lastly, is there any other advice you have for community oncologists who would consider PARP inhibitor for the first time? Just in your experience, what would you tell them?

So, when we looked at the safety and tolerability after we demonstrated rPFS and OS data for patients, who have HRR mutations largely driven by BRCA2, who benefitted from the use of olaparib, I think it’s really important to recognize that these patients had very high tumor burden, had previously undergone many other lines of therapy. Two-thirds of our patients had also received taxane therapy, and I think 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. So a lot of lines of treatment, heavy tumor burden and yet the overall safety and adverse events profile entirely consistent with what we’ve seen with other PARP inhibitor experiences in other tumor lines. Yeah, you want to look for myelosuppression. Yeah, there can be some mild to moderate GI issues but overall very manageable.

I think our medical oncology colleagues have seen this when they’ve used PARP inhibitors in non-prostate advanced disease states. I think for our uro-oncology colleagues, they will embrace the use of this oral twice daily medication and feel excited about having a) the testing. When you have positive results, it just expands your treatment armamentarium and options for your mCRPC patients at the current time. And for all of us who do clinical trials, it’s a very fertile area for combination and ultimately for moving PARP inhibitors more proximally in the prostate cancer journey