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Metastatic Castrate Resistant Prostate Cancer: 65-Year-Old African-American Male


Around the Practice: Metastatic Castrate Resistant Prostate Cancer

Dr. Raoul Concepcion: Let's go ahead and get onto the second case, which is a patient with metastatic castration-resistant prostate cancer. And in this particular case, we have a 65-year-old African-American male referred from primary care with a recent elevation of his prostate specific antigen level of 4.4 nanograms per deciliter, and an abnormal digital rectal exam. His past medical history is as listed. He's had some knee arthroscopy, nothing major surgically, he's on some thyroid replacement and a beta blocker. He is not a smoker, does not consume excessive amounts of alcohol.

He does have a family history of prostate cancer in his paternal uncle and older brother, both diagnosed in their 50s, on digital rectal exam his prostate was felt to be about 45 grams with a 15-millimeter nodule to the right base. He underwent transrectal ultrasound, guided bias to the prostate, and unfortunately had 12 of 12 positive cores for Gleason gray group 5, four plus five, had a staging workup which showed a CT they had known in pelvis, no evidence of metastatic disease.

Bone scan showed increased uptake, multiple ribs, right T8 for Tibro body, left posterior acetabular region, right proximal femurs. So, this is a patient that essentially is now presenting with newly diagnosed, very high-risk, metastatic castration-sensitive prostate cancer. Here are representatives of his bone scan and polling question one, what is the role of genomic testing for this patient? Yes, germline only. Yes, somatic only. C. Yes, both germline and somatic. D. Unsure.

So, while the audience is opining on those, Dr. Kim, I'm going to start off with you. So obviously a patient presents with high-grade tumor, multiple match, probably not in the category of oligometastatic disease, multiple bony mets. In your mind, what is going to be the role of managing his primary tumor? Is that something that's currently ongoing in your practice with your urology colleagues, tell us where you consider managing the primary tumor in somebody that presents with metastatic disease? Do you have any great data to support that?

Dr. Paul Kim: I think that radiotherapy to the primary site has 2 roles: one, if the patient was symptomatic, then you can give a palliative course radiation. But interestingly, part of the stampede trial, they did look at patients with low-volume disease. In that trial. there was fewer than 4 bone metastases. And they gave a pretty therapeutic dose to the prostate, it was like 36 and six-grade fractions. And then they did find that those patients that had improved clinical outcomes as an alternative to dose attacks, also there is good data to support radiation to the primary site for metastatic disease.

So in this case, since there's a bit more than 4, it would be a stretch to apply that data to this particular case, but there is good grounds to do with all of them metastasis.

Dr. Raoul Concepcion: This is an area of interest, especially as we try to control local disease as well as systemic disease. So, here's the polling: some would say germline only, nobody would vote for sematic only, and one is unsure. So, Dr. Kassabian in your practice, how are you currently deploying genomic testing? And what is your preference in somebody like this as it is? Are you doing both germline and somatic?

Dr. Vahan Kassabian: Yeah. So for patients who present with metastatic hormone sensitive prostate cancer, which unfortunately we're seeing more of, because of the PSA debacle in 2012. I start off with germline testing, especially if they have a family history, but per the NCCN guidelines, the fact that they're presented with metastatic disease, they clearly are candidates for germline testing. If the germline testing is positive, I stop there, I now no longer need to go to somatic testing. If the germline is negative, I will proceed at some point in time in their journey of prostate cancer with somatic testing.

I may do it now if I have enough tissue, but as you know, it only affects treatment once they fail an anti-androgen, either abiraterone (Zytiga) or enzalutamide (Xtandi), along with androgen deprivation therapy (ADT). So it's further down the road that we can prescribe one of the PARP inhibitors. So for that reason, I sort of wait to see when I get enough tissue, for example, if they have a channel to URP because they wanted to retention, then I'll do it then, or I have a significant amount that's easy to biopsy.

As you know, bone biopsies are difficult, it can be painful. So for these patients, I start with germline and if it's positive, I stop. If it's negative, I'll consider somatic testing at some point down the road in their journey. With regards to the treating the primary with radiation therapy, I'm in favor of that notion, especially if they have a big bulky prostate, the bigger, the bulkier, the more chance they're going to have bladder outlet obstruction and local progression, so I think it helps alleviate some of that.

I don't necessarily start the radiation right away, I'll give him several months of ADT and then consider giving him the radiation. But in patients who present with a benign feeling prostate, I may have second thoughts about initiating radiation to the prostate.

Dr. Raoul Concepcion: Okay. Dr. Tripathi, what's from the medical oncology standpoint? How do you deploy genomic testing in these newly diagnosed patients who are very obviously very high risk and present with metastatic castration sensitive disease?

Dr. Abhishek Tripathi: Yeah. So, our approach has been to test for both. We can talk about the sequencing of those, and I think that's not as much important as the importance of doing both, because it's important to understand that they both provide complimentary pieces of information. So, the germline testing is mostly limited to a smaller panel of genes that are of inheritance and have implications for family in terms of cancer screening and cannot identify therapeutic options down the [inaudible 00:31:38] as well. Germline testing panels actually a month larger and are able to capture a lot more of those genes.

I think the current number is about several hundred genes, depending upon which platform you use and whether using tissue or blood. And a lot of them are not captured by the germline testing currently because they may not have screening and publications, or we don't know their implications for hereditary part just yet. And they may still open up a treatment option for these patients and for example, PARP inhibitors is a stark example, but the, the list of genes that is listed in the approval for PARP inhibitors is actually quite extensive, it's about 15 genes. And not all of them may be captured in the germline [inaudible 00:32:24].

So, I usually do both and I help the patient understand why we need both, because they both offer a complimentary pieces of information that is helpful in individualizing the care of the patient. I think everybody should get germline at the minimum and then this somatic testing can be done. As previously mentioned when they become castration resistant or potentially early on, sometimes farther down the line, there's not enough tissue to do biopsy that has not been radiated and treating them in different modalities. If they have bone only metastases as previously said, they can be quite painful to biopsy.

So in those situations, our options are usually limited to either going back to the prostate specimen that we originally had or doing a blood based biopsy and liquid cell-free DNA, I say, but you also has quite concordant results. So you use both of them interchangeably, but I do now make sure that all of our patients get both sequencing at some point during the course of their treatment history.

Dr. Raoul Concepcion: I think that that is at least what I can tell, and then talking to some of your colleagues and our colleagues in both the urology and medical oncology field, is that there is obviously a bigger push to test early, even in the newly diagnosed patients, because even though as Dr. Kassabian appropriately stated that, "Yes, we do have, we do have PARPs, and there seems to be more of a preponderance to, to discover those mutations later on after they've been heavily pretreated." But I think as you just made, mention Dr. Tripathi is that testing early, obviously I think also it opens up potentially many more options.

So his germline testing was negative. So he basically did not have any mutations in homologous recombination or mismatch repair. Somatic testing really showed a mutation. It looks like it was a nonsense mutation with loss of function, tumor mutation burden was low, and he was MSI stable. So you've got a patient really here with [inaudible 00:34:46], not a lot of big tumor mutation burden, MSI stable doesn't appear to have a pathogenic variant that sometimes you might see.

Again, looking at mostly at the, at the DNA damage repair genes, looking at mismatch repair as well as homologous recombination. So in this particular patient, let's summarize, we've got a fairly healthy 65 year old African-American strong family history of prostate cancer, Gleason group grading group 5, 5 + 4, germline negative, no pathogenic somatic mutation, and who presents with metastatic castration sensitive disease. I would treat this patient with ADT, whether it'd be an agonist, antagonist, injectable, or an oral only as monotherapy, ADT plus docetaxel, ADT plus an androgen receptor targeting agent, which could be enzalutamide., it could be abiraterone D other.

So Vahan while the audience is voting. What's your preference for this guy?

Dr. Vahan Kassabian: So he has high volume metastatic hormone sensitive, or castration sensitive prostate cancer. So I think your options are ADT obviously as the foundation, but I think adding either taxotere or abiraterone or enzalutamide or apalutamide, I think are all reasonable options. I think it depends on, do you want to be one and done and then follow these patients? And that's the case of chemotherapy or for patients that are chemotherapy averse, I think I would consider the orals. A lot of studies that have shown a significant advantage of adding any of these therapies, especially in these high volume patients. Low volume patients, that's a little bit of a different story, but in this high volume patient, I think all options are on the table.

Dr. Raoul Concepcion: Dr. Kim, what's the role of the ADT plus an additional agent plus maybe adding radio external beam to say he had some symptomatic areas. What are your thoughts on that?

Dr. Paul Kim: Since T has high volume, it will be hard pressed to say that he has metastasis, but certainly if he has symptomatic disease, palliative therapy would be an order. And there was a recent trial from Canada looking at using high dose SBRT regimen when to fractions and that's offered a couple of things, compared to conventional radiation over 1 week, it offered more durable palliation, but also offered better local control.

So I think we're kind of getting into an era, since the technology to deliver such a great therapy has been improving, some of the blurring of the lines of what's SBRT? What's conventional and what these doses mean? For the purpose of the palliation, that is where we're heading.

Dr. Raoul Concepcion: Okay. Thank you. Dr. Tripathi: ADT plus something else, whether it be a taxane, docetaxel or an antigen receptor targeting agent, what are your thoughts from a medical oncology perspective?

Dr. Abhishek Tripathi: Yeah. I absolutely agree. I would just rephrase that question for the patient and the question would be not really which one, it will be which one first? Because we know that these patients are going to need all of these therapies in different sequence. And we know that androgen receptor inhibitors are cross resistant based on the phase 2 crossover data that if you receive abiraterone, you don't want to follow it up with enzalutamide directly over because of cross-resistance and the response rates go down significantly.

So I've talked to the patients that there is hormone-based therapies, abiraterone, enzalutamide, and apalutamide, and so forth, and there's chemotherapy options. If he chooses a hormone-based therapy, then chemotherapy will be most likely his second option going forward. And if he chooses chemotherapy now, his options would be open to both hormonal therapy or the novel taxane cabazitaxel.

So to have the patients understand that it's not a matter of which one to pick and choose. I think it's more a matter of sequencing. And there comes in some of the other aspects of the discussions is it just toxicities? How old is the patient right now? What's the performance status? How symptomatic are they? And those things go into the picture. Other things that can be an issue to discuss would be financial toxicity. So taxotere is a facility administered drug, patients usually do not have a lot of financial liability in that.

But I think some of these oral agents can be a little bit expensive specifically for the copay part of it that the patients may have to bare now, or we may have to apply for assistance for those patients. So I think all of these things kind of work together in forming a decision. I think absolutely this patient has high volume disease by charter criteria, he would have been eligible for inclusion in most of those studies in the hormone sensitive setting and all of them would have shown an improved overall survival than the therapy intensification.

One thing I would like to bring out, which I'm asked to frequently is can we do both of them? So for example, chemotherapy followed by switching them to apalutamide and enzalutamide. And I don't think that we have the data to support that adding both a novel hormonal agent and a chemotherapy agent improves. We sort of got a glimpse of that data in the ends of med data that was presented and that allowed for docetaxel. And the patients who got docetaxel on that trial, did not really seem to have an incremental benefit. So, I think there's a Goldilocks sort of a way of intensification that going beyond, uh, doublets at this point is not supported by data just yet.

Dr. Raoul Concepcion: Great comments. So a follow-up on that question you had mentioned the use of cabazitaxel obviously is still out there. We haven't really talked too much about cabazitaxel or Jevtana, so obviously the current approval is for patients that have failed or did not tolerate prior docetaxel therapy.

But I, I think actually, there was an article that came out today in one of the publications that using cabazitaxel, especially in patients with aggressive high-grade disease, seems to have some advantages. Dr. Tripathi, do you have any experience with that using cabazitaxel very early on? In a patient like this, obviously it would be off label per se, but say the patient maybe was not a candidate for docetaxel for whatever reason, have you ever used cabazitaxel in that setting with these very aggressive Gleason 4 + 5s?

Dr. Abhishek Tripathi: I would say not in the upfront setting, especially considering the comparison trial between cabazitaxel and docetaxel, would show the cons of similar outcomes. That'd be off-label use and honestly we haven't used that upfront for these patients. And the interesting thing is some of these patients who are not chemotherapy candidates might not be candidates cabazitaxel either.I think there is some shared patient characteristics that may play a role there.

That being said, there are patients who have very low PSA, high volume of disease, and they do not make much PSA and are not as much hormone dependent. And I always feel concerned about those patients being on hormone therapy and whether it should we expect a response or not. And for those patients, we can consider early chemotherapy, again, I would probably give docetaxel a try just to be compliant with the indication of the patients are going to switch to cabazitaxel immediately.

Dr. Raoul Concepcion: Yeah. And, and I think the key point here is which we've been trying to really hammer home to the audience, in the patients that present with metastatic castration sensitive, it is no longer acceptable to put them on androgen deprivation therapy alone, that the addition of a second agent, whether it be a taxane, whether it be an androgen receptor targeting agent, the data supports that its use as it delays the time to castration resistant prostate cancer and obviously improves survival.

So let's keep going with this case. The patient was given ADT, was started on Denosumab to basically reduce skeletal related events. He was also given the abiraterone acetate, as you both have mentioned some supplement vitamin D and calcium, PSA Nadir to 0.1 nanograms per deciliter, at year 1 bone CT scan showed no evidence of metastatic disease, year 1 bone scan, market improvement. These are representatives of his bone scan at year 1, as you can see multiple lesions throughout the skeleton as you both have noted a high volume disease.

But then in year 2, he starts to have a progressive rise in his PSA. Remember he did have a nice response to abiraterone acetate. His PSA started to rise a year or 2, that a PSA of 5.1, had some back pain, left hip pain, ECOG status of 1, progression of a bone scan now with new lesions to the right maneuver, BREEAM sternum, left T6 vertebrae, right posterior seventh rib, the left acetabular region, which obviously is now symptomatic based upon his clinical presentation.

As you said, Dr. Tripathi, he was moved from abiraterone, was given docetaxel, developed some symptoms, he had some peripheral neuropathy, some mucositis on a rash following cycle 1. They changed his dosing, split it, and basically from 75 milligrams per meter squared per meter square to 30 milligrams per meter square with split dosing. So again, he presented with metastatic castration sensitive, ADT abiraterone progressed with new bone lesions, received docetaxel and had some mild symptoms, had a reduction in his dose, year 1, post-taxane, PSA stable, bone scan, no further progression.

Year 2, patient reports, worsening pain to left hip and back again, was re-imaged and obviously has some lesions, got radium 223, as many in the audience know this is a radiopharmaceutical alpha emitter given once every 4 weeks for 6 doses. By year 3, post-taxane, progression of new lesions and now some pelvic lymphadnopothy, so he's got worsening bone lesions, has some new pelvic lymph nodes, and now his PSA is 16. So now, we have a patient who has seen multiple lines of therapy.

So he presented with metastatic castration sensitive disease, received ADT plus abiraterone, progressed to metastatic castration resistant prostate cancer, received docetaxel, had some mild side effects due to the docetaxel. And then continued to progress, got radium 223 from multiple bone lesions, and now is progressing again. So Dr. Kassabian, taking it to you, what are his options at this point?

Dr. Vahan Kassabian: Yes. Well, I would have treated him a little bit differently. When you became castrate resistant, I would have offered him immunotherapy in the form of sip tea, and then given him chemotherapy after some time. The reason I say that is because, I believe this patient was African-American and his PSA was in the single digits when it became castrate resistant, and that's the ideal patient, in my opinion to get immunotherapy. I don't disagree with the treatment that he had. I think the chemo is absolutely efficacious, but I would have reserved it for a little bit further down the line after I've given him immunotherapy.

You know, we have a limited amount. Actually, we have a lot of treatment options in the patients with advanced prostate cancer and I like to offer them all these therapies at some point in their journey of prostate cancer. So right now, I don't think he's an ideal candidate for immunotherapy, he's post-docetaxel and he's already gotten radium 223 and that's great. So I think at this point I would offer him cabazitaxel.

Dr. Raoul Concepcion: So we had an earlier discussion about how cabazitaxel is not approved currently in upfront therapy, but is approved for patients who have failed or not tolerated docetaxel, so which this patient falls into that category. Update us a little bit on some of the data that has come out regarding cabazitaxel, especially the CARD data and as well as the dosing data, as it relates to side effects with the use of that agent.

Dr. Abhishek Tripathi: Cabazitaxel as we know, it was approved initially in the post-docetaxel setting and it was compared to best supportive care at that point. And it resulted in an overall survival benefit and was subsequently approved for use. I think at the initial dose at 25 milligram per meter square, we were seeing a lot more hematologic toxicity, which was turning out to be dose limiting in certain instances in practice, it was quite frequent to see dose reductions to 20.

And subsequently, we had the non-inferiority study of 20 and 25 milligrams per meter square and ensure that, but even with the dose reduction to 20 milligrams per meter square, the overall survival was non-inferior and we had lower incidence of adverse events. And in practice, I think most of our patients are treated with 20 milligrams per meter square as the starting dose, because of that data. In terms of sequencing, I think there's been interesting data presented over the past year or so about sequencing between hormonal agents from the randomized crossover trial that abiraterone and [inaudible 00:50:47] and then supported by abiraterone is perhaps not the best and most ideal strategy.

But the question remained as to what should these patients be treated with, and what's the randomized data to guide that discussion. And in that setting CARD data fill that data gap quite nicely. It was randomized study and patients who had received prior AR targeted inhibitors and had a response, had progression within 12 months of it, were randomized to receive either cabazitaxel and a second hormonal agent, which they had not received previously, and which showed improved outcomes with the patients who were randomized to come out of the cabazitaxel. [inaudible 00:51:25] that are there previously, what we knew about cross-resistance between AR inhibitors.

So in practice, most of these AR inhibitors, you get one good shot at it because your best chance of response and longest response and most durable response happened for the first one, whichever one we end up choosing. And I think the responses are not as durable when the second one is used for a majority of the patients. And that's where I think cabazitaxel outcomes comes in for patients who are refractory to prior AR inhibitor therapy as a more ideal therapy compared to another AR inhibitor.

Dr. Raoul Concepcion: Great. Dr. Kim, tell us, what's going to be forthcoming from a radiologic nuclear medicine perspective for this type of patient, obviously with progressive bone lesions. Specifically what I'm asking you about is radioiodine therapy.

Dr. Paul Kim: That's an exciting new modality that is goinig to be arriving shortly with the PSMA diagnostic agent. There is no a PSMA agent that is being considered right now. And so, the first step would be to get a PSMA diagnostics again and see if there are other areas that we don't know about and see what extent bony and visceral disease and soft tissues disease exist and an armed agent like a PSMA therapeutic agent would be able to deliver radiation to both these sites of disease, both bony and soft tissue.

So now the patient trial just closed, apparently they met their end points and don't know much beyond that though, looking forward to their data. And even along that pathway, there are more agents coming on the pike. There is also now alpha meters being developed, and that's also exciting as well.

Dr. Raoul Concepcion: So in this particular patient, Dr. Kim, he's symptomatic in his left hip, and obviously he has progression. Do you have much experience relative to the delivery for palliation of external beam radiotherapy in a patient who has already received radium? I don't know that there's any contraindication to that, but I don't know that I've necessarily seen a lot of patients who have received palliative therapy post-radium. Do you have much experience with that?

Dr. Paul Kim: Overall it seems to be well tolerated. Certainly, it's encouraging that he got through all 6 cycles that tells us that wasn't stopped due to hematologic toxicity.
If you can give [inaudible 00:54:22] focally to areas that are symptomatic, I think patients find that they get a clinical benefit out of that. So, a lot of it has to do with volume you're trying to treat.

And if it's a focal, it should be very well tolerated without much impact on their hematological parameters. And now we can give doses and as few as a single fraction, two fractions, so you can adjust according to what you think the concern is.

Dr. Raoul Concepcion: Perfect. That's great. Vahan, I'm going to let you close this out. So in this particular patient, obviously cabazitaxel is an option, in clinical trial, as Dr. Kim mentioned, there's all kinds of trials out there. For the clinical urologists then, and this is a fairly typical patient, unfortunately, we do see these patients. What is your thoughts for this particular patient now on repeating genomic testing relative to metastatic biopsies, relative to liquid biopsies, other panels that are available to determine what other, what other next lines of therapy might be appropriate for this particular patient?

Dr. Vahan Kassabian: Yeah, great question. So I think it is the time to revisit somatic testing. As you know, these tumors can mutate. And so what may have been negative and somatic testing in the past, you may now find something that is worthwhile and treatable. How you go about that somatic testing there are several avenues. You can certainly go back to our KIBO tissue, you can go after a new lesion, as I stated earlier, and it was agreed upon bone lesions can be painful to, to biopsy.

Another option is a liquid biopsy, which can pick up some of these somatic changes. Circulating tumor cells, if you think they're abundant enough and I think in this case, they would be. I think a liquid biopsy test may also be worthwhile especially if their cargo tissue is insufficient or too old, or there aren't any good new lesions to go after in biopsy.

Dr. Raoul Concepcion: Great. And, and I think that's the important point. I think that what we're getting to now is that we are starting to obviously have more lines of therapy. We didn't talk too much about PARP inhibitors, and obviously there are, there are patients now as a small percentage, probably less than 15% that actually may be candidates for immunotherapy. As Dr. Kim mentioned, there's obviously clinical trials looking at novel agents, there's also bi-specific, therapies out there that are being investigated by multiple companies.

So I think this is true precision medicine, and I think this area is becoming more complex. And, it's really important that all of us continue to stay abreast of this.

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