Hi, I’m Nick Vogelzang, a medical oncologist in Las Vegas, Nevada.

Hi, I’m Dan Petrylak, a medical oncologist, Yale University, New Haven, Connecticut.

We’re here today to talk about the changing landscape of castrate-resistant and hormone-sensitive metastatic prostate cancer. Dan and I have both had the opportunity to be in this business for a full 30 or 40 years, and we’ve seen a lot of changes. The changes we’re seeing are continuous, and I’d like to spend a little time going over some of those changing landscape issues that Dan and I both have enjoyed watching and sometimes leading. Dan, what do you see as the biggest change in the last say 5 years or so?

I think the biggest change is the earlier use of agents that we had traditionally used in castrate-resistant prostate cancer, moving these agents up to the hormone-sensitive state. And we’ve seen a tremendous increase in the overall survival of men with metastatic prostate cancer by the early use of these agents.

What do you think about the use of docetaxel earlier? Is it catching on or is it not catching on?

I think it’s had a wave. It’s had 2 different waves of popularity so to speak. When it was first introduced by Chris Sweeney, MBBS, in the CHAARTED trial, we saw about an 18-month improvement in median survival for those patients who had high-risk disease, and 6 cycles of docetaxel without prednisone, and you were basically finished with your treatment.

Then with the introduction of abiraterone and prednisone in the same space, also now with enzalutamide, as well as apalutamide. We have other competing drugs, each of which have their own advantages and disadvantages; we’re seeing less of a use of docetaxel in this particular space.

I heard an interesting statistic the other day that only about 5% of patients in the United States are getting docetaxel in the hormone-sensitive state. Do you have a theory or a hypothesis as to why that is?

I think there are several reasons. There’s always this stigma that goes on with chemotherapy that it’s toxic, and you have to go to the doctor’s office to get an infusion as opposed to getting an oral pill with abiraterone or enzalutamide or apalutamide.

Well, I know I’m personally still using a lot of docetaxel, and I find that if you approach the patient right when they’re diagnosed, they’re not so negative about it, because they’re frightened. More importantly, you say, “Look, then I’ve got all these androgen receptor inhibitors that I could use after the docetaxel.” How do you use it in your practice?

I have a discussion about the short-term and the long-term adverse effects of these particular agents. Particularly with docetaxel we know that you can get some neuropathy and neutropenia. When you do the  6 cycles of treatment, you’re done—it’s over with, you don’t have to worry about taking a pill. We know that abiraterone and prednisone do have some cardiovascular effects. In fact, from Thomas Jefferson University last year there was a report that there was a high rate of cardiovascular events in patients with pre-existing cardiovascular events. For a patient who has cardiac dysfunction, I’m going to lean away from giving abiraterone and prednisone, and perhaps docetaxel, apalutamide, or enzalutamide.

Have you used a lot of the enzalutamide up front in the hormone-sensitive space?

I’ve used it to some degree, not a lot but to some degree.

Yes. I’ve shied away from it because of the CNS [central nervous system] toxicities, and I’ve been a little reluctant to push really hard, particularly because these guys often are older.

I agree with that, and I think that one of the drawbacks to these agents, and we have underappreciated this, are the long-term effects on muscle mass, on mental function. I’m seeing patients having more and more fatigue on a chronic basis as they’re getting out to 2 years on abiraterone. This I think is something we have to be very careful of. Remember in the castrate-resistant state, you’re only giving these drugs for a shorter course of time. Over a longer course of time you may see other adverse effects that may impact significantly on quality of life.

In this changing landscape where do you think the PARP [poly ADP ribose polymerase] inhibitors will go in the earlier hormone-sensitive phase?

Well, I think it’s certainly something we need to do on a trial basis. We don’t have any evidence at this point of using PARPs in the BRCA-positives in hormone-sensitive disease. Again, we’ve got to think about the long-term side effects, including the effect on the bone marrow, because anemia and thrombocytopenia are significant adverse effects with the PARP inhibitors. But I think at the same time we have active agents. Perhaps we need to give these in short courses, like docetaxel. There are trials that are being designed to look at that particular question.

I think they are going to be potentially useful in that space, but I’m not sure yet. They’re fairly difficult on the bone marrow.

I’m not sure where we’re going to go with that.

The Use of Taxanes Earlier in Prostate Cancer

Moving on to the castrate-resistant space, let’s say that you’ve given a patient docetaxel and ADT [androgen deprivation therapy], and you’re 6, 12 months into it, and the patient’s PSA [prostate-specific antigen] is still 4 ng/mL and beginning to rise. Where do you go next?

If the PSA starts rising, I will go then to a next-generation antiandrogen such as abiraterone or enzalutamide as the first treatment. I also think of SIP-T [sipuleucel-T] in that situation as well. Sipuleucel-T from the data should be given early, before the PSA gets to 22 ng/mL is one of the thoughts. Remember back to the IMPACT trial, there are patients who had chemotherapy on that study.

I know. And the median PSA was like 100 ng/mL and something.

Exactly. I think that it’s underused, and I think it’s underappreciated. But it is a process that has activity, and it has a proven survival benefit.

 At ASCO GU [the American Society of Clinical Oncology Genitourinary annual meeting] this year, there was an interesting database analysis showing in, not a multivariate but certain single variate, that the sipuleucel-T in the era of second antiandrogen therapy, was still showing a survival advantage.

I think we’re still underappreciating and not fully understanding the important role of sipuleucel-T in these patients.

Exactly. I think too in underserved populations such as African-Americans, we know that sipuleucel-T seems to have a better survival benefit. The same thing with chemotherapy, if you adjust for the different poor prognostic factors. I think it also lends to the fact that for patients from different ethnic backgrounds, we should consider that in terms of our treatment.

Moving then to the refractory castrate-resistant space, or landscape, where do you see as having had the most impact in the last several years?

This would be after sipuleucel-T. Is it the radium? Is it cabazitaxel? Is it PARP [poly ADP ribose polymerase] inhibitors there?

 I think right now the PARP inhibitors are going to have the most influence. And in some of the patients who I’ve treated both on and off study, I’ve seen some fairly dramatic and long-term responses.

Small populations. Again, the issue is really trying to assess, first, we all have to check our patients molecularly now. This is now an absolute, absolute. You have to check them for MSI [microsatellite instability]. You have to check them now for DNA repair mutations, because we can make an impact on our patient’s care by administering drugs based upon these particular markers.

It’s interesting, I just found 2 patients with Lynch syndrome, just by molecular testing. Not a very strong family history at all. So it’s like, look at that. Therefore, you have the needle IPI [ipilimumab] or PEMBRO [pembrolizumab] option for those patients.

In the sequencing changing landscape, sipuleucel-T, you still have radium in there, and then you have Jevtana, cabazitaxel, and then you have the PARP inhibitors. What’s your preferred sequence at that level?

My preferred sequence is to go first with next-generation antiandrogen after sipuleucel-T; then to docetaxel chemotherapy; then to cabazitaxel chemotherapy; and then radium at some point if they have bone-only disease. Or if perhaps between the time they’ve had docetaxel and cabazitaxel, if they need a break from that type of treatment.

There was an intriguing work from Emmanuel Antonarakis, MD, looking at sipuleucel-T and radium. I was intrigued by that because there were 4 PSA [prostrate-specific antigen] steep declines in a small population of patients, which we don’t usually see with either radium or sipuleucel-T. What’s your take on that?

Well, I think it’s a very interesting biological observation. I think what also was interesting about that study is the fact that they looked at immune parameters. We would have expected that there would have been some upregulation of the immune function because of the abscopal effect that we see with radiation therapy. We saw actually the opposite, that there was a downregulation of some of the immune parameters they were looking at. I think the PSA observation is very intriguing. You do see some PSA declines with sipuleucel-T. I’ve seen it, and I’ve seen it with radium as well. The question really is, are we going to be getting more? And then mechanistically, what’s the  real issue here?

We’re seeing more and more now that we’re taking drugs and combining them that may have had little activity of single agents and seeing some very interesting synergistic patterns.

 He said, “We’re affecting the stroma. We don’t know much about the stroma and what that means in terms of supporting and allowing the growth of prostate cancer.” The bone marrow stroma is a target that really has not been addressed except potentially with Cabometyx.

And cabozantinib is an interesting drug. Where do you see those kind of drugs going, and particularly the TKI [tyrosine kinase inhibitor] combinations?

One of the most exciting abstracts at this meeting was a combination of cabozantinib along with atezolizumab. Both of these drugs really have, as an objective response rate and by PSA responses, a less than 10% rate. And we’re seeing a 28% rate of tumor shrinkage with responses in visceral sites such as liver. I think that we have to really understand more about the biology of the immune function. We know that cabozantinib can cause the reduction of myeloid suppressor cells, and this may be a way that we can convert a cold tumor to a hot tumor, and then we hit it with a checkpoint inhibitor. This is one of the fun things about being in this business right now, the biology is all coming to a focus, and we’re understanding more about how to take better care of patients.

It’s a very complicated time because we’re now for the first time able to combine agents, and moreover, we’re seeing longer and longer response durations.

Well, I think the fact that you mentioned about the stroma. We’ve always had tunnel vision of thinking about the tumor cell only. Now we have to think about this in terms of the environment and the actual patient and how there’s an interaction between the stroma and the tumor. And also, how the biology changes as you give drugs over time; the emergence of the neuroendocrine phenotype. This is evolution within the body. This is what’s so neat about looking at these particular systems, because they’re changing. And you can’t have unidimensional thought when you’re thinking about how to take care of these patients.

Sequencing Therapy in Castrate-Resistant Prostate Cancer

One of the themes that you brought up was this idea of the tumor evolving. Can you describe how you think about this?

Well, there are different points at which we’re administering treatment. There are different switch points in terms of how the imaging changes. In other words, if a patient goes from bone-only disease to then bone plus visceral. Because clearly by giving treatment you’re selecting clones, you’re selecting those cells that are sensitive to the drug that you’re administering, and you’re left with resistant cells.

So we’re now moving into the era of molecular targeting and molecular tests for our patients. When do we do these? Should we do these right at the beginning of treatment? Should we do these as the patients evolve on treatment? There was a very interesting article that came out of Memorial Sloan Kettering Cancer Center about microsatellite instability. And they looked at a series of patients with prostate cancer, and they found that the rate was about 3%, as what we would expect. But there were 6 samples, 6 patients with consecutive samples, and half of those patients developed microsatellite instability over time.

The question is, how often should we sample our patients? Again, an each treatment decision? Right at the beginning? Who’s going to pay for this because these are expensive tests? We’re developing these new tests, but we’re really evolving as to how we should use them and when we should use them.

Are you using any of that in your practice?

Initially we look at the patient. The question, of course, is there germline 

 in our patients? And that has important implications for the entire family—the children, the sisters&mdash;do they have, are they susceptible to having breast cancer or other tumors that could be curable? Of course now genetic counseling is going to be very important in all of our patients as well.

The guidelines are basically not really distinguishing which of the patients we should be looking at genetically, and I think we do this in everybody now. We also get a good family history. But I’ve seen 

 germline mutations in patients without a family history.

Are you using the cell-free DNA at all, or does this mean that you rebiopsy patients?

We try to biopsy when we can, and we do our own inhouse genetic testing at Yale University. It’s called Oncomine, which looks at the somatic mutations in tumor cells. We also look at germline as well in our patients because we want to know the family history, and there are tests that can be done on saliva that can tell us what the germline mutations are.

I basically try to think about the patient and how things have changed. And I’m looking for every opportunity to treat my patient with a drug that may impact their lives. If for example, their tumor gets more aggressive, I may repeat a CTC [circulating tumor cell], assay to look at their different genomes, or how things have changed.

CellSearch and those types of patterns as well. We’re looking at those particular things. The question is, what’s best? And then, of course, quality. Are you going to get the same answer from the same test? This is a heterogeneous disease, and you may get different answers by the different sampling techniques.

Repeat Molecular Testing in Advanced Prostate Cancer

If you explain these things to the patients, what I often tell the patient is: “Look, the cancer that we started treating you with way back when with androgen deprivation therapy and perhaps docetaxel, now after AR [androgen receptor] inhibition the tumor has evolved. The tumor is now a different tumor.”

We saw the Stand Up to Cancer Dream Team biopsies from UCSF [the University of California San Francisco] showing that a good 20% are neuroendocrine, and there’s no particular clinical feature that predicts for neuroendocrine. So do you have a trigger point for when you’re going to use, for example, cabazitaxel? Let’s talk briefly about that evolution. How early are you using cabazitaxel?

I’m looking at the CARD trial. I think that’s the way I’ve based my practice in the past. The CARD trial was a study that looked at sequential treatments in castrate-resistant disease. Generally we would use a next-generation antiandrogen like abiraterone or enzalutamide first. Then go on to docetaxel. And the question has always been with our patients, what’s the next step that is right? A lot of people will try another next-generation agent. ABI [abiraterone] versus ENZA [enzalutamide], ENZA [enzalutamide] versus ABI [abiraterone]. Or of course go on chemotherapy. And the thought was, well chemotherapy is more toxic, we don’t want to use it in this situation.

But the CARD trial helps answer that particular question. It actually was a very clinically relevant study. Patients who had received either ABI [abiraterone] or ENZA [enzalutamide], then docetaxel, they received the opposite antiandrogen in a randomized fashion, and it was compared to cabazitaxel. And lo and behold, cabazitaxel had a better radiographic progression-free survival, overall survival, better PSA [prostate-specific antigen] decline rate, and also better objective response rate. It seems the cabazitaxel is a superior drug in this particular situation to enzalutamide.

And lending a lot of credence to the idea that the tumor has evolved away from androgen receptor dependence into this more neuroendocrine, more chemotherapy responsive. Have you identified or maybe potentially used the idea that if you have a 

 or one of the driver mutations, are you thinking that these should be given chemotherapy earlier?

 I’ve always wondered about that because my limited experience with 

 is that they can get long responses to androgen inhibition. But sometimes they’re very short, and then you’re going, OK, I need to treat these guys, and chemotherapy is right there for you.

This is I think one of the key points about DNA repair. One of the things that we never really, I guess one of the surprises I had in the last couple of years, is that we administer drugs such as abiraterone and you look at the DNA repair enzymes, there’s a downregulation. The same thing with androgen blockade. I could never really rationalize why we were giving radiation therapy plus hormone therapy together. I couldn’t understand the mechanism for that. Now it makes complete sense. By giving combined radiation therapy, hormone therapy, for localized disease you’re downregulating some DNA repair enzymes, you’re making the tumor more sensitive to radiation therapy, and there’s your mechanism. I think we’re understanding more about the biology not only of late-stage disease, but early stage disease by these particular agents.

Going back to the CARD trial, is this practice changing?

In say for example, the patient you and I talked about hypothetically, you’ve given them say docetaxel up front for metastatic, or abiraterone up front for metastatic, along with LHRH [luteinizing hormone-releasing hormone] agonists. You’re then moving into a resistant, an AR independent, and you’re going to do SIP-T [sipuleucel-T], and then you’re going to not do a second-generation enzalutamide, or are you? Do you use it the duration?

The duration, I think this is something that the CARD trial did not account for. One of the things I think we’ve all seen anecdotally is if you respond for a long period to an initial next-generation antiandrogen, you have a lot more likely chance of responding to the second one if it’s a long duration. I’ve had some patients who I’ve treated with multiple hormone treatments. I had 1 patient recently who had been on ketoconazole and hydrocortisone for almost 7 years, and then we put him on abiraterone, prednisone for another 3, and then he got some mileage out of enzalutamide afterward. So biologically what’s different about this patient?

Right. Suggesting that it’s addicted to the androgen receptor.

There’s something about some of these tumors where they stay androgen sensitive, or at least somewhat androgen sensitive.

The difference in the CARD trial was that they were required to be independent of androgens as based on lack of, or short duration, but not necessarily short duration response to androgen inhibition.

It’s a challenge, isn’t it, to know what to do.

It is. You’ve got to tailor to your patients. Now the other issue, too, of course that I think is very important is should you be adding carboplatinum to cabazitaxel based upon The University of Texas MD Anderson Cancer Center data? I tend to do that in a patient who may have liver or visceral disease. And the MD Anderson data are very exciting. It’s being confirmed in a larger randomized trial right now. That’s also another avenue.

Carboplatinum or the platinums have been always there, and they’ve always had a level of activity. We don’t necessarily think about those up front, but these are something we have to think about.

I had a funny anecdote from one of my friends who was trying to get cabazitaxel, got it approved; he wanted to add carboplatin. And when he told them that he was going to give carboplatin and cabazitaxel, they said, “We’re not paying for either one.” He said, “Wait a minute, carboplatin is cheap, and we’ll be happy to eat that cost.” They said, “No, you can’t give the combination.”

I’ve had something similar where patients have had the cabazitaxel approved, but the carboplatinum disapproved, for you know $300. They said, “Fine, we’ll pay for it.” That’s actually very interesting. It’s unfortunate that the drug satraplatin that we used a number of years ago, that we didn’t understand the DNA repair path. Because I think that trial that Cora Sternberg, MD, Oliver Sartor, MD, and I did would have been a positive study that had....

We saw those small number of patients who had dramatic responses, and the FDA’s look at it was that it didn’t have enough power to show a survival advantage, even though there was a tail. We probably missed an opportunity there.

Absolutely. I actually tried to recently get that drug for a patient. You can’t get it anymore.

You can’t get it, it’s not available. That’s disappointing. But it’s sad to think that the insurance companies are not letting us use carboplatin, which is well established, and it’s very sporadic, do you notice that?

One company will say, “We’ll let you use CARBO [carboplatin],” and the other will say, “No, you can’t.”

I had a patient who, well unfortunately this patient passed away, but he had a 

 mutation, and he unfortunately could not qualify for any of the PARP [poly ADP ribose polymerase] inhibitor trials because of his platelet counts. He actually sued his insurance company; he lost.

Unfortunately he passed away 2 weeks after that event. This again is showing us, we’ve got so much information, and how do we use that, and how do we convince the people who are paying that this is useful? The rapidity of the knowledge is logarithmic. Unfortunately, everything else is lagging behind in getting these to our patients.

Certainly the insurance companies and third-party payers are not necessarily understanding what we are learning. The faster we learn, the harder it is for the insurance companies to keep up.

Perhaps we need as academicians to educate them and help them understand because our patients really deserve this.

Impact of the CARD Trial for Treating Metastatic CRPC

I want to talk about PARPs [poly ADP ribose polymerase inhibitors]. We want to spend a little time on some of the PARPs and also on some of the trials. We want to cover both PROfound, which was phase III, and TRITON, which was phase II.

Dan, we’ve talked about PARP inhibition. Where do you see this, and what’s the basis for our use of these PARP inhibitors in prostate cancer?

 There have been a number of exciting trials that have recently released data for the use of PARP inhibitors in castrate-resistant disease. The PROfound trial took those patients with DNA repair mutations, stratified them based upon 

 versus other types of DNA repair mutations, randomized patients to receive olaparib or a dealer’s choice treatment, which could have included anything from abiraterone to chemotherapy.

They found that there was an improvement or a significant difference in radiographic progression-free survival, as well as objective response rate, in favor of those patients who received the PARP inhibitors. It’s very exciting that we’ve been able to select patients with a different molecular mutation, and then administer a drug based upon that mutation.

TOPARP I think was the predecessor trial.

This is not a big population of patients though.

 It’s about 20% of patients with castrate-resistant prostate cancer. About 10% of all patients have 

Yes, and you have to do germline testing on these, or can you do it on somatic?

 You can do it on somatic as well as germline.

I believe that PROfound didn’t allow cell-free DNA, or I thought they required somatic, didn’t they?

 It was tissue that they used. There’s a difference with other studies where they’re using the liquid biopsy test to look for these particular mutations—TRITON2 and TRITON3&mdash;which are using rucaparib rather than using olaparib. TRITON2 is a phase II trial, which has about a 50% response rate in those patients who have 

 mutations. TRITON3 is a randomized study that would of course confirm the results from TRITON2, but these are a little bit broader in their use of the molecular markers.

That’s coming, and that’s another PARP inhibitor, right?

We’re going to be dealing in this coming year probably with at least 2, maybe 3 PARP inhibitors.

If you’re testing early on in all patients, and if you don’t find a 

, or you don’t find a DNA repair deficiency, would you retest your patients?

 I do retest because this could be a clonal evolution of something that may not be picked up in the original test. I’m also excited about drugs that are trying to induce 

, and I think that this is going to be the next step in this particular pathway. As we said, only about 20% of patients have this mutation, but then how can we induce the cell to downregulate the DNA repair pathway such that you are sensitive to a PARP inhibitor? And this is where the combination trials are starting to come into play.

Abiraterone downregulates DNA repair enzymes. Hypoxia will do the same thing. At the ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] meeting we saw some other further abstracts looking at the combination of abiraterone plus olaparib. A randomized phase II trial showed an improvement in radiographic progression-free survival. And the interesting thing was it was irrespective of your 

. I think that that was a very interesting aside to this particular hypothesis.

Joe Kim, MD, at my institution has looked at olaparib combined with a drug called cediranib, which is also an antiangiogenesis agent. He demonstrated a 7-month improvement in radiographic progression-free survival in favor of the combination. Now we haven’t yet examined the different molecular markers.

That analysis is underway. What I thought was particularly intriguing about this case was one of my patients who happens to be a physician, and is 

-positive, he was initially randomized to the olaparib only arm. He had about a 6-month response and then progressed. And the trial allowed for crossover. He went on olaparib/cediranib, he responded again. So this is again a very interesting little observation, and perhaps now we have to start looking at these combinations.

The third combination that I’m excited about is the combination of PARP plus immune checkpoint inhibitors. There is a synergy between the 2, and Fatima Karzai, MD, from the National Cancer Institute a couple of years ago presented some data of a PARP inhibitor combined with a checkpoint, and also saw the same pattern that you did not need to have a DNA repair mutation to have a response. These are ways that we could potentially expand the applicability of these PARP inhibitors to our patients.

PARP Inhibitors in Castrate-Resistant Prostate Cancer

In the world of checkpoint inhibitors, do we have any data yet that monotherapy with checkpoint inhibitor has a role in prostate cancer?

Well, we all should be testing our patients for microsatellite instability. That is an FDA-approved indication for pembrolizumab. About 3% of prostate cancer patients do have that. In that paper that I cited before from Memorial Sloan Kettering Cancer Center about microsatellite instability there was a section on those patients who were treated. About half of those patients responded to a checkpoint inhibitor. I think that can make a significant difference in our patients’ outcomes.

Charles Ryan, MD, has got a case that I think is very interesting about a patient who had a complete response to a checkpoint inhibitor who was microsatellite unstable. Now he doesn’t know what to do as to far as whether he should continue treatment, and whether this patient should stop hormone therapy.

One of my friends, David Shaffer, MD, in Albany, has a similar case where he gave atezolizumab in an earlier trial, that was an atezolizumab/enzalutamide trial, which you may want to comment on. And the patient is in a 5-year remission. There’s no clear genetic reason for him to be in this remission. They’ve biopsied him several times and there’s been no obvious, there’s no Lynch syndrome, there are no DNA repair issues. Occasionally there are these unusual responses to checkpoint inhibitors.

I think we underestimate. We think about a drug’s mechanism as being monolithic. The kinase inhibitors inhibit multiple kinases. Abiraterone, as we talked about before, can downregulate DNA repair. Enzalutamide, a couple of years ago, surprisingly has an immune-modulatory effect.

And Julie Graff, MD, from Oregon has actually exploited that particular observation, looking at combinations of pembrolizumab plus enzalutamide, and showing that there is significant activity between the 2.

Now there was a randomized trial of atezolizumab with enzalutamide. Unfortunately, it’s only been reported in press release form at this point; it was negative. Again it emphasizes the fact that we cannot treat all-comers. We have to understand the biology and tailor our treatments for individual patients.

As I understand it, Merck & Co, Inc is looking at a number of combination trials. I remember there’s at least docetaxel with or without PEMBRO [pembrolizumab].

I think there are 4 interesting trials that Merck is doing right now. The docetaxel, plus or minus pembrolizumab, which I’m one of the PIs [principal investigators] on, so I’ve got to disclose that. The enzalutamide plus or minus pembrolizumab. There’s an olaparib plus or minus pembrolizumab as well. And the other interesting trial that is about to open, which I am very excited about, is pembrolizumab plus enzalutamide, and androgen blockade, up front.

Yes, in hormone-sensitive disease. The question is, is the immune milieu different in hormone sensitive versus castrate resistant? A lot of people do think that you have a different immune response in that particular situation. Certainly, when you’re inducing hormone therapy, you’re causing a large release of antigens from the prostate cancer cell apoptosis, and perhaps that’s the right time to administer immune therapy because then you can use that system to clean up the cellular debris. It’s going to be an interesting trial to be coming out.

Well these are big trials. MERCK has put a large amount of effort into designing and conducting these. There are some negatives. One, for example, is that it’s placebo controlled. The enzalutamide trial, there are patients getting placebo pembrolizumab. We’ll see if the patients accept those kind of restrictions.

Talk about the full gambit of these trials, nivolumab is also being looked at in a randomized trial, nivolumab plus DOCE [docetaxel] versus docetaxel alone. There are a number of different trials that out there looking at immune checkpoints.

The interesting thing about both nivolumab plus docetaxel as well as pembrolizumab plus docetaxel, is that radiographic progression-free survival does seem to be a little bit better than what’s been reported in the past. And remember, these patients are supposed to have abiraterone. And the survival of docetaxel from some reports is a little bit less in those patients. Perhaps, you know, it’s hard to compare this because they are different eras.

I think there are very interesting data that are going to be generated from this.

Well, your initial work with docetaxel, which really laid the foundation for docetaxel in metastatic disease, has now spawned a whole series of docetaxel-plus trials.

I think it’s fair to say that those first-generation trials didn’t enhance docetaxel. What’s your perspective? Are we barking up the same tree again, or is this different?

I think that’s a great question. I think it’s a little bit different. When those trials were all designed after the SWOG study and after the TAX-327 trial, I think everybody was looking to get into the game of having their drug married to docetaxel and then moving forward. We understood the biology to some degree, but we didn’t understand it that well. Now I think we’re really understanding the biology better; docetaxel is still a great drug for this disease. It’s hard to knock it off as a comparator arm. You’ve got to move the bar up much higher to see it.

If you’re a betting man, are you going to bet that the immune checkpoints are going to add something to docetaxel?

I’ll bet on that. But you know the other line too is that 1 in 20 trials are going to be positive based upon statistics. We’ve got to have 1 positive study. But no, I think there’s good reason to be optimistic with these.

Checkpoint Inhibitor Therapy in Prostate Cancer

Some of the other new agents that are along the pipeline of pathway or FDA approval include lutetium. Where do you see lutetium going?

 There are a number of trials that are looking at PSMA [prostate-specific membrane antigen]—based therapy linked with isotopes too in prostate cancer. I think these are going to be looked at in terms of competition to chemotherapy. There’s a randomized trial looking at lutetium versus dealer’s choice standard of care, such as enzalutamide or abiraterone, in patients who had failed other treatments.

I see this moving up earlier because, again, looking at the biology you do need PET [positron emission tomography] scanning to detect the PSMA-positive patients. Not all prostate cancer cells make PSMA, particularly the visceral disease that tends to have less PSMA expression.

The responses have been impressive—40% or 50% PSA-decline rates, objective soft-tissue responses. I do see this being integrated within the armamentarium. The question is, do you combine it with a checkpoint, combine it with other agents?

You’re betting that lutetium is going to get FDA approval.

 I’m betting it’s going to get approved, yes.

Do you worry about the bone marrow problem of lutetium?

 I do worry about that about time. We need more long-term data in terms of how the patients will react to it. Surprisingly, with radium 223 dichloride that has not been a problem. As far as the reports from the databases are concerned, you can safely give other treatments—such as chemotherapy&mdash;afterward. But it is something that needs to be monitored.

Yeah. My 1 experience—I’ve had several experiences in people who have had radium&mdash;is that the lutetium is difficult to administer because of bone marrow issues.

We do have to be aware that you can potentially damage bone marrow in these patients. Let’s try to wrap it up a little and think about the big picture. Let’s take now your current plan of treatment for a relatively young healthy patient who comes into your clinic with bone pain and high-volume disease. Where are you going to take this patient over the next 3 to 7 years?

 A young patient, bone pain, high-volume disease—that’s a patient to whom I tend to give docetaxel up front with androgen blockade. That would be my treatment of choice. Of course, what do we do at the time they become castrate resistant. It all depends on where their sites of disease are. If they’re bone only, if they have minimal pain, I tend to give sipuleucel-T right at progression. If they’re not bone only, if they’re visceral, then I tend to move chemotherapy up front earlier in these patients. The question, of course, is next-generation anti-androgens. How do you integrate those? Same thing, right after sipuleucel-T, I tend to go with ABI [abiraterone] or enzalutamide. Of course, we do see some visceral responses with these agents as well. Again, these are useful in this situation. You have to again tailor it to the patient. As the course goes on, they may need radium to take care of their bone pain. They may need cabazitaxel to also treat lymph node or visceral metastases. We tailor it based on the sites of disease, the molecular profile. I’m going to check for MSI [microsatellite instability]. I’m going to be checking for 

Another question that comes up often is right now we’re using 2-drug therapy up front. We’re using either docetaxel and ADT [androgen deprivation therapy] or an AR [androgen receptor] inhibitor and LHRH agonist. Do you think we’re going to see a move to 3-drug therapy up front? When will that occur?

 I think we have to also keep toxicity in mind. That’s got to be the key because remember we are treating some patients when they’re older. I think we’re going to start seeing quantum leaps in survival with triplet regimens or multidrug regimens. That’s when we’ll start coming to play, but we’ve got to balance this against adverse effects and toxicities.

Right. I believe the trial is darolutamide.

It’s LHRH agonist, darolutamide, and docetaxel. I think darolutamide is the variable, so it will be LHRH agonist and docetaxel with or without darolutamide. Do you know when that’s going to report out?

OK. So that would be a practice changer as well.

Using Taxanes Frontline in Metastatic Prostate Cancer 

One of the underlying themes of prostate cancer has been maintaining quality of life. There are a lot of patients who are very afraid of getting chemotherapy. I mentioned that figure of 4.8% getting chemotherapy in the hormone-sensitive phase. Even overall during the entire course of prostate cancer, many patients refuse chemotherapy, and perhaps less than 50% even of all patients get chemotherapy. Is it really a quality-of-life issue, or is it just a fear factor that we haven’t figured out yet?

 It’s a fear factor because of the prevailing wisdom what people see on television and what they may see from their friends who may receive completely different forms of chemotherapy than what we’re administering. One of the key things to emphasize is that talking about adverse effects early, communicating with your doctor, communicating with the nurse practitioner who works with you is crucial in managing the adverse effects. If we catch a fever early, if we catch fatigue early, we may be able to do some things to fix those so that the patient can tolerate chemotherapy better.

What I’ve seen over the years is improvements in bone pain, which people don’t really capture. Performance status in somebody who is doing poorly to begin with actually can improve. And it’s very difficult to select that patient out beforehand, but I’ve seen dramatic improvements in quality of life as time has gone on. The crucial thing is a good relationship between the patient and the physician, carefully explaining what to expect, carefully explaining what adverse effects to expect, and also emphasizing the positive that you may have an improvement in quality of life as you treat it.

My impression is that docetaxel still is rough on patients.

There’s still hair loss. There’s still neuropathy. Do you see any difference in the cabazitaxel? What about the dose of cabazitaxel? And what about the issue of the CARD trial, where cabazitaxel and the second-generation hormones were impaired?

 Well, as much as I hate to say it, I think cabazitaxel is a better drug than docetaxel. Cabazitaxel is easier tolerated.

 Patients don’t have the same degree of asthenia and fatigue that they do with docetaxel. Also, neuropathy is an issue. I recently took care of a patient who was a violinist, and we gave him cabazitaxel up front because I was afraid he was going to lose his sensation playing his instrument.

 The insurance covered it. They actually accepted the rationale behind it. I think it’s a better drug from that standpoint. It’s better tolerated than docetaxel is. Some patients, you’re absolutely right, can get pretty beaten up by docetaxel, particularly as you go further down the line. The CARD trial had some interesting observations. Karim Fizazi has presented some data looking at the quality of life of abiraterone or enzalutamide versus cabazitaxel in that particular study. Didn’t see much of a difference between those, so that tells us the activity of the drug may actually be helping overcome some of the adverse effects. And you get the same result with ABI [abiraterone] or ENZA [enzalutamide] as you do with cabazitaxel. The fatigue with enzalutamide is significant in some patients, and that has to be watched very carefully.

The other drugs we use that are easily tolerated include sipuleucel-T and radium 223 dichloride. Is starting with sipuleucel-T and radium sort of a first-grade look at quality of life? Does this help the patients get ready?

 Yeah, it helps the patients get ready, and there are different situations that we can use this in to help patients maintain a good quality of life. I do see PSA [prostate-specific antigen] declines with radium. I’ve seen that. It’s actually very nice when you see it because your patients don’t expect that at that particular point. With sipuleucel-T we potentially can delay patients going on other treatments afterward. I’ve seen patients’ PSA flatten out over time, although you may not see declines. The drug does have a role in this disease. It’s about transitioning to more aggressive treatments later on, you’re absolutely right about that.

The disappointing thing about the studies with radium is that there was that observation that there was a higher fracture rate when you combine that with abiraterone. We know that adding bone anti-resorptive agents may abrogate that particular observation. I would love to try to move radium up front more by combining it with novel anti-androgens.

Well, my practice has been to move radium as early as I can. It’s always a challenge to know whether to give sipuleucel-T first or radium first. And the whole integration of second-generation AR [androgen receptor] agents has been disappointing that it didn’t show a survival advantage.

But you still have to give the drugs because they’re life prolonging. Even though they may not be synergistic in prolonging life, they certainly independently prolong life.

 My goal in treating patients is to make sure they receive every class of drug that we have available to them, whether that is immune therapy, next-generation anti-androgens, DNA-damaging agents like radium, the PARP inhibitors, and the chemotherapeutic agents as well. If we can do that, then I feel that I’ve accomplished the best-possible care for my patients in this situation.

In the long run their quality of life is maintained for longer periods of time.

 Exactly. And the quality of life as well. I was thinking last night. I was out with Maha Hussain and Tia Higano, good friends from SWOG, and we were talking about all the interesting people we’ve run across in this business. And I think back to that review about chemotherapy in prostate cancer and the survivals being only 12 months at that time. Look how far we’ve come—3 years, 4 years these patients are living, as opposed to where we were at that time. We’ve made a huge amount of progress in this disease, and it’s from using these drugs and integrating them properly.

It seems to me that we still need better education. I still have patients who are refusing chemotherapy. I still have patients who aren’t getting all the optimal therapies, so we still need to do a better job not only educating the patients but also all medical oncologists.

 Also, embracing populations that may not have had the opportunity to get these treatments before. There was a very telling statistic that was published in 

] in a letter a couple of years ago that the number of African Americans participating in clinical trials is about half of what you would expect from the projected data of the number of patients having castrate-resistant disease. That’s our fault. We need to educate patients better. We need to embrace them and embrace people in the community and make sure that they understand what’s out there.

Also, we have data suggesting that docetaxel in African American patients is actually more effective than you would expect. And now we have this preliminary data on sipuleucel-T suggesting again that the African American population has an altered immune response and longer benefit to sipuleucel-T. We really need to communicate better with our doctors who treat these patients but also with the patient populations.

 The question is how do we best do that, and there are a number of answers to that. It’s exposing people to media, to other types of venues. I often say that in an era when we have more tools for communicating with one another, we communicate less than we ever did. It’s incumbent on us to communicate with our patients, as well as our colleagues, and let them know what’s happening.

Cabazitaxel for the Treatment of mCRPC

: The CARD study was a trial that compared cabazitaxel with next generation antiandrogen therapy in men with castration-resistant prostate cancer. Sequencing is a complex issue in the treatment of men with castrate-resistant disease, and the CARD study was one of the first trials to help answer this question. Patients with castrate-resistant prostate, who had progressed either on abiraterone or enzalutamide, as well as docetaxel, were randomized to receive either cabazitaxel or the alternative antiandrogens. If they received enzalutamide, they received abiraterone in the study; if they initially received abiraterone, they received enzalutamide in the study. Patients had to have progressed within 1 year on abiraterone or enzalutamide as their first next-generation antiandrogen treatment. The CARD trial demonstrated a radiographic progression-free, as well as overall, survival benefit in favor of cabazitaxel compared with the alternative antiandrogen. The data were then further analyzed in terms of prognostic factors, in terms of other factors that may have influenced the overall outcome, because again, this was a small randomized phase 2, and small differences in patient populations could have actually accounted in part for this survival benefit and the radiographic progression-free survival. What was looked at was the metastatic disease at the diagnosis, whether they had metastatic disease at diagnosis, or whether they were localized and then developed metastatic disease, visceral metastases, Gleason score, prior therapy with curative intent, and type of progression. Other covariates that were looked at were hemoglobin, lactate dehydrogenase, visceral metastases, the Gleason score, the alkaline phosphatase, and the PSAs [prostate-specific antigens], and these were all were all in terms of the absolute value log of 10. At a significance level of 0.1, this multivariate analysis was used as a way to determine whether these variables were significant. What fell out in this analysis was treatment with cabazitaxel was the most significant, with a hazard ratio of .628, followed by neutrocytes to lymphocyte ratio, hemoglobin, as well as PSAs. Cabazitaxel treatment seems to trump these prognostic factors in terms of our patients.

They also looked at a variety of different variables in terms of overall survival, from the development of metastatic disease from the time of castration resistance to the time that patients go on study. There was a survival rate in favor of cabazitaxel. This analysis helps weed out those patients who may be slower progressors. The overall survival from the time of the second LET [life-extending therapy] to initiation OS [overall survival], again, it was in favor of cabazitaxel in this situation. The office concluded that the data were robust, and that cabazitaxel was a reasonable option in those patients who failed docetaxel as well as an antiandrogen within 12 months.

Practical implications are that we have a way to sequence our patients with castrate-resistant disease, and we didn’t really have good guidance. In fact, what was used before were quality of life issues. People argued that because somebody was being treated with a next generation agent sequentially, we all know that responses are not necessarily the best in a sequential fashion. In other words, abiraterone after enzalutamide, or enzalutamide after abiraterone usually has a lower response rate and a shorter duration of response, if they do respond. The tendency was to put patients on oral agents because it was easier and better tolerated. I think, here, the survival benefit does seem to cancel out any effects that may have.

One of the major questions that is involved in the CARD trial is the types of toxicities that you would expect to see, is there a difference between older patients versus younger patients. The CARD data were based upon age and split the group into patients either less than 70 years of age, or greater than or equal to 70 years of age. The interesting thing that was noted was that any grade 3 or grade 4 AE [adverse effect] was similar, about a 6% difference in favor–higher in cabazitaxel in those younger than 70, and it’s about 8% in those greater than 70. There doesn’t seem to be that much of a difference between them.

CARD Trial In Metastatic CRPC

: Patients do have a bias against chemotherapy. There’s a lot of press and literature saying that chemotherapy is difficult to tolerate, and I think that chemotherapy’s adverse effects are dependent upon patient selection. Their age,comorbidities, and also some of the cancer comorbidities, as well. Weight loss, fatigue, bone pain. We know that we can see improvements in bone pain with both chemotherapy as well as next generation antiandrogens. We saw in the CARD trial, patterns of toxicity are different. You need to counsel the patient that they may expect adverse effects; we can alleviate some of them, such as neutropenia, with growth factors. Also, if they develop edema from chemotherapy, they can also receive diuretics. Same thing with next generation agents, you’ve got to watch their blood pressure, you watch their liver function tests, all of these need to be monitored. Good monitoring is very important for these particular patients.

Counseling Patients With mCRPC

: The interesting observations that have been made about COVID-19 and prostate cancer actually stem from the observation and may be involved in viral entry into normal cells. When one looks at the Italian data, where they do a multivariate analysis, and they look at those patients who have a per 300,000 serious events or deaths that were recorded, that were related to COVID-19, patients with prostate cancer on hormone therapy have a much lower rate of those events than those patients with prostate cancer who aren’t on hormone therapy. How do we explain that? It could be that simple observation that the antiandrogens or the lack of testosterone is having that effect. We do know that the disease is more severe and more prevalent in men. It also could be that those patients who are on hormone therapy are more debilitated, they tend to more socially isolated, and they may not be exposed to the virus in the same fashion. There’s a lot of hypotheses that can be generated. I wouldn’t make the immediate assumption that because you’re on hormone therapy that you’re going to be immune to the COVID infection, I’m not saying that at all. But this is something that people are now investigating, and there are a variety of different clinical trials that are being designed in different states of COVID infection, whether this be in patients who are asymptomatic versus patients who are hospitalized, trying to determine whether viral load changes with various different antiandrogens, or whether hospitalization or the respiratory parameters change. The VA just opened up a trial that’s looking at degarelix in men who are in the ICU, to see if they can shorten their stay. These are very important hypotheses that need to be borne out. As far as my practice is concerned, there has been a huge effect on patients, staff, and physicians. On patients of course, some are afraid to come into the office because they’re afraid of infection, all of our patients are wearing gloves, we prescreen all of our patients. In terms of symptoms the night before, we are not requiring, as some institutions do, that the patient have a negative COVID test before coming. I am face-to-face seeing patients who are going to be treated, I have not changed my algorithm in treating patients based upon this particular pandemic. Actually, in fact, I have not missed seeing patients, although I may see more video visits. My video visits were 60%, I think, at one time. Now they’re about 50%. I am seeing all of my patients face-to-face who need treatment with chemotherapy. And that’s still ongoing for both patients with prostate cancer as well as bladder cancer.

I think that the NCCN guidelines are helpful in understanding how we should deal with our patients, but you have look at the individual patient. The risk of COVID versus the risk of what’s going on with their cancer. What concerns me the most is data that’s come out suggesting that the rate of new cancer diagnoses is down by 20%. I also have known from personal experience, just seeing patients and family members, that being isolated in the house for 2 months, your conditioning goes down, and your ability to tolerate things go down. Especially men with prostate cancer on hormone therapy, where we’re trying to maintain their muscle mass by exercise and weightlifting, and other ways of doing so. That’s something that I think may be overlooked. You’ve still got to exercise; you’ve still got to be active. Whether that be in your house, whether that be somewhere else, you still have to do it.

Management of mCRPC During COVID-19

: We’ve seen everything go full circle. I remember that there was a warning out that ACE inhibitors shouldn’t be used on patients with COVID-19, then that got pulled back, and now they’re saying that patients on ACE inhibitors do better. Same idea with chemotherapy. There doesn’t seem to be any major difference in patients treated with chemotherapy versus not in terms of susceptibility. The question is, if you have a patient who is positive for COVID-19, are you at more risk? We know that in surgery you are, but in terms of chemotherapy, I can’t remember what the data was on that, so we may just want to go with a small portion of this. You’re blocked up.

The only recommendation I can give is to remember that there are long-term consequences to not treating patients with standard-of-care treatments. We must remember, we have to balance out what the effect of COVID is going to be on our patients, versus the effect of lack of treatment or delay in definitive surgical procedures for prostate and bladder cancer, also the delay of chemotherapy or hormone therapy. Those will impact on survival if we don’t do them in a timely fashion.

The Emerging Role of Chemotherapy in Metastatic Prostate Cancer