This study examined evidence for the benefits of adding chemotherapy early to hormone therapy for metastatic prostate cancer. Authors concluded that early evidence indicates a survival benefit with the addition of chemotherapy for metastatic prostate cancer.

This paper studied factors that might influence prostate-specific antigen (PSA) nadir levels following high-intensity ultrasound treatment in patients whose cancer has not spread beyond the prostate.

Video information:

Have there been advances in treating advanced prostate cancer symptoms?  Andrew Schorr discusses approaches for treating symptoms and complications in men with advanced prostate cancer with Dr. Philip Kantoff of Memorial Sloan Kettering Cancer Center. Watch as Dr. Kantoff explains how radiation therapy and various medications could improve a patient’s quality of life.

Transcript:

Andrew Schorr:                

There’s a man from New York. I don’t know if he’s one of your patients. But he got a call from his adult daughter, and things have progressed, and he has pain. He has bone pain. So where are we now in dealing with some of these complications of metastatic disease? Now, not just the treatment of the cancer but the treatment of the complications? 

Dr. Kantoff:        

First of all, I want to agree with Dan about this shared decision-making process and having a trusting relationship between the doctor and the patient, and there’s no question that shouldn’t go unanswered. So that’s a critical part of this, and the balance between longevity and quality of life—all those have to be taken into consideration with every decision that’s made.

Symptom control is a very important part of cancer care in general. It’s complex, it’s multidisciplinary and should involve not only the treating physician but other caregivers as well. But right now, probably the most effective way of handling the symptoms is actually treating the cancer. Because we do have, in the case of prostate cancer, many potentially effective therapies that can control the cancer and in turn control the symptoms.

Having said that, there are times when that doesn’t happen, and we do have tools that we use to control pain. We use radiation at times to places in the bone that may be painful. We use narcotics at times. We use other medications that treat the bone that reduce pain, including liquid radiation treatments that control pain in bone.

So we have a lot of modalities. And I will say that the vast majority of patients with prostate cancer when pain becomes an issue, it can be controlled by a variety of different modalities. A patient should not have ongoing pain without it being attended to.

Andrew Schorr:

One follow-up question. You were talking about the progress with this meeting and the pace of change, etc. for the treatment of prostate cancer and maybe some identification hopefully approving of who gets what. So related to these complications or side effects, you see progress there too? 

Dr. Kantoff:        

Related to the side effects of the treatments.

Andrew Schorr:

First, side effects of the disease; you want to reduce the disease. But if let’s say it’s spread, and you have bone pain and things like that, you’re developing it sounds like multidisciplinary…

Dr. Kantoff:        

…multidisciplinary. We involve supportive care folks, we involve anesthesia if necessary; we have tools. Radiation oncology, so it’s multidisciplinary. But we’re much more cognizant of the effects that the cancer can have on the patient as well as the side effects of the treatments that we administer at this point. We have to always be knowledgeable about that.

Is chemotherapy a good option for my advanced prostate cancer? APC experts, Dr. Russell Szmulewitz, Dr. Emmanuel Antonarakis, Malecare Director, Joel Nowak, and moderator, Dr. Tomasz Beer, discuss  the efficacy of chemotherapy for prostate cancer patients.  The panel shares information on quality of life studies and TUPOR (treat-until-progression-or-toxicity).  According to Dr. Beer: Our job is to “make chemo as tolerable and effective as it can be for our patients.”

Sponsored by the Patient Empowerment Network through educational grants from Sanofi Oncology and Astellas Pharma Inc.

Transcript

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you. 

Dr. Beer:

I'm going to turn to Russ and ask him to comment a little bit on the developments with cabazitaxel (Jevtana). Cabazitaxel is a novel taxane which is currently approved as a second-line chemotherapeutic. There were some hopes that it might move up front. But the results of this meeting suggest that it’s going to stay where it’s currently used. Russ, do you want to comment on what we learned?

Dr. Szmulewitz:

Sure. Cabazitaxel was a designed therapy that was hoped to overcome certain resistance mechanisms with the initial drug docetaxel. The company that makes both of them conducted a randomized study comparing one to the other for patients with advanced prostate cancer in whom initial hormone therapy is no longer effective. It should be noted that cabazitaxel doesn’t prove survival in patients who have already received docetaxel and had progression with docetaxel.

The question wasif we move it forward, does that improvement persist up front? I was not entirely surprised by these data. The cabazitaxel was sort of designed to overcome resistance to docetaxel (Taxotere), and perhaps the men who receive docetaxel and then progress are the ones who are inherently going to drive the most benefit from cabazitaxel. So I would add that we aren’t moving docetaxel even more forward into the hormone-sensitive setting, meaning that patients who haven’t yet had their hormone therapy fail them are receiving docetaxel up front. So we might, in fact, be still using cabazitaxel in the castrate-resistant setting first, and this study doesn’t really answer that question. 

Dr. Beer:                

So in another study, two doses of cabazitaxel are compared to one another, and both showed by and large that we have the option of using a slightly lower dose of cabazitaxel with a similar result—a little bit less toxicity.

So with cabazitaxel is here to stay. It’s likely to be a second-line drug after docetaxel. But as Russ alluded to, we’re using docetaxel earlier. Emmanuel, maybe you could comment. The study that established docetaxel early first was the so-called charted study. In that study, men were treated for metastatic prostate cancer with standard hormonal therapy and six cycles of docetaxel right away. That study showed a significant survival advantage to moving chemotherapy up earlier. That’s why we’re doing that work. At this meeting, we heard about some of the quality-of-life results from that trial. Would you want to put that in context for us? 

Dr. Antonarakis:                

Two groups of men, the one had the hormone therapy alone up front, that is what we were doing for many years. The other group of men had the hormone therapy plus six cycles of the docetaxel givenevery three weeks. 

So the quality-of-life study was basically showing the three-month quality-of-life data, and the subsequent long-term quality-of-life data after the chemotherapy actually had ended. And perhaps not surprisingly, at the three-month time point the patients that were receiving the chemotherapy and the hormone therapy had a slightly lower quality of life per their own report. However, the interesting thing and I think the take-home message is in the long term, several months after the chemotherapy had ended, the quality of life in those patients who had received the double therapy, the chemo and the hormones, was actually improved.

So, of course, our goal is the long-term horizon for these patients and not just the immediate toxicity of the therapy. Again, in experienced centers, I think the short-term toxicity can be well managed. So I think the lesson there is patients should try to get through it, with the help of their oncologist and their family members and their peers—try to stickwith it.

And in the long term, that their quality of life will actually go up rather than go down, having had that chemo early.

Dr. Beer:                

Joel, let me turn to you with a specific question. I must say when chemotherapy came along for this early use, I think some of us thought patients wouldn’t want it. Chemotherapy has a bad name, if you will. But in our practice, our patients really have embraced it. When they hear about the survival advantage, they’re in favor of being quite aggressive. Is that what you’re hearing, or how do people feel about this?

Joel Nowak:

I don't have a statistic, but I will say I think a fair number of people, probably the majority of people, do feel the way you’ve just indicated, that you see in your practice. However, there’s still this significant smaller number who think of chemotherapy and all the negative effects. It’s not the chemotherapy that Aunt Edna had 25 years ago, and that’s the reputation that chemotherapy still has.

And it takes a fair amount of work to get the men to understand that it’s worth the risk, reminding them that you can start and if it’s really something you can’t tolerate, you can stop. There’s no rule that says you can’t stop. You need to discuss that with your doctor. And I think that this study is really going to give us a lot of conversation, an opportunity. Because I think if I remember correctly from the study, that a year after the chemotherapy, that the quality of life was actually reported as being better. And I think that that is really important and is something that I will continue to really stress with men who are having that “I don’t know if I really want it.”

Dr. Beer:                

Emmanuel, I'm going to come back to you. You were involved in a trial called Taxinergy. It’s going to be a real challenge to explain that trial to our audience, but we’ll give you a crack at it. It’s an interesting study.

Dr. Antonarakis:                

It’s an interesting study. The usual way that we prescribe chemotherapy is that we start the drug, either cabazitaxel or docetaxel, and we either continue that until the patient can’t take the side effects anymore,or their cancer continues to grow despite the chemotherapy. 

So we call that treat until progression, or toxicity. In this case, we tried to see whether switching the chemotherapy from one drug to another by some early indicator of response might be better than just sticking with the drug until the end. So what we did was we randomized patients, so they either started of with cabazitaxel or docetaxel. After four cycles of therapy, they had their PSA checked. And if the PSA had dropped by 30 percent or more, we said hey, listen, these guys are having a good response. They should remain on the same drug that they started with.

If their PSA had not dropped by 30 percent or more, or even if it had increased, in those patients we would switch them after the fourth dose, and then their fifth dose would be with the alternative drug. So, for example, a patient receiving docetaxel for four doses whose PSA doesn’t go down adequately after the fourth dose, he will be switched to cabazitaxel rather than waiting for the docetaxel to stop working. 

And what we found was in about half of patients who did not have that adequate PSA response with the first four doses, if you switched them to the alternative drug, you could salvage some of those patients. In other words, you could get them to respond to the second agent. And that was true in both directions. So in some patients, docetaxel was not as effective up front, but then the cabazitaxel can salvage them.

And the inverse was also true. Some men started with cabazitaxel, may not have had appropriate response but then would be salvaged by the older taxane, docetaxel. I'm not sure if that’s ready for clinical practice, but it really does provide some interesting hypotheses that could be tested in other studies 

Dr. Beer:                

So I think at this ASCO we’re learning that chemotherapy continues to have an important role in the management of prostate cancer. Docetaxel is an important component of the initial treatment of metastatic disease, and we have some good data to suggest that the quality-of-life penalty that men pay in the first three months goes away, and in fact in the long term there are gains to doing that.

We’ve learned that cabazitaxel is going to stay as a second-line treatment, but we’re learning how to refine it. There are studies of a lower dose. There are studies that Emmanuel pointed out where we may be able to switch into cabazitaxel therapy a little earlier in the appropriate patients. So the work continues to make the chemotherapy as tolerable and as effective as it can be for our patients.

Are there any immunotherapy approaches currently available to advanced prostate cancer patients?  Patient Power Founder and Host, Andrew Schorr, leads a discussion with prostate cancer experts Dr. William Catalona of Lurie Cancer Center and Dr. Russell Szmulewitz on immunotherapy research.  Dr. Szmulewitz gives a short account of immunology and cancer biology, explaining the difficulty of targeting prostate cancer’s immune system.  Together, Drs. Catalona and Szmulewitz explain adoptive cell therapy and how current research is working to answer safety and efficacy questions.

Sponsored by the Patient Empowerment Network through educational grants from Astellas, Medivation, Inc. and Sanofi. Produced by Patient Power in partnership with the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and Us TOO International.

Transcript

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you. 

Andrew Schorr:

Let’s go on to the next slide where we talk about immunotherapy. Dr. Catalona has mentioned this. Now, it came up with sipuleucel-T, Provenge. 

But some of you have been doing your research and hearing in other cancers, they’ve been talking a lot about what are called checkpoint inhibitors, immune modulators. And we’re going to get to adoptive cell therapy. So Dr. Szmulewitz, demystify this for us. What’s the buzz, and how does it apply to prostate cancer?

Dr. Szmulewitz:

Okay. I’ll do my very best. But it really requires a really deep understanding of immunology, as well as cancer biology.

Andrew Schorr:                  

Give us a little class.

Dr. Szmulewitz:

So I’ll do my best. So in order for the immune system to work, to kill anything, it needs to be there. So it needs to be in the environment of what it needs to kill. And it needs to recognize what it needs to kill and recognize it as either foreign or different in order to kill it. And so cancers, what they often do is have mechanisms to either deter the immune system from coming in or to deter the immune system from recognizing it as foreign, because the challenge is it is derived from the body. 

So it isn’t entirely foreign. But we know that, in some way, it is. And so one of the things that you alluded to are these checkpoint blockades. And so the cancers, many cancers, they make more signals on their surface that say don’t eat me, don’t attack me. I’m just like you, I’m your friend. And what has been developed are therapies that slap them down, that block those signals so that the immune system will go, wait a second. You aren’t friendly. We should try to get rid of you. And so these checkpoint blockades therapy have been utilized effectively in a subset of other cancers, melanoma and kidney cancer and lung cancer and, pretty soon, bladder or urethral cancer.

So prostate cancer has not been on the leading edge of checkpoint blockade use. And the question is why, and what do we need in order to best harness our immune system? So the why is complicated, and the what should we do is complicated. The why has an advantage, because the earliest studies with these checkpoint blockades didn’t show a lot of efficacy in prostate cancer. We now realize that prostate cancer, the environment, is not that immune. So it’s something about the environment that deters the immune system or keeps the immune system out. 

And one of them is what Dr. Catalona mentioned is that prostate cancer doesn’t express a lot of the target for the immune system. And so can we use radiation to increase the amount of targets for the immune system? Can we suppress some of the signaling that stops the environment from being receptive to the immune system?

I think that, for prostate cancer, there is a lot of research and a lot of hope that, now that we understand this biology better, we can, through a combination of therapies is what it’s going to take, better utilize these checkpoint blockades. 

Andrew Schorr:                  

What do you think?

Dr. Catalona:      

I agree. And, first of all, prostate cancer hasn’t been studied that much with the checkpoint inhibitors. But the other thing is when you get into the complexities of the immune system, it’s very unlikely that one immunotherapy by itself has a chance. But either by combining say the immunotherapy with either hormonal therapy, radiation, chemotherapy, or bringing in two immunotherapies that work by different mechanisms is going to have really a better chance than just simple therapy with a checkpoint inhibitor.

Dr. Szmulewitz:

And I’d like to add that there is in patients’ promise. And so there was a very large study of a drug called ipilimumab in prostate cancer, which is an immunotherapy. And it is a blockade of sorts. And in this study with prostate cancer, it was very nearly FDA approved for prostate cancer. The problem with ipilimumab, and this was a first-generation immune therapy, is that it was quite toxic. It had a lot of side effects, which dampened its clinical benefit. So if we can refine our immune therapy, especially in our patient population, which is tired and has other already burden of illness, I think that there’s a window where we can really have magnitude.

So adoptive cell therapy, I have no clue what that is, Dr. Szmulewitz. What is adoptive cell therapy?

Dr. Szmulewitz:

Well, I can’t pretend to be an expert. What I will say is it’s a way of using a person’s specific immune system and modulating it and then giving it back. And so sipuleucel-T is actually, in some ways, an adoptive immune therapy. I think the next generation of immune therapies are going to take T cells, the cells within the immune system that can eat up the cancer, and modify them in the laboratory to specifically fight prostate cancer. They’re doing it in leukemias and lymphomas, because we have a good sense of what those targets are. And they’re very uniform.

And I think the challenge with prostate cancer is that, outside of the hormone receptor, it is very diverse and heterogeneous in what’s driving it and in what is made at the surface of the cancer to be targeted. And I think that adoptive T-cell therapy will have a role but still needs a fair amount of research to harness its benefit.

Andrew Schorr:                  

But the idea is in sipuleucel-T, I’m going to get that right, I’ll say Provenge, maybe that’s easier, was kind of that idea a little bit of making a drug for you.

Dr. Szmulewitz:

Yeah. So in sipuleucel-T, your own cells are taken out. And they are then primed outside of the body. What they’re primed with is a prostate protein. And so it’s a bit of a combination between an adaptive therapy and a vaccine. What it doesn’t do is take the T cells and engineer them to fight the cancer.

And so the challenge with immunotherapy and prostate cancer is if the T cells aren’t there in the environment, then all of the stimulation with vaccines isn’t going to be as effective as it could be if the T cells both aren’t there and aren’t recognizing the target. And I think that’s really what the next generation will be.

Andrew Schorr:                  

Dr. Catalona, you’re the professor. Let me see if I get this right. When someone develops a cancer, any cancer, your immune system let you down, in a way, because you are developing aberrant cells, and they were able to fool your immune system and continue to develop. So is the future, do you think, if this can continue to develop where your immune system gets revved up safely somehow with few or, wouldn’t it be great, no side effects to do its job that it hadn’t done earlier?

Dr. Catalona:      

Well, basically, one of the problems is that if your immune system is too reactive, then you can get autoimmune disease like colitis or arthritis oror, you know all of these terrible, lupus, all of these terrible autoimmune diseases. So the reason the immune system incorporates these properties of being able to dampen down an immune response is really to protect the patient from autoimmune disease. So what you need to do is you need to alter the immune system in a way that it’s not going to dampen the specific response against the tumor.

And you want to make the response against the tumor be more specific for those antigens that are only expressed on the tumor cells but are not expressed on normal cells. And that’s why I think, to have successful immunotherapy, you really have to focus on specific antigen recognition and knock down the immune system in appropriate but not in an excessive manner. And I think when that occurs, it’s more likely to be successful.

Andrew Schorr:                  

It’s all about safety. These are powerful weapons you’re working on, right, Dr. Szmulewitz. But it’s how to use them, when to use them, who to use them for, and use it safely. 

Dr. Szmulewitz:

Yes. That’s right. And I think that to get to those three questions in reverse order, how to use them safely. So to use them safely, you have to make them not blanket immune dysregulators, because that we know is not safe, especially in our patient population who is already ill. And whom to use them and when to use them, I think in whom, we have to know each specific patient’s—the Holy Grail, if you will —will be to know, okay, your tumor has this mutation.

Therefore, it will make this aberrant protein that will be foreign to the immune environment. Therefore, we’ll give you a vaccine to boost or modify the T cells to fight that specific protein. And I think the when is perhaps just as challenging. In my opinion, and based on the sipuleucel-T literature, would be early. The earlier, the less the volume of the disease, the perhaps bigger the magnitude of benefit. Now, I would encourage the community to say we need drug development early on in the process, not necessarily late in the process.

We need end points that the FDA can act on that are early in the process, so we can get potent and useful drugs to patients earlier on.

The authors aimed to review immunotherapies available for prostate cancer treatment.

The authors concluded that further research into immunotherapy for prostate cancer is needed to more accurately assess the effect of immunotherapies as a viable treatment option for prostate cancer.