Prostatepedia

Conversations With Prostate Cancer Experts


Leave a comment

Dr. Fatima Karzai is the Director of the Prostate Cancer Clinic for the Genitourinary Branch at the National Cancer Institute. She’s keenly interested in developing novel strategies for harnessing the power of the immune system for hormonally driven cancers, particularly in advanced prostate cancer.

Prostatepedia spoke with her about a clinical trial she’s running that combines PARP inhibitors and a class of immunotherapeutic agents called PD-L1 inhibitors in men with advanced prostate cancer.

Not a member? Join us.

Why did you become a doctor? What is it about medicine that keeps you interested?

Dr. Fatima Karzai: I decided to become a doctor at a very young age. I’ve always wanted to help people. When I was younger, I thought that being a doctor was the best way to do that. I really enjoy patient interactions, so that’s why I’m a clinical researcher and I see patients on clinical trials. I find that it’s the most rewarding experience to be able to interact with patients. It’s always been a goal of mine to be able to help people in this manner. I think oncology was best suited for me to do so.

What are PARP inhibitors and PD-L1 inhibitors? How do they work, in which patients are they used, and how effective are they?

Dr. Karzai: PD-L1 inhibitors are members of a group of drugs called checkpoint inhibitors that have been developed for the treatment of cancer. PD-L1 is a protein that is present on the surface of cells. In cancer, PD-L1 on the tumor cells interacts with another protein on a person’s white blood cells, which are immune cells that help fight cancer. This PD-L1 protein prevents the immune system from attacking the tumor cells. A PD-L1 inhibitor blocks that ability of the tumor cell to suppress our immune system, which can help our immune system kill cancer cells. They’ve been successful in certain cancer types like lung cancer and bladder cancer.

PARP inhibitors are a type of targeted therapy. We all have DNA in our bodies; when it becomes damaged, our bodies know how to repair it. Many things can cause DNA damage: exposure to UV light, radiation, or substances in the environment. There is an enzyme in cells called PARP. PARP helps repair DNA when it becomes damaged. By blocking PARP in cancer cells, we can keep cancer cells from repairing their damaged DNA, which causes them to die. PARP inhibitors work very well in a subset of patients whose tumors harbor something called “DNA damage repair mutations.” These mutations can occur in the tumor itself or it could be something that a patient is born with. PARP inhibitors were initially studied in ovarian cancer and breast cancer. We’re starting to use them more in prostate cancer.

What is the rationale between combining the two agents for prostate cancer?

Dr. Karzai: We wanted to expand the use of PARP inhibitors. Like I mentioned before, right now they’re used in patients with these specific mutations. We’re trying to figure out if we’re able to get this class of drugs to work in patients without these mutations if we combine them with another drug. Historically, PD-L1 inhibitors have not been that successful in prostate cancer, so we decided to put these two drugs together to see if there is any additive or synergistic mechanism that could help patients with advanced prostate cancer.

What have the studies revealed about the combination?

Dr. Karzai: We are still accruing to the study. We’ve looked in-depth at the first 17 patients and seen deep and prolonged responses in men with castrate-resistant prostate cancer with the combination, in men who have these germline or somatic DNA damage repair abnormalities. We’re now adding additional patients to the study to better define the activity and to help us evaluate the biology more.

You said you’re still looking for more patients?

Dr. Karzai: Correct.

Tell us a little bit more about eligibility criteria and who men can contact if they think they’re a fit.

Dr. Karzai: We are looking for patients with advanced prostate cancer—i.e. the prostate cancer has gone outside the prostate and is in either the soft tissue, organs, and/ or bones. We would like to have these patients previously treated with either Zytiga (abiraterone) or Xtandi (enzalutamide). We think patients who have progressed on these two treatments might be more amenable to our combination. We allow previous chemotherapy, so if a patient has had Taxotere (docetaxel) or some other chemotherapy, they would be eligible. We are looking for patients who are still able to perform their activities of daily living and would be willing to participate in our trial and travel.

Some of our patients are local, but many come from across the United States. We even have some international patients.

You help defray the cost of travel for some of your clinical trial participants, don’t you?

Dr. Karzai: We do. Once a patient is on one of our protocols, then we reimburse flights in the United States. We also have a stipend for meals and hotels.

Any further thoughts on this particular combination or other combinations that you think may hold promise?

Dr. Karzai: Even though this type of immune therapy hasn’t been very successful thus far in prostate cancer, I still think that we need to do more studies and research to be able to find the subset of patients that it might work in. Immunotherapy is very exciting. We shouldn’t count it out in prostate cancer yet. The first vaccine that was FDA-approved in cancer was actually for prostate cancer. I think that the whole realm of immunotherapy is still open and could provide benefits for our patients. I am happy to see any patient for a consultation —those with newly diagnosed disease or those who are more advanced. We have clinical trials that span that spectrum of prostate cancer.

Join us to read about more immunotherapy clinical trials for prostate cancer.


Leave a comment

Combining Keytruda (pembrolizumab) and Xtandi (enzalutamide) For Prostate Cancer

Dr. Julie Graff is a medical oncologist at Oregon Health & Sciences University.

Prostatepedia spoke with her recently about her continuing work on combining Keytruda (pembrolizumab) with Xtandi (enzalutamide).

What are Keytruda (pembrolizumab) and Xtandi (enzalutamide)? How and when are they used in prostate cancer patients?

Dr. Graff: Keytruda (pembrolizumab) is an intravenous antibody to PD-1 or programmed death 1 on immune cells, in particular T cells. When that protein is present, it can interact with tumor cells that have PD-L1 and through that interaction the tumor cells turn off the immune system. We consider it a checkpoint inhibitor.

We’ve known for a long time that in some cancers T cells, which are the part of the immune system that can kill cancer cells, are present in the tumor and yet they’re not actually killing the tumor. Over the decades we’ve learned that some of those cells, not necessarily T cells but immune cells in the environment, are actually helping the tumor grow. We’ve also learned that some of them are trying to fight the tumor, but they’re being turned off by the tumor.

Keytruda (pembrolizumab) can block that negative signaling, thereby activating the immune system. It was first approved in melanoma and has received multiple subsequent approvals. So far we don’t have great markers for knowing who will benefit from the drug and who won’t, but we are working on that.

Xtandi (enzalutamide) is a drug that binds to the androgen receptor, which is inside the prostate cancer cells, and prevents it from interacting with androgens or male hormones. In that fashion, it leads to some cell death and helps people live longer. It’s been FDA approved since 2012 in the post-chemo setting, and now it has been approved in the pre-chemotherapy setting. It used to be approved only in metastatic disease, and now it’s approved in non-metastatic castrate-resistant disease. It’s being applied in different stages of the disease.

What is the rationale behind combining these two agents?

Dr. Graff: In studies where checkpoint inhibitors like Keytruda (pembrolizumab) are used alone, there’s not a lot of tumor activity. There’s certainly not a good rationale to use Keytruda (pembrolizumab) by itself in prostate cancer. Maybe as time goes on we’ll find that perhaps 2 out of 100 patients have certain mutations that make the Keytruda (pembrolizumab) alone helpful, but we’re not yet there.

There wasn’t a great reason to use Keytruda (pembrolizumab) by itself, so we began to think about combinations. Xtandi (enzalutamide) was felt to upregulate PD-L1 on dendritic cells, in particular when people became resistant to the Xtandi (enzalutamide), so that was one initial reason.

Castration therapy may reinvigorate the immune system. When you’re maturing as a child, you have a thymus gland behind your sternum that helps create new T cells. As you go through puberty, that gland shrinks and becomes inactive, so you don’t make new T cells.

It looks like maybe the thymus increases again during castration therapy; there’s a hypothesis that you’re creating new T cells.

There is also a reason to think about Xtandi (enzalutamide) in particular. It’s helping in those two regards.

Also, if you used Keytruda (pembrolizumab) in combination with chemotherapy, you would be at risk of killing a lot of immune cells with the chemo itself. If you used Keytruda (pembrolizumab) in combination with Zytiga (abiraterone), which is like Xtandi (enzalutamide), you would have to use prednisone, which would perhaps dampen the immune response. When our study was designed in 2014, it made a lot of sense to combine Keytruda (pembrolizumab) with the Xtandi (enzalutamide).

What have studies revealed about the combination? Is it effective? What kind of side effects do patients experience?

Dr. Graff: We did a Phase II study looking at 28 patients with metastatic castrate-resistant prostate cancer whose cancers were progressing on Xtandi (enzalutamide). We added 4 doses of Keytruda (pembrolizumab). We saw 5 responded in that group of 28. That’s only 18%, but when they responded, they responded spectacularly.

The most extreme case was a gentleman who started out with a PSA of 2,500 that went down to 0. He had big, bulky liver tumors that just shrank away. He must be two and a half, almost three years out from treatment and he’s still in complete response. His case is extreme. But when we do see responses, they’re spectacular.

If those five patients had only had a dip in their PSA or something less impressive, the study wouldn’t be as important as it was. Then we had four other people who had very durable responses as well. That’s the benefit part of the study.

But there are known side effects with each of these drugs. With Keytruda (pembrolizumab), when you stimulate the immune system you run the risk of the immune cells killing or attacking healthy tissue. For example, a patient on Keytruda (pembrolizumab) could develop autoimmune hepatitis where the immune cells are attacking a healthy liver. There are some bad sides to stimulating the immune system.

In our study, we did see some of those side effects. In these 28 patients who were treated, we did have patients who had autoimmune toxicities in which their own immune cells attacked healthy tissue. We had four patients who had thyroid dysfunction, which is a fairly well recognized side effect of Keytruda (pembrolizumab) that is easy to manage with thyroid medicine. We had a couple people with colitis, which happens when the immune system attacks the colon; that has to be managed with high-dose steroids and sometimes biologic drugs that GI specialists use. We saw side effects that we would expect from Keytruda (pembrolizumab) and we saw some side effects that we would expect from Xtandi (enzalutamide) such as fatigue. Since these patients had already been on Xtandi (enzalutamide) for a long time, we did not observe worsening of the Xtandi (enzalutamide) side effects with the addition of Keytruda (pembrolizumab). We mostly just saw those Keytruda (pembrolizumab) side effects.

Any follow-up studies planned?

Dr. Graff: We got funding from Merck to add another 30 patients on to that study. Those 30 have already been enrolled and treated. For those patients, we insisted on a biopsy. For the first 28 patients, we asked them to get a biopsy if they had a tumor that could easily and safely be biopsied. In the next 30 patients, we required that they have a biopsy. We have now a nice array of tissue from these 58 patients and we’re working on getting the results. We have some multiplex stains and hope that the paper can come out next year.

Join us to read about another of Dr. Graff’s clinical trials that will be accepting patients shortly.


Leave a comment

Prostate Cancer Vaccine Clinical Trials

Dr. James Gulley is the Head of the Immunotherapy Section and the Director of the Medical Oncology Service at the National Cancer Institute’s Center for Cancer Research in Bethesda, MD.

Prostatepedia spoke with him recently about ProstVac and open prostate cancer vaccine clinical trials.

There is a vaccine that was under investigation called ProstVac. Can you tell us a little about that vaccine and whether or not it has been effective? 

Dr. Gulley: ProstVac is a pox viral-based therapeutic vaccine that has the genes for PSA, as well as three different human T-cell co-stimulatory molecules. What that means is that the vaccine is something that we can give that can train the patient’s immune system to recognize and attack cells that make PSA. Normal prostate cells or prostate cancer cells can make PSA. There are cancer patients who have had their prostates removed. The only cells left behind that would express PSA are the cancer cells.

There are two basic viruses that are used. One is vaccinia for the initial vaccine. It’s a really good jolt to the immune system. All the subsequent boosting vaccines are given with fowlpox that again contain the same genes for PSA and co-stimulatory molecules. That can continue to boost an immune response.

There were initial studies done with this agent that showed that it was safe to give in patients with advanced cancer and that when given it could generate immune responses to PSA in those patients. If you took cancer cells with the immune cells from those patients, those immune cells could recognize and kill those cancer cells that make PSA.

We then did additional studies looking at this activity, including one randomized Phase II study that was double-blinded. 125 men received vaccine versus placebo. In that study, we found that there was no difference in progression-free survival, but there was an improvement in overall survival, which was our secondary endpoint.

This is very similar to what was seen with Provenge (sipuleucel-T). So we followed this up with a larger study to confirm whether or not these findings are correct. We embarked on a 1,200-patient study that over enrolled. There were 1,297 patients enrolled on that study. We presented the results at the conference of the American Society of Clinical Oncology in 2018: there was no improvement in overall survival with the vaccine.

I should mention a little bit about the trial design. There were three arms in the study: one group received the vaccine plus GM-CSF. This was used in the Phase II trial and showed an improvement in survival. GM-CSF, or Granulocyte-macrophage colony-stimulating factor, can further boost immune response. We don’t know if it is required for the vaccine or not. Interestingly, because of the difficulty in getting this outside of the United States and because we didn’t know if it was needed or not, we did one arm with GM-CSF and another with no GM-CSF. The third arm got a placebo. The placebo vaccine was just comprised fowlpox vector.

What we saw in that study, which showed no improvement in survival, is that we don’t really have a clear explanation of what happened or why we saw a difference in the Phase II study. It could be that the Phase II study was just under-powered and the results we saw were based on chance. (I’m just going to lay everything out here.) It could be that the vaccine was effective and that it did generate immune responses, but that those immune responses did not translate into improved survival for a variety of different reasons.

First, multiple agents have been approved since the initiation of the drug; Zytiga (abiraterone), Xtandi (enzalutamide), Jevtana (cabazitaxel), Xofigo (radium-223), and Provenge (sipuleucel-T) were all approved after that study was designed. It’s possible that when these agents are used afterwards they delete out any treatment effect.

If you look at the overall survival data from Xtandi (enzalutamide) and Zytiga (abiraterone), you’ll see huge improvement in survival in the post chemotherapy setting. In the pre-chemotherapy setting it’s very difficult to see an improvement in survival. In fact, there was no statistically significant improvement in survival with Zytiga (abiraterone) in the pre-chemotherapy setting, suggesting that that could be another explanation for why an improvement in survival just wasn’t seen. The lines are really overlapping. Finally, it could be that the vaccine was generating an immune response. That immune response went to the tumor, but those cells were held in check because of regulation of PD-L1 or something like that. It turns out that when you have activated T-cells that recognize a tumor, they make gamma interferon and cause the other T-cells there to recruit other cells, but that gamma interferon will cause up-regulation of PD-L1. (PD-L1 is a stop sign to T-cells.)

As soon as the T-cells see that stop sign, then they stop everything and they can’t do anything while that’s there. If you come in with an immune checkpoint inhibitor and block either the PD-1 or the PD-L1, you basically cover that stop sign and those T-cells go back to work.

Perhaps that is what’s going on. We did a study in the neo-adjuvant setting where we gave a ProstVac vaccine to patients undergoing surgery. We did see immune cells getting into the prostate, but often not into the tumor, so it may not just be the PD-L1. There are other things excluding the T-cells from the tumor, for example there may be no HLA-A2 expression. Maybe there is up-regulation of TGF-beta. These are still things we’re grappling with, things we’re trying to understand. We’re also trying to come in with other clinical studies to address these different aspects of what might be going on in the tumor microenvironment to lead to a better outcome.

You’re still looking for explanations?

Dr. Gulley: Correct. There are ongoing studies looking at ProstVac in men with a biochemical recurrence. There are ongoing studies in active surveillance—with patients who don’t need treatment.

There are ongoing studies in combination with other agents, like ProstVac and Opdivo (nivolumab). We’ve looked at that combination in men with metastatic disease. I mentioned earlier two of the twelve patients had good responses. Ten of them didn’t. We’re trying to understand that better, so we’re taking it into the neoadjuvant setting. We’ve enrolled one out of the seventeen patients we need to understand a combination of a vaccine plus Opdivo (nivolumab). We’re getting biopsies and comparing that with the prostatectomy specimen to see if there is an increase in immune cells. Do we get more of an increase in immune cells from that combination than we get from the vaccine alone? How do we improve upon that?

If a man reading this is interested in joining a trial, there are multiple options for him to consider?

 Dr. Gulley: Absolutely.

Join us to read about additional trials that Dr. Gulley and his colleagues are running.

 


Leave a comment

Who Is Dr. James Gulley?

Dr. James Gulley is the Head of the Immunotherapy Section and the Director of the Medical Oncology Service at the National Cancer Institute’s Center for Cancer Research in Bethesda, MD.

Join us to read Dr. Gulley’s comments about prostate cancer vaccine clinical trials.

Why did you become a doctor?

Dr. James Gulley: I think this has to go back to my high school biology teacher. His name was Vernon McNeilus. He was a retired orthopedic surgeon who just found a way to instill inspiration and that sense of curiosity about life. He drove us to really be excited and interested in science and in biology in particular. I had decided that I wanted to do something in science or medicine, but there was no way that I was going to go spend all that time to become a doctor. I’d been in school long enough. One of my friends decided he was going to go into medicine. I said if he can do it, I can certainly do it.

Then it actually evolved even further than that because during my stint in college I got the opportunity to do a summer research program. I decided I liked research, so I applied to MD/PhD programs and got accepted into two. I decided to go to Loma Linda.

What is it about medicine that keeps you interested?

Dr. Gulley: I think the thing that really drives me is how fascinating it is to understand how things work. I’ve always been fascinated in what makes things work. As a little boy I would take things apart trying to figure out what made them work and then put them back together again. If something was broken in the house, my mom would just give it to me and I’d tinker with it and get it to work again.

To me, the ultimate machine is the human body and one serious puzzle is to figure out ways to bring back health from sickness. Not just a puzzle for curiosity’s sake, but because of the effect that cancer can have on families, to uncover ways to effectively treat cancer. I think it’s truly something that I have seen patients who were close to death who have had remarkable and prolonged clinical responses. That, to me, begs the question that if we can do it for some people, then why can’t we do it for all people? That is what I am passionate about.

Are there any patients you’ve had over the years whose cases changed how you see your own role or the art of medicine?

Dr. Gulley: I’ve had several patients that have been exceptional responders; that really has changed how I view things. One of my more recent exceptional responses from this past year is a retired army surgeon who has advanced metastatic castrate resistant prostate cancer. I have been treating him since 2005. He was initially treated with radical prostatectomy. It turned out that he had a high Gleason disease. He had radiation therapy, but he had recurrence of his disease, unfortunately. He was treated with hormonal therapy, with chemotherapy, with Provenge (sipuleucel-T), and Xtandi (enzalutamide).

He came to me last year having had multiple therapies including other experimental immunotherapies. He was clearly not doing well. His PSA was going up very quickly with a doubling time of less than a month. His symptoms were getting substantially worse. He articulated to me that even going to church every week was becoming difficult: one week he was able to sing the songs and the next week he was too tired to sing. Then the next week he was almost too tired to stand up.

We were able to enroll him in a study combining a vaccine with checkpoint inhibition. When we gave him that combination, his PSA dropped dramatically. It has now gone to undetectable. His lesion in his bladder, which was causing local symptoms so that he had to have a chronic indwelling Foley catheter, shrunk away. When we biopsied it there was no evidence of tumor there. He has some lesions that are seen on bone scan, but I’m not sure if that represents viable tumor or not.

He is now over a year out from when he started treatment. His energy level hasn’t been better since before he was diagnosed. He is out doing everything he wants to do. To me that is amazing. It is amazing we can see responses like that.

From a scientific standpoint, of course, I was stunned to see this and wondered could he have micro-satellite instability that leads to lots of mutations. It turned out that he had micro-satellite instability in his cancer, suggesting that the immune system was able to see his cancer much more readily, so all we need to do is allow those immune system cells to be functional with the Opdivo (nivolumab).

We also had one other patient that didn’t have micro-satellite instability with this combination who also had a really nice 90% or so drop in his PSA. It’s not undetectable, but he hasn’t had the immune checkpoint inhibition for well over a year now. He’s just on vaccine alone because he had some bleeding in his urine from the checkpoint inhibitor. To me, having responses like that changes my outlook. It says the immune system, even in patients with prostate cancer, can be harnessed to attack the tumor. We just have to figure out ways that we can make this more applicable to all patients.


Leave a comment

Immunotherapy: Looking Ahead to 2019

Dr. Charles G. Drake is the Director of Genitourinary Oncology, Co-Director of the Cancer Immunotherapy Program, and Associate Director for Clinical Research at the Herbert Irving Comprehensive Cancer Center, New York-Presbyterian/ Columbia University Medical Center.

He spoke with Prostatepedia about the current state of affairs for immunotherapy for prostate cancer and what he anticipates happening in 2019.

“Over the past year, we’ve looked at early data from several anti- PD-1-based immunotherapy combinations. In 2019, we’ll be looking to see more results from these combination studies, to see which combinations will actually work in patients. It’s pretty clear that although PD-1 blockade has some activity, it doesn’t have a lot of activity. The idea is if you combine PD-1 blockade with some of the more standard therapies for prostate cancer, you might get more activity.

One of the more interesting combinations is PD-1 blockade plus a PARP inhibitor like Lynparza (olaparib). PARP inhibitors have activity in prostate cancer, particularly in patients who have mutations and proteins that repair DNA; these mutations are called called homologous repair defects. These patients have a good response to PARP inhibitors. A combination of PD-1 plus PARP inhibitors is being tested both in patients with the mutations and in patients without the mutations.

What has emerged in other diseases likes ovarian and breast cancer is that if one blocks PD-1 and treats with a PARP inhibitor, sometimes it looks like it doesn’t matter if the tumor has those DNA repair mutations or not. There are ongoing trials combining several of the anti-PD-1 / PD-L1 agents like Keytruda (pembrolizumab), Opdivo (nivolumab), and Imfinzi (durvalumab). All these drugs will be combined with PARP inhibitors. The question is whether that combination will lead to objective responses similar to what has been seen in other tumor types. Interesting early data from the NIH group suggest that the PARPi / anti- PD-L1 combination is active.

The second interesting combination involves PD-1 / PD-L1 blockade with hormonal therapy. We showed a while ago that hormonal therapy seems to at least temporarily block tolerance to prostate tumors in murine (mouse) studies. A vaccine plus hormonal therapy can lead to improved responses. The idea is that by giving initial hormonal therapy with immunotherapy, or adding an immunotherapy when you switch hormonal therapies, you will get better responses.

One randomized Phase III trial already tested this combination. The study enrolled patients who were on Zytiga (abiraterone) and then randomized them either to Xtandi (enzalutamide) or the combination of Xtandi (enzalutamide) plus a PD-L1 blocking antibody called Tecentriq (atezolizumab). I’m on the steering committee for that trial. Those patients were pretty healthy in general, though, and so it’s probably going to take a couple of years until we read out whether the combination leads to an improvement in survival.

Other PD-1 or PD-L1 blocking agents will be combined with hormonal therapy as well. At Columbia, we’re doing a really great trial called Magic-8. We’re giving anti-PD-1 in combination with the first hormonal therapy. This is for patients who have had surgery or radiation, who have evidence of a rising PSA, and have a fast doubling time. They will get the anti-PD-1 Opdivo (nivolumab) plus hormonal therapy with degarelix for a short course. Patients will first get two doses of immunotherapy— a prime and a boost. A month after that, they will get the combination of immunotherapy plus hormonal therapy with degarelix. They only get four months of hormonal therapy and then we stop everything to see if they can recover their testosterone and not have a PSA relapse.

To enroll in Magic-8, patients have to have had primary therapies, so they had to have either surgery or radiation. Then they have to have a PSA that’s rising quickly, with a PSA doubling time less than 12 months. Immunotherapy, as you know, is not without risk, so this trial is not for everyone. Patients have to have a reasonable indication that their recurrent prostate cancer is aggressive. They have to have a testosterone level greater than 200, so that their cancer will respond to androgen ablation. One thing that’s a bit different from other trials is that we don’t care if the patient has radiographically detectable metastases or not. If they have metastases, we’re asking them to agree to get a biopsy because we want to try to understand in which patients this combination works. Their PSA also has to be reasonable. It has to be more than 2 but less than 50. This trial is open and accruing.

Not a member? Join us to read the rest of his comments and to find out about other immunotherapy trials looking for patients.


Leave a comment

Immunotherapy For Prostate Cancer

In January, we’re talking about immunotherapy for prostate cancer. Dr. Charles Myers introduced the issue for us.

Not a member? Join us to read this month’s conversations about immunotherapy.

The goal of this issue is to capture the current state of the art in immunotherapy of prostate cancer. We live in a time when immunotherapy is making major contributions to the treatment of many malignancies. The Nobel Prize was recently awarded for the discovery of checkpoint inhibitors that have revolutionized the treatment of melanoma. Chimeric antigen receptor T (CAR T) cell therapy represents a major advance in the treatment of B-cell lymphoma.

Unfortunately, immunotherapy has not yet had such a dramatic impact on prostate cancer treatment. The Provenge (sipuleucel-T) vaccine has been approved for prostate cancer treatment because it results in a modest improvement in the survival of patients with advanced disease. The checkpoint inhibitors have not shown useful activity in prostate cancer, although a small group of patients have had dramatic responses. The current situation may be best summarized by saying that immune response to prostate cancer can be demonstrated in patients, but various factors appear to limit cancer cell kill.

In this issue, we feature conversations with investigators who are doing interesting research on how to overcome factors limiting the effectiveness of immunotherapy in prostate cancer.

Dr. Charles G Drake talks about the state of immunotherapy in 2018 and looks ahead to what we can expect to happen in 2019.

Dr. James Gulley talks about why the initial trials with the prostate cancer vaccine ProstVac didn’t prove as promising as we’d all hoped. He also outlines a number of prostate cancer vaccine clinical trials looking for patients.

Dr. Julie Graff discusses clinical trials—both completed and those looking for patients—that combine Keytruda and Xtandi.

Dr. Fatima Karzai tells us about clinical trials at the National Institute of Health that combine PARP and PD-L1 Inhibitors.

Dr. Bruce Brown, Chief Medical Officer of Dendreon, discusses a clinical trial that looks at using sipuleucel-T in men on active surveillance.

Each conversation this month includes information on clinical trials that are recruiting prostate cancer patients. If you think you may be a fit, please don’t hesitate to contact the investigator.

Join us for more information.