Prostatepedia

Conversations With Prostate Cancer Experts


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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.


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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.


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Why Combine RT + Immunotherapy?

Dr. Charles G. Drake, of New York-Presbyterian/Columbia University Medical Center, discusses the thinking behind combining radiation therapy with immunotherapy.

Not a member? Join us. We’re talking about radiation therapy and prostate cancer in July.

Dr. Drake says: “The basic idea is that radiation, and perhaps other local modalities like cryotherapy, leads to destruction of tumor cells. If they’re destroyed in a way that’s immunogenic or pro-immunogenic, then the dying cells are taken up by resident antigen-presenting cells. These antigen-presenting cells get activated; they traffic to the draining lymph node, if you’re lucky. If they traffic to the draining lymph nodes, and then activate a systemic immune response (T cells), then maybe you can turn a local therapy into a systemic therapy. When that happens, it’s called the abscopal effect. We can demonstrate this in mice fairly readily, but it’s quite hard to demonstrate in humans.

In the literature, it’s not that common. There’s a review paper that reports around 60 total cases in the world that are clearly documented. But if you talk to people who take care of patients, everybody has one or two that they can talk about.”

Join us to read the rest of Dr. Drake’s comments on combining radiation therapy and immunotherapy.


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Snuffy Myers On Immunotherapy For Prostate Cancer

This month, Prostatepedia is talking about immunotherapy for prostate cancer.

Dr. Charles “Snuffy” Myers offers his thoughts on this month’s conversations.

Not a member? Join us to read the issue.

Every January we publish an issue on immunotherapy. If you compare our January 2017 issue with this year’s conversations, I am sure the advances in the science behind immunotherapy will excite you. While we only have one FDA-approved immunotherapy called Provenge (sipuleucel-T), the future looks promising.

As Dr. Tomasz Beer points out in his conversation, we’re at an interesting intermediate stage in immunotherapy development. We know that various immunotherapy approaches like vaccines, checkpoint inhibitors, and CAR T-cell treatments can control a variety of cancers, but we don’t yet have an immune-based treatment that has a consistent, major impact on prostate cancer survival or even quality of life.

I’d like to highlight several important themes in this issue. First, evidence continues to suggest a favorable interaction between hormonal therapy and various forms of immunotherapy. Second, there is continued interest in combining immunotherapy with radiation therapy. This offers the hope that immunotherapy might open the door for more effective multimodality treatment.

The emergence of CAR T-cell treatment for leukemia and lymphoma has been very exciting; patients with very advanced disease are entering remission. It will be interesting to see this approach applied to prostate cancer. Also note that major funding for CAR T-cell trials in prostate cancer comes from the Prostate Cancer Foundation (PCF), a nonprofit, and not the United States government. This is a trend I noted last month.

There have been some notable disappointments. The randomized trial testing the Prostvac vaccine failed to meet the requirements for FDA approval. It is still possible that this vaccine might prove valuable in patients with less advanced prostate cancer.

Also, the available checkpoint inhibitors continue to show only modest activity. It may well be that CTLA-4 and PD-L1, the two checkpoint proteins currently targeted, are not the only checkpoint proteins produced by prostate cancer.

For example, earlier this year, investigators from MD Anderson Cancer Center showed that Yervoy (ipilimumab), an agent that targets CTLA-4, triggers production of another checkpoint protein called VISTA. It may well be that prostate cancer can block immune response in a variety of ways and that we need to inactivate each of these defenses.

Even with these difficulties, immunotherapy offers potential benefits that warrant the attention it is receiving.

One of the benefits is that the immune response can evolve over time to match the evolution of the cancer cell population’s resistance. In the laboratory, immunotherapy also offers one of the most robust means of attaining durable and complete remissions.

Join us! Next month we’re talking about what happens when your cancer recurs.