Conversations With Prostate Cancer Experts

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Prostate Cancer, NIH + Clinical Trials

Dr. Ravi Madan (@Dr_RaviMadan), the clinical director of the National Cancer Institute’s Genitourinary Malignancies Branch, focuses on immune stimulating therapies. In particular, he’s interested in how we can combine these approaches with other therapies to improve patients’ lives.

Prostatepedia spoke with him about clinical trials for prostate cancer patients.

Why has it been difficult for doctors to enroll patients in clinical trials?

Dr. Ravi Madan: The reasons vary from case to case. Sometimes physicians don’t mention relevant trials at the right time for patients (when they’re making treatment decisions). Sometimes patients don’t want to go through the process of enrollment because of the perception that it delays their care and that delay will somehow impact their outcome. There is also personal preference. Some patients really don’t like the uncertainty of a clinical trial—uncertainty in terms of what their treatment will be if there’s a randomization or uncertainty about the outcome.

Trials should be discussed with patients when they’re making a decision to change therapies. While enrollment does take time, it’s usually only a few weeks, and for the most part, that doesn’t impact the patient’s outcomes or overall course. Ultimately, patients need to have a risks/benefits conversation with their doctor to determine if a clinical trial fits into the personal treatment strategy that they’ve developed with their doctor and their family.

Perhaps many people assume clinical trials aren’t really available until you have advanced disease, but that’s not really true is it? There are trials available at all stages along the journey.

Dr. Madan: Correct. Trials exist in all stages of the disease. The ones that often get the most notoriety, either on television or in the news, are the ones for late-stage patients. But for example, here at the National Cancer Institute (NCI), we have trials for every stage of prostate cancer, from patients who are newly diagnosed to early recurrence to non-metastatic, and then ultimately, late-stage disease.

Why would someone want to join a trial? Just to gain access to a treatment he may not otherwise have access to?

Dr. Madan: Sometimes you get access to treatments earlier than they may be available to the general public. People should understand that clinical trials often involve the standard of care they would get anyway plus an experimental agent.

There is an altruism component to a lot of this as well. It never ceases to amaze me, but when I deal with the patients here at the NCI, so many of them tell me: “If this helps me, that’s great, but I just want to help someone else later on.” It’s not like everybody has to have that reason, but it’s remarkable how many do. So, the reasons are variable. Sometimes it’s because there aren’t other options, but sometimes it’s because it adds options or adds cards to the playing deck, if you will, and sometimes it’s just pure altruism.

I guess that’s especially true in earlier-stage diseases, where you don’t necessarily need experimental treatment or access to something that you wouldn’t otherwise get access to, such as those on active surveillance.

Dr. Madan: Correct. We have patients in studies who just have rising PSAs where we’re trying to evaluate the potential of immunotherapy in that setting, but the alternative therapy is just really observation for a lot of those patients. For them, the trial is an opportunity to do something when the standard of care might be to do nothing.

What about the concept of the placebo? I’ve heard patients say they’re afraid of getting a placebo, which could make their cancer worse. Is that still a part of the clinical trial world?

Dr. Madan: It is part of the clinical trial world. Many trials require a placebo because in order to scientifically answer a question, there may have to be a group of patients who are untreated. In those circumstances, the protocol (a document that is often over a hundred pages) is designed to protect those patients. Whenever patients are on placebos, there are very strict guidelines about how they’re watched and the parameters used to remove them if there’s evidence that their cancer is getting worse. In some cases, they have scans very frequently. They’re not left unminded, and it’s usually for a short time.

But many trials don’t involve placebos. We conduct trials to see if we can take a standard therapy that’s in use and add something to it to make it better, and this is especially true in this new age of immunotherapy.

In that process, everybody will get the standard therapy, and some of the patients will get the experimental therapy in addition.

They’re not just getting a placebo, and then left unmoored.

Dr. Madan: Right. There are very strict criteria about how patients are monitored so that, if there is evidence that the cancer is getting worse—regardless if it’s standard therapy or placebo—then they move onto something else. In many trials with placebos, oftentimes the physicians don’t even know what the patients are getting, so the physicians often treat them all like they’re getting the placebo because that’s really the safest thing from a patient’s standpoint.

That’s interesting.

Dr. Madan: We need to monitor placebo patients closely in case they are getting nothing, and we need to move on to something else. But if a trial involves placebo, patients should be comfortable with that and comfortable with the relationship with their doctor who’s going to help them make these decisions. Otherwise, it creates a lot of stress, whether in the initial process with the randomization or while they’re on the study.

What about the financial end of trials? Do patients have to pay to participate in clinical trials—for the therapy itself, the procedure, the scan, or more? Or are the costs just travel expenses and time away from work?

Dr. Madan: Generally speaking, patients don’t pay the price for the drug treatments on a clinical trial. Sometimes trials are billed so the insurance company will cover standard costs that would be covered anyway. But for the most part, the patients do not incur the cost of the clinical trial. Costs are borne out by the companies or research bodies that conduct the trials.

Here at the National Cancer Institute (NCI), we are able to conduct trials that are completely free of charge to the patients. And in addition to that, because we are a government entity designed to really benefit the entire country, once patients are enrolled in our trials, we are able to fly them in from different parts of the country.

We can incur the travel costs for patients who travel from anywhere in the United States. That’s part of our mission here: to bring the benefits of this institution to everyone in the country.

Wow! So your clinical trial patients only have to pay for their hotel and time away from work?

Dr. Madan: Correct. And most patients qualify for a subsidy toward their hotel.

That’s unusual, isn’t it? Most non-government- funded trials don’t offer things like that, do they?

Dr. Madan: Yes. It’s an unusual circumstance. It allows our institution to address diseases that may not affect many patients within one geographical area. It’s a unique opportunity to conduct studies on rare diseases, but we also use it for studies in more common diseases.

You don’t want to just study prostate cancer in men in the metropolitan D.C. area, right?

Dr. Madan: Correct. For example,

I have studies with medullary thryoid cancer, which is a very rare disease. But we’re able to get people from across the country and do it in a way that no other institution can because our catchment area is the entire country.

How can men find out about clinical trials? My impression is that the usual path is that their doctor brings it up, or perhaps they hear about it in a support group, but what are some ways that men can find out about trials? Just by visiting

Dr. Madan: I would actually recommend because is more for clinicians. One of the greatest features of is you can search by zip code or city, and it tells you trials within 25, 50, 100 miles, or whatever you like. But either website has a great patient-based resources. I encourage patients to bring up clinical trial options with their doctors and get their doctors’ thoughts on what they find.

Patient support groups are another excellent resource. Depending on the cancer, there are also online support groups that are more prevalent and will probably become more so. Over about a third of our patients are self-referred from around the country, and not just referred by doctors, so it’s common for patients to advocate for themselves in this manner.

I was under the impression that if, for example, a man found one of your trials on and thought he was a perfect fit, he had to go back through his doctor to get involved in the trial. Is that true? Or can he contact you or the researcher directly?

Dr. Madan: Yes; he or she can contact the researcher directly. I get some calls directly from patients saying they saw this on the internet. We also have a clinical trials contact, so no, they don’t have to go through their doctor. I often encourage patients to speak to their doctor just to get an impartial perspective or additional perspective.

Also, patients and doctors have very good relationships usually, and it’s important to get a second opinion before you embark on the clinical trial journey.

But certainly they can contact us directly, and they very frequently do.

When studies are finally completed and published in academic journals, are patients informed, or do they have access to those results?

Dr. Madan: There’s not often a direct mechanism by which patients are informed about the results of the trial. But often, through the course of a study, patients will ask about the experiences so far. We’ll certainly fill them in, and then we have had patients call us up for results. We certainly publish the results and can share them, but there’s not a direct mechanism.

Interesting. There probably should be.

Dr. Madan: That’s an interesting idea. It’s possible some institutions have that. I’m not aware of any at this time.

But patients can always ask their contact directly, right?

Dr. Madan: Yes.

What else should patients know about joining clinical trials?

Dr. Madan: Clinical trials can be an important part of each patient’s individual treatment strategy. Especially for patients with cancer, it’s important for them to develop these strategies in conversations with their doctor and their families, and to develop that strategy based on personal preferences.

Clinical trials are a way to get additional treatment options over time, options beside the standard options that are generally available. Being on a trial requires a little additional time, and there is potential for side effects. If there’s a randomization process, patients should be comfortable with that, no matter what they get.

As the patients who come to NCI from all over, consider local trials and those around the country. Sometimes travel is not optimal, but we’ve had patients come in from as far away as Hawaii and Alaska. Take advantage of the opportunity if you can. The pace of cancer research today is remarkable, especially in immunotherapy, which is one of the biggest focuses here at NCI.

All of us should remember that none of these advances would have happened without remarkable patients who decided to enroll in clinical trials. I consider it an honor to be able to work with the types of people who enroll in trials here at NCI and around the country. It’s really an extraordinary and humbling experience for me.

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Genomics, Predicting Side Effects, + Clinical Trial Design

Dr. Felix Feng is a physician-scientist at University of California, San Francisco (UCSF) keenly interested in improving outcomes for patients with prostate cancer.

His research centers on discovering prognostic/predictive biomarkers in prostate cancer and developing rational approaches to targeted treatment for therapy-resistant prostate cancer. He also sees patients through his prostate cancer clinic at UCSF.

Prostatepedia spoke with him about genomics, predicting side effects and the future of prostate cancer clinical trials

Can genomics predict who will have certain side effects?

Dr. Feng: There have been a number of studies that have used single nucleotide changes within DNA sequences, called single nucleotide polymorphisms (SNPS), to predict who will be most likely to experience side effects from radiation therapy for cancer.

In general, the signal from these toxicity studies has been weaker than the signals from biomarkers that predict responses to particular therapies, like the ones that I mentioned earlier. This may be reflective of the fact that radiation acts through a variety of mechanisms, so any single biomarker may not work well. Even when you cluster biomarkers, it may not account for the heterogeneous manner in which radiation causes a biological effect.

What should patients know about how genomics is impacting treatment?

Dr. Feng: Many of the clinical trials being developed nowadays incorporate genomics. We have clinical grade assays to look at genomics. We have strong biological rationale for why certain genomic biomarkers may identify subsets of patients who can respond to specific therapies. Because genomics is routinely used to personalize treatment in the context of diseases like breast cancer, colon cancer, and melanoma, it’s only expected that genomics will have a major role in prostate cancer going forward.

Will incorporating genomics into clinical trial design accelerate the speed of innovation?

Dr. Feng: I think it will. If you look at metastatic castration-resistant prostate cancer, for example, a number of therapies have been approved by the FDA over the last decade for those patients, including agents like Zytiga (abiraterone) and Xtandi (enzalutamide), next generation taxanes, Provenge (sipuleucel-T), and Xofigo (radium-223). All of these agents extend survival by just a few months.

This is invariably what happens when you treat prostate cancer as one disease entity rather than a variety of different entities that are governed by different genomic events. As we become better at selecting therapies based on a patient’s genomic events, we should see longer response times to available therapies and those currently being developed.

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