Decoding Exceptional Responses: The National Cancer Institute's Unique Prostate Cancer Study - Fatima Karzai & Rana McKay

June 13, 2023

Alicia Morgans host Fatima Karzai and Rana McKay to explore the National Cancer Institute Natural History Study. This study focuses on prostate cancer patients with unusual mutations and exceptional responses to treatments, aiming to understand their disease progression over time. The trial, conducted across multiple sites including UCSD, follows participants longitudinally, particularly those with specific germline or somatic variants, or those deemed as exceptional responders. Dr. Karzai explains the effort to track the participants' disease course to gather more data on the genomics landscape in prostate cancer. Dr. McKay highlights the study's potential for revealing prognostic and predictive capabilities of these rare variants and for understanding the genomic alterations behind exceptional responses. The study, being a significant academic initiative, invites further collaboration and patient participation.


Fatima Karzai, MD, Associate Research Physician, Clinical Director, Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD

Rana McKay, MD, Medical Oncologist, Associate Professor of Medicine, UC San Diego School of Medicine, La Jolla, CA

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

Read the Full Video Transcript

Alicia Morgans: Hi, I'm so excited to be here with Dr. Fatima Karzai, who's an associate research physician at the National Cancer Institute, and Dr. Rana McKay, who is an associate professor of medicine at the University of California San Diego. Thank you guys so much for being here.

We're talking today about the Natural Cancer Institute Natural History Study, which is a study being done in patients with interesting mutations, and sometimes exceptional responses, and it's a natural history study to understand how they do over time. I wonder if you two could tell me a little bit about that, and we'll start with Dr. Karzai. Why did you start this trial?

Fatima Karzai: Thank you, Dr. Morgan. So this was a trial that was conceived with a lot of investigators in the realm of prostate cancer, where we know certain information and data about certain mutations, either germline or somatic. And we've garnered that information over several years, including the BRCA mutations and other DDR mutations.

What we don't know is, what happens with patients who have lesser known mutations, and how do we follow those patients and kind of look at their course of their disease? So from that, we all conceived this idea of a natural history study. It is out of the NCI, where we are longitudinally evaluating patient patients with prostate cancer, with known germline or somatic variants in PIK3 and/or AKT, PALB2, BAP1, the RAD family, RB1, SPOP, Wnt/β-catenin pathway, and the MMR genes.

We really want to better understand the natural history of the disease with patients with those mutations. We're also longitudinally evaluating subjects with prostate cancer, who are TM, have disease that's TMB high. Which is defined as more, greater than or equal to 10 mutations per megabase.

And another interesting caveat to this trial is that, we do have a cohort of what we call, exceptional responders. So these are participants who have prostate cancer, may or may not have these mutations, but the PI has deemed that they've had some kind of an exceptional response to a treatment, either on a clinical trial or a standard therapy, and they should be evaluated longitudinally. So we have those patients too as a cohort.

We have tried to make this as easy for patients to sign on as possible. If patients fall into those categories, all they need to be is over 18 years old, have prostate cancer, have one of those mutations, or be deemed an exceptional responder, and they can sign onto the study. The study will then follow them throughout the course of their disease. And every so often, we will follow up, to get clinical information, and also occasionally, laboratory data, and if possible, biopsies, if done on the outside at their treating institutions.

We're very excited to have multiple sites on this trial. One of those sites is UCSD, and I will hand it over to Dr. McKay.

Rana McKay: Wow. Thank you so much, Fatima. We're super excited about this study, really filling an unmet need in the field, trying to understand these rare variants, that may potentially have prognostic and potentially predictive capabilities down the road, and really understanding those exceptional responders. And the reason why that is, is we want to understand, how can we emulate such responses for all of our patients who have prostate cancer? What are those unique genomic alterations that really drive somebody having an exceptional response?

And this was actually a collaborative effort, actually developed through organizational infrastructure within the Prostate Cancer Foundation, bringing together investigators who are interested in precision oncology in prostate cancer, and understanding what the significance of these various mutations are.

Alicia Morgans: Well, I think it's so exciting, and really to emphasize for all that are listening, this is an ongoing clinical trial, a clinical trial that is seeking participants, and is encouraging clinicians to potentially open the trial, or send patients to the sites that are currently open. And for patients to reach out, get involved. If you think that you might be someone who could screen into this trial, and certainly, the sites can determine whether or not you are eligible as a patient, we would love to hear from you.

I'm sure this is a study that is posted on We'll make sure that we have that information there, which of course, we'll have contact information and ways for people to get involved.

But Rena, you have put patients on this trial, and are always thinking about how to get patients on trial. And one of the things that I do, as a clinical investigator, is try to understand, when can a patient get involved? How do they get involved? Does this study only include patients who have not yet started therapy, or about to begin therapy? When can a patient actually enroll on this trial?

Rana McKay: Honestly, the enrollment is pretty simple. As long as they have one of these set mutations, they've got metastatic disease, they've over 18 years old, or they have an exceptional response, which is defined in the eligibility criteria to what that is, they can enroll. They can on a therapy that's working for them. They could be about to transition to therapy. As long as they kind of meet those gene mutations and exceptional response mutations, they can go on. And then, we follow them retrospectively with whatever happened to them prior to them enrolling. And then after they're enrolled, they're followed kind of prospectively for what happens to them.

Fatima Karzai: And we really think it's important to fit, to follow these patients, these participants, throughout the course of their disease, because we really need to garner more information on the genomics, and the landscape of genomics and genetics in prostate cancer. So this is a really important initiative, we think, for all prostate cancer patients across the board.

Alicia Morgans: I mean, I really think of it as a fact finding mission. It's basic discovery. It's just discovery in people, in patients who are going to lend their time, and their genetics, and their outcomes data, rather than in a laboratory under a microscope. So this is the way that we need to make these cancer discoveries. At this point in time, we have so many opportunities to dig into this data, and this is one of the most exceptional, and one that I'm really excited about. So if each of you could, we'll start with Fatima. Just give, I guess a pitch. Why should someone get involved with this trial?

Fatima Karzai: Sure. So we would love to have participants involved who would like to give us more information on the nature and the course of their disease, of their mutation, but also, for us to be able to help others with those same mutations. We find that we have a patient population who is very interested in being involved in research for the greater good. But also, to figure out what therapies most benefit these patients and which don't. I think the participants would be able to figure, have more information generally, in terms of treatment options, and what the best next solution is for them.

Alicia Morgans: Wonderful. And Rana, why should a clinician either send a patient to one of the centers, or consider opening this trial at his or her own site? What's in it for them?

Rana McKay: No, I think this is, for one, this is really a great academic initiative. I think we have come together to really try to understand these genetic alterations. I think there's huge opportunity to really delve into this data, once it's all captured, and for all the investigators that are involved, it's really been a collaborative effort.

So one, I would say the collaboration, the networking. It's really easy to get involved. If you're thinking about potentially opening this study at your site, please reach out to us, reach out to Dr. Karzai. She's been leading this effort at the NCI, which is really spectacular.

And for those patients that think that they could potentially be eligible, because they've had an exceptional response, or have one of these mutations of interest, certainly, you can look up through, and see if you're close to one of these sites that has the study open.

And really, it's a way to give back. It's a low resource study. You could say we're really just following clinical data, and occasional specimen collection, and should be a little left for those investigators and patients that want to get involved.

Alicia Morgans: Wonderful. At the end of the day, I think the information gathered will be invaluable. And really, it's our opportunity to have a diverse group of patients to engage everybody. There's no real barriers. As long as these patients have those alterations, or have that exceptional responses defined in the protocol, we want to hear from them, and we want to get them on there, so that we can all learn as a prostate cancer community.

So thank you both so much for the research that you're doing, for the time that you took to tell us about it. And we wish you luck. We will be circling back with you to hear how things turn out in the end.

Rana McKay: Thank you.

Fatima Karzai: Thank you.