Understanding the Potential and Challenges of Sipuleucel-T and Radium-223 in the Management of Metastatic Castration-Resistant Prostate Cancer - Sumit Subudhi

July 7, 2023

Alicia Morgans hosts Sumit Subudhi to discuss underutilized therapies for metastatic castration-resistant prostate cancer (mCRPC). Dr. Subudhi expounds on the complexities of Sipuleucel-T and Radium-223, highlighting their benefits for maintaining patient quality of life. He clarifies that while these therapies do not reduce prostate-specific antigen (PSA) levels, they slow down cancer growth, explaining the PSA paradox for patients. Dr. Subudhi distinguishes Sipuleucel-T as an immunotherapy vaccine that trains immune cells to combat cancer, arguing that its optimal use is as first-line therapy for asymptomatic mCRPC patients. They note intriguing data on extended responses in Black patients. For Radium-223, used for symptomatic patients, they emphasize symptom monitoring over PSA levels. Drs. Morgans and Subudhi encourage clinicians to consider these therapies in their treatment sequence, aiming for maximum therapy lines to extend both patient lifespan and quality of life.


Sumit Subudhi, MD, PhD, Associate Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD, Anderson Cancer Center, Houston, TX

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

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Alicia Morgans: Hi, I'm so excited to be here with Dr. Sumit Subudhi, who is visiting us from MD Anderson Cancer Center. Thank you so much for being here.

Sumit Subudhi: Thank you for having me.

Alicia Morgans: Wonderful. Always excited to talk to you. And in this case I'm really excited to talk to you about some therapies that we have available in the metastatic castration resistant prostate cancer setting. And importantly, these are two therapies that are not necessarily used as often as some of the other options that we have. And these are Sipuleucel-T and Radium-223. I think importantly, when we think about patients with mCRPC, we know that on average they're getting one or two lines of therapy when there are multiple lines available. And ultimately, if we can give more lines of therapy to our patients, we hopefully can extend their lives but also make them feel better. Especially since many of these therapies, including the two I mentioned, are associated with a maintenance of quality of life. Why do you think this is happening? What's going on with these particular therapies that they're not being used to their capacity potentially?

Sumit Subudhi: I think that one of them is that, although both therapies improve overall survival in randomized phase III studies, unfortunately, they do not change PSA. Meaning that in most patients that receive either one of the therapies, the PSA of the patients will continue to go up. So the patients always ask me, "How can my PSA go up and how can future scans look worse and the drugs still make me survive longer?" And the way I think about it is the only way that works is if the cancer is going at a hundred miles per hour and what these drugs are doing, it's slowing it down so it's going 50 miles per hour so that the PSA is still going up, but probably not as fast as it would without the treatments.

Alicia Morgans: And that makes a lot of sense. And you have a specific expertise in immunotherapy, immunology, and really using the patient's own immune system to try to attack the cancer or at least slow it down as we just mentioned. I wonder if you can talk through what you think is happening with Sipuleucel-T? Really enlighten us, and remind us of how this drug works.

Sumit Subudhi: So it's a vaccine. A lot of people confuse immunotherapies with the anti-PD1 drugs that which are immune checkpoint therapies. But this is a vaccine and the way it works, the way I describe it to my patients is that we're going to put you on a table and we're going to take... for three to four hours you'll be laying on this table and they'll take away your immune cells, not all immune cells, just some of them, so they're not going to be immunosuppressed. And then they mail the immune cells to the company that teaches the immune cells how to fight the cancer. And then three days later, those immune cells are now put back into the patient so they can fight the cancer. The truth is what's actually going on is that when the cells are going to the company, the company is putting it and mixing it with a drug called Provenge or Sipuleucel-T, and that's a combination of a fusion protein, a prosthetic acid phosphatase, and a cytokine known as GMCSF.

GMCSF is a dendritic cell activator. So what happens is these immune cells become active, they take up the PAP, which is prosthetic acid phosphatase, they present it on their class one and class two, and then when this product is put back into the patient, it stimulates the T-cells. So the T-cells will then interact with these activated dendritic cells and then go enter the tumor and kill the cancer. Larry Fong did a great study where he published in a pre-surgical trial where they gave Sipuleucel-T before surgery. When they took out the prostate surgically, what they found was that you get a significant infusion or infiltration of T-cells into the prostate. So it's a vaccine that basically boosts immune system to get the T-cells into the prostate to kill it.

Alicia Morgans: Which is so interesting and smart. And again, trying to get our own bodies to recognize this intruder that should not be there. I think there's some really interesting data about Sip-T and about timing, and I wonder if you could comment on timing? PSA being lower, perhaps might be associated with better responses to treatment.

Sumit Subudhi: There's a retrospective analysis done that's showing that the lower your PSA, the more likely you're to respond or have a longer survival benefit with Sipuleucel-T. And so what I do as a clinician is that as soon as I see the patient have a rise in PSA, I use Sipuleucel-T as my first line therapy in metastatic castration-resistant prostate cancer. But the patients have to be asymptomatic from their cancer and they cannot have any visceral metastases, like metastases to the liver or the lungs.

Alicia Morgans: And this is really a population that may be progressing slowly, perhaps after a doublet or a triplet therapy that is going to be the population with the longest time to live, but also the most time to benefit perhaps from this sort of an education of their immune system.

Sumit Subudhi: We're getting a manuscript ready to... because we actually have a subset of patients that we've given Sipuleucel-T to and they've not required any other subsequent therapies for three to five years. And so there are some patients that actually are benefiting much longer than we anticipated.

Alicia Morgans: I think that's such an important point. I have definitely had patients who have had these prolonged responses for over a year even. And it's not necessarily always who I think. There is some data that Black patients may have longer responses and then there may be other immune related ways that we can characterize these patients. I'm not sure what's going to be in your paper, but I'm really eager to hear when that comes out, of course.

Sumit Subudhi: Yeah, no, you brought up a great point because Black patients are thought to... not thought to, they have a more aggressive cancer than their counterparts, White counterparts. And so it's one of the things that when I have a Black patient in clinic that is considering first line metastatic castration resistant prostate cancer therapy, I'm actually telling them that the data shows that you're more likely to benefit. Which is nice because there's not many therapies that actually the Black patients benefit more than the other ethnicities.

Alicia Morgans: And that is so important. Wonderful. So that's one option certainly. And Radium-223, another option. Another option associated with, as we said, PSA increasing. So it's a little bit difficult to think that through sometimes. Is this a drug that you use in clinic and how do you use it optimally?

Sumit Subudhi: Yeah, so I do use it a lot in clinic and it's a good point. In most patients the PSA will go up. In fact, in the phase III study there's only 16% of patients had a 30% decline in PSA. But we have to remember the phase three was not Radium versus placebo, it was Radium-223 plus best supportive care versus placebo plus best supportive care. So the PSA decline was probably more as a result of the best supportive care. What ends up being a good biomarker for Radium-223 is in those patients that have elevated alcohol and phosphatase levels, those can actually decline with the drug. The thing that I have to do, whether patients are getting Radium-223 or Sipuleucel-T, I have to tell patients, don't worry about their PSA, I'm more concerned about your cancer related symptoms. So Radium-223, unlike Sipuleucel-T, is given for symptomatic patients and it's meant for patients with bone predominant disease and they cannot have visceral metastases either. And I do give it to some patients that have bone metastases and lymph node metastases, but the lymph node metastases on the scan have to be stable, they can't be actively growing. And then I feel comfortable giving it because it's given once a month for a total of six doses.

Alicia Morgans: And so how do you know if we're not really watching PSA if a patient is responding or stabilizing rather than progressing?

Sumit Subudhi: So we actually don't know. And that's why it's so important that when you meet the patient before they start the treatment, you really understand where the cancer related symptoms are. And we ask them whether they're getting worse. So if they're on narcotics, because Radium-223 is supposed to be given with symptomatic patients, that may be on Ibuprofen or non narcotics or they could be on narcotics. And what we do is we really monitor how much they're taking. It's not good to ask the patient, "Are you feeling more pain or not?" Because they could be taking more narcotics than they started with and their pain is better because they're just taking more drugs. So it's very important that you ask how much are they taking? And with Radium-223, there is actually a benefit symptomatically from cancer. So that's how I can tell and I'll just continue it if I feel like their cancer related symptoms are worsening.

Alicia Morgans: Absolutely. And there has been some recent data to suggest that a decline in Alk Phos, even in patients who have a normal Alk Phos to start and they still have a decline, that can be a population that's responding even better. So really, really exciting. So as you think about these two therapies and really how we do the best we can for our patients with all of the options that we have available, what would your message be to patients and the clinicians?

Sumit Subudhi: I think that the way... we do have a lot more options available, but we have to remember that three of the options are drugs that are similar to having in your medicine cabinet, Ibuprofen, Advil, and Motrin. They all work on the same exact pathway. And so I think of them almost as one drug because you're not going to give most patients more than one or two of those. And so I don't think we have as many drugs as we'd like to have in the metastatic CRPC setting and especially with many of those drugs that have been approved in the past moving up into the castration sensitive setting. So I feel like with the median survival of about two to three years in the CRPC setting, that it's on us to make sure that all the patients or most of our patients get most of the FDA approved drugs. And the way I think about it is I think about Sipuleucel-T as my first line in as castration resistant prostate cancer. And as far as Radium goes, we have to remember Pluvicto is FDA approved in the post chemotherapy setting. So I would actually consider Radium-223 before chemotherapy.

Alicia Morgans: These are great tips and great reminders of things that have been tried and true. And I do think, again, in my clinic and what I hear from you is it's the same in yours. We try to get as many lines of therapy into patients as possible to give them time and to give them quality of time and really do the best we can. So thank you so much for sharing your expertise today.

Sumit Subudhi: Thank you.