Podcast with Rana McKay- Real World Data About Survival With Provenge Along with A Peek Into the Future of Treatment

Dr. Rana McKay: When Provenge was FDA approved, we did not have a lot of the oral hormonal therapies to treat prostate cancer. But now, in the real world, we have a lot more drugs for people who have prostate cancer, abiraterone, enzalutamide, daraludamide, apalutamide, there's a lot of oral agents that are used to treat this disease.

This is why we did the study. In the current treatment landscape of advanced prostate cancer, how does Provenge fair out? You know, the trial was done over a decade ago or about a decade ago. do we still see a benefit to this therapy?

If so, what would that benefit be and how does it play into the landscape for advanced CRPC. That was really, the genesis for this work. It was sort of to better understand in the current treatment era, how does this therapy fair out?

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Joel T Nowak: [00:00:00] Welcome to this podcast, sponsored by cancer ABCs. I am Joel Nowak, founder and CEO of cancer ABCs. For this podcast, we are fortunate to have Dr. Rana McKay, who is a medical oncologist with Moore's Cancer Center at the University of California, San Diego, where she is an associate professor of medicine. We've invited Dr. McKay to join us so that we can discuss her recent publication about her real-world analysis, examining the possible survival advantages that men with metastatic castrate resistant prostate cancer may gain by using the immunotherapy called Provenge or Sipuleucell-T in their treatment protocol.

Welcome and thank you, Dr. McKay for joining us. Before we dig into your most informative paper, I would ask if you wouldn't mind telling us a little bit about Provenge and what makes it so special and how does it work?

Dr. Rana McKay: [00:01:04] Wonderful. Thank you so much for having me, I really appreciate it. So sipuleucel-T is actually one of the first vaccine therapies that was actually approved for any solid tumor.

It is an autologous cellular immunotherapy designed to stimulate the patient's own immune system against cancer and sipuleucel-T is manufactured in several steps. First, the patient's blood is run through a machine in a process known as leukapheresis. During this process, the patient's immune cells are collected specifically,

their antigen presenting cells are collected. The immune cells are then exposed to a protein intended to stimulate those cells to fight against the cancer. And then these now activated cells are then returned into the patient to treat the prostate cancer. It Is a therapy that is administered intravenously, it's usually given in three doses that are two weeks apart.

In a large phase three trial, Provenge demonstrated improved survival in patients with advanced metastatic hormone resistant, prostate cancer.

So, sipuleucel-T is a type of immunotherapy that is designed to stimulate a patient's own immune system against the cancer. The way that it is manufactured is the patient's blood is run through a machine and the immune cells are actually collected from the patient.

And then the immune cells are exposed to a specific protein that's intended to stimulate those immune cells, , and have them be better directed against the cancer. These activated immune cells are returned into the patient to actually treat the cancer. Patients will have this procedure done or receive this therapy for three doses that are about two weeks apart.

Then essentially the treatment is complete.

In a large phase three trial presented in 2010 sipuleucel-T demonstrated improved overall survival and the results of that trial actually led to its FDA approval for men who have minimally symptomatic prostate cancer with no visceral metastases who have developed resistance to hormonal therapy.

Joel T Nowak: [00:03:29] So, if I understand correctly, what we're talking about is taking out the immune cells from a person's blood, treating them so that it becomes sensitized to the prostate cancer and then giving it back. Would that be a relatively accurate summation?

Dr. Rana McKay: [00:03:47] That’s Correct,

Joel T Nowak: [00:03:49] I know there's some issues on pain for the FDA label.

If I'm in severe pain, according to the label, can I qualify to take Provenge.

Dr. Rana McKay: [00:04:00] So the label is for people who are minimally symptomatic from their disease. We know that Provenge does not actually result in a decline in PSA or improvement of cancer on scans, it does make people live longer. So, if somebody is having symptoms and we think that those symptoms are being driven by their cancer. Provenge is probably not the ideal next therapy to put them on. It's not going to result in any immediate improvement of that pain.

Joel T Nowak: [00:04:33] That leads us to an interesting question. If a man does have significant pain and he takes another treatment, whatever it is and , the pain goes away, would he at that point, qualify?

Dr. Rana McKay: [00:04:47] Yes,

Dr. Rana McKay: [00:04:47] the patient has received some other therapy to control their cancer, they're not really symptomatic , and we deemed that whatever therapy they were on is working that would be an ideal candidate.

Joel T Nowak: [00:04:57] That's terrific because I don't think a lot of men and some doctors realize that you can use it later on as long as you resolve some of the pain issues. I think that's terrific news. You also mentioned castrate resistant, if you wouldn't mind, would you just describe what that actually means?

Dr. Rana McKay: [00:05:15] I know this actually is a terrible name. The other term that we use is hormone resistant. What that means is despite a patient's testosterone being very low, whether that's because of a medical therapy or a surgical therapy, their testosterone is very low.

The cancer is still getting worse. Either the PSA is climbing and the testosterone is low, or the scans are getting worse and the testosterone is low, when cancer gets to that state is termed castration resistance. So it's, things are getting worse, the testosterone is low.

Joel T Nowak: [00:05:54] So besides being castrate resistant or hormone resistant they also need to be metastatic, meaning that the cancer has left the prostate gland and has appeared somewhere else in their body.

Dr. Rana McKay: [00:06:06] That is correct, sipuleucel-T is indicated for metastatic castration resistant prostate cancer.

Joel T Nowak: [00:06:13] You touched on an issue that has created some misunderstanding and confusion among men and I suspect also among some doctors that Provenge will not affect PSA, or rarely does. So a lot of people say, well, if it's not going to affect my PSA, how do I know it's working? I'm just wasting my time and I'm wasting money. What would you say to that?

Dr. Rana McKay: [00:06:40] Well, I would say that there's many therapies that we give for prostate cancer that don't necessarily impact PSA, but make people live longer. Ultimately at the end of the day, PSA is just a biomarker. The level of PSA is not necessarily going to hurt anybody. It's just a reflection of the current disease state, and there are some patients that have a very low PSA, but have a high disease burden in their system.

PSA is just a barometer. When people have hormone resistant disease, PSA may not be the best marker to assess whether something is or isn't working. Stopping a therapy just for a PSA rise without any clinical evidence of things getting worse. You end up cutting short the lifetime of any given therapy and we know that we don't have a million therapies to treat this disease. So, we need to be really prudent with when we decide to stop and start at therapy.

There are other therapies that are not hormonal therapies that don't really impact PSA. We know that they actually improve patient's survival, radium 223 is an example of that. It's a life-prolonging therapy for men with prostate cancer, but it doesn't have an effect on PSA. Drugs like abiraterone that actually target the androgen access do have an effect on PSA because PSA is a readout of the androgen access. But we know that in people who have hormone resistant disease, the androgen access, isn't the only access that's at play. There is other things that drive the disease to grow. Just because there's no PSA response doesn't mean that somebody can still derive benefit from a given therapy.

I would argue that survival was probably more important than therapies that can make a PSA go down or cause a PSA to go up. I think we just have to be really careful about that.

Joel T Nowak: [00:08:43] I think that's true. The problem is that once a man becomes metastatic, we get drilled that PSA is your best friend, because it tells you what's going on.

It's a little nerve wracking to see your PSA going, especially why you're doing a treatment and to continue it and not move on to something that might affect a PSA. But, as you said, what's really important is survival and the data shows that men will live longer or have a better chance or they lower their risk of dying if they use Provenge. I guess that's kind of where we're at with that, correct?

Dr. Rana McKay: [00:09:20] That's correct, yea.

Joel T Nowak: [00:09:22] I think this really leads us right into your study, which I think is really interesting. It's termed real world data, that's actually right in your title. What does that mean and why is that important?

Dr. Rana McKay: [00:09:36] Well, the reason that's important is when Provenge was FDA approved, we did not have a lot of the oral hormonal therapies to treat prostate cancer.

But now in the real world, we have a lot more drugs for people who have prostate cancer, abiraterone, enzalutamide, daraludamide, apalutamide, there's a lot of oral agents that are used to treat this disease.

Joel T Nowak: [00:10:32] How does it pan out?

Dr. Rana McKay: [00:10:34] So, in this retrospective analysis we utilized a large claims database, a Medicare claims database, to really delve into the data. We corrected for lots of factors that could account for a patient's disease status, we controlled for opioid use pain medication use.

We controlled for sites of metastases and other prognostic variables that could predict why somebody would do better or worse, especially given the label indication that sipuleucel-T is utilized in people who have minimally symptomatic disease. What we showed was that people who received, compared to those patients who did not receive, sipuleucel-T actually had a 41% reduction in the risk of death compared to those who didn't. So, I think that that is really important information to have. We found that any first-line use in any time use, actually resulted in improved outcomes.

If you used to be the sipuleucel-T right, when somebody develops metastatic hormone resistant disease or a patient received it at any point in time during their state of being hormone resistant if they got Provenge, they seem to do better than people who never saw Provenge. I think that speaks to the efficacy in part of this regimen.

I think probably the differing mechanism of action of this regimen. This is a short therapy they’re done with it and they go onto the next thing. I think that this data were quite impressive and, and even in a analysis where we try to adjust for a lot of variables that could confound what we saw.

So, we adjusted for a lot of confounding variables.

Joel T Nowak: [00:12:18] I think this is really amazingly important information. As you pointed out, the original trials were done over 10 years ago and landscape has changed significantly. It's really good to know that this treatment still has a place despite all of the changes that we have.

I think this is so timely and so important. I think you've made a major contribution. I was curious as you looked through your data, did you look at, any survival differences depending upon when man had Provenge? I know you referenced that it was good in various stages, but is there actually a difference or a more optimum time that someone should consider taking it?

Dr. Rana McKay: [00:13:02] So we did not specifically look at when is the best time to receive Provenge, but we looked at all the different times that any patient could receive Provenge. And at any point in time, in the first line use people who got Provenge seemed to do better than people who didn't. And that any time you use people who got Provenge seemed to do better than those who did it.

If people got it beyond second line compared to other people beyond second line who didn't get it, they do better. We didn't compare which line was the best. I think that's harder to do because people's disease evolve as they are farther along in their disease course, their cancer may be more resistant.

Any line of therapy seems to be associated with it improves survival compared to those who didn't get it.

Joel T Nowak: [00:13:47] some doctors, don’t believe that Provenge adds value to a treatment protocol.

As a result, it's often underutilized. I'm wondering from your perspective, in your experience, have you seen that and what would you attribute that to?

Dr. Rana McKay: [00:14:01] I do think that it is an underutilized therapy. It has a very niche FDA indication in that people have to be asymptomatic or minimally symptomatic and not have visceral metastasis.

Actually, a lot of our patients fit that category. The majority of people who have prostate cancer that's advanced, don't necessarily have spots in their lungs or spots in their liver. They have bone predominant disease or bone and lymph node predominant disease. Depending on where they're at in their disease course, especially those people who may be just early in their course of becoming castration resistant, maybe they'd been on Lupron for a long time.

There's nothing happening on their scans, but their PSA is rising and they've got metastases. That would be a perfect individual for sipuleucel-T and it may be somebody where you may not even be thinking about switching them and putting them on a therapy because their scans aren't changing, they're just having a slow rising PSA, and you may be wanting to drag your feet about subjecting them to the next systemic therapy, whether it be chemo or whether it be hormonal therapy with prednisone.

I do think that there is a sweet spot for utilizing the therapy as it is a short therapy. it is a little bit more cumbersome to give than just prescribing an oral pill. I think it takes time to educate patients and family members about the therapy. It's a process.

You have to kind of coordinate things with the blood bank. There are more steps involved, but those steps shouldn't necessarily hinder us utilizing it in the clinic, if we think that there's value, especially given the mechanism of action. It's a very different kind of medication than just chemo and hormone therapy.

Joel T Nowak: [00:15:42] You've kind of touched on it, how is it different than say hormone therapies or chemotherapy?

Dr. Rana McKay: [00:15:47] Its actually an Immune therapy, it works to stimulate the immune system to fight the cancer. It works by removing the patient's immune cells, stimulating them and then reinfusing them back in to actually fight the cancer. So it's a totally different type of therapy than hormone therapy.

Quite honestly, other than just it being a little bit of a cumbersome therapy to give it has pretty minimal side effects. It's generally a very well tolerated medication. The major side effects with its use can be fatigue, maybe of the day the cells get administered there could be sort of a reaction to the cells, like a rash or, maybe some shortness of breath or infusion reaction, but it’s not very common. So it tends to be a fairly well tolerated procedure. The Leukapheresis process takes about generally three to four hours.

Yes, it's annoying to be hooked up to a machine for three to four hours doing the immune cell removal. It's not all your immune cells that get taken out. It's essentially, you can think of it almost like a pint of blood, like doing a blood donation.

It's not all your immune cells, but just a small amount of your immune cells that get removed for this procedure.

Joel T Nowak: [00:17:00] You're not going to compromise someone's immune system and make them more susceptible to something else?

Dr. Rana McKay: [00:17:06] No, generally not with this therapy, it doesn't drop your immune counts. Generally, it doesn't work in that kind of way. It doesn't take away your lymphocytes. It works to remove the antigen presenting cells, not necessarily your T cells that are doing the heavy lifting with regards to fighting infection.

Joel T Nowak: [00:17:25] And again, when it gets reinfused, you're actually reinfusing that person's own cells.

Dr. Rana McKay: [00:17:33] Correct.

Joel T Nowak: [00:17:34] So we're just, supercharging my cells and making them recognize the prostate cancer as being a cancer and hopefully go after them. That’s kind of amazing it's so simple and yet it's such an amazing process.

Dr. Rana McKay: [00:17:48] Yeah.

Joel T Nowak: [00:17:50] So, are there other immune therapies that we use in prostate cancer?

And if, there are, how do they differ from Provenge?

Dr. Rana McKay: [00:18:00] Very good question. So , there are currently, currently there is one other immunotherapy that's FDA approved for prostate cancer. That immunotherapy is called pembrolizumab and it's FDA approved for prostate cancers that have a very distinct molecular alteration called microsatellite instability, or MSI high tumors.

They are genetically altered tumors that have alterations in the way that those cancers repair their DNA and those tumors are very sensitive to pembrolizumab. Pembrolizumab is indicated for any solid tumor that has such alterations, prostate cancer being one of them.

Pembrolizumab is an immune checkpoint inhibitor that blocks PD -1, the monoclonal antibody to PD -1, and it's FDA approved for multiple malignancies.

Joel T Nowak: [00:18:57] MSI high is actually a genomic mutation.

Is that right?

Dr. Rana McKay: [00:19:02] That's correct. It's a subset of prostate cancers. It's probably accounts for 1% to 2% of all prostate cancers. For people who have advanced prostate cancer, they should all undergo molecular testing to see what kind of genetic mutations their prostate cancer has.

One of the things that the genetic test looks for is this MSI status.

Joel T Nowak: [00:19:25] So one should actually talk to one's oncologist if they have not had genetic testing to arrange for that [a genetic test].

Dr. Rana McKay: [00:19:33] That's correct. I'll add that this is not related to immunotherapy, but just this past year the FDA approved two drugs; one called Olaparib, one called Rucaparib they're both PARP inhibitors and they were FDA approved for cancers that have defects in the way they repair their DNA. The only way to find out if the cancer has defects in the way it repairs its DNA is to do a genetic test of the tumor.

I think in aggregate probably 20 to 30% of all advanced prostate cancers fits that criteria. But again, the only way to know if somebody fits that category and could be a candidate for a PARP inhibitor is to test them.

Joel T Nowak: [00:20:12] I'm glad you brought that up because we have, on our webpage a chart, describing the two drugs and when they might be active or not active. So, you can even print that and bring it to your doctor if you want to find out if perhaps a PARP inhibitor might make sense for you. Updating the data about Provenge is so important.

I think your point that things have changed is important. I’m really glad that you undertook this study because it should give confidence to patients, to caregivers and to their doctors that Provenge should definitely be considered in the course of one's treatment protocol.

I want to thank you for that because that's a really important piece of work. It doesn't sound like it's really important, but it really has such ramifications and such a ripple effect. So, thank you very much.

Dr. Rana McKay: [00:21:01]

Yeah, no problem. My pleasure.

Joel Nowak: Before we wrap up, I was just curious if there's anything that you wanted to add or share about either Provenge and your study or anything else that I have missed, or I haven't asked you, or you think is important as a man goes off and makes a decision whether or not to do the treatment.

Dr. Rana McKay: [00:26:27] Very good question. I think you were asking me about what are other immunotherapies for prostate cancer, and we chatted a little bit about pembrolizumab, and then got a little bit distracted and talks about DNA repair and Olaparib and PARP inhibitors because that's just been a landmark breakthrough in the disease, but there are other immunotherapies that are currently being tested for men with advanced prostate cancer, specifically T-cell engaging therapies.

Several that are in testing right now include, PSMA targeted bi-specific antibodies that basically work to bring the immune system closer to the cancer cells and actually put the T-cells within the vicinity of the cancer cells so that they can actually fight off the cancer.

There's been a lot of excitement around PSMA targeted Car -Ts, which are re-engineered T-cells designed to actually attack PSMA expressing cells. Studies are currently underway testing T-cell engaging immunotherapies to treat prostate cancer.

I think it's still early on, but I think there's a lot of potential immunotherapies on the horizon for prostate cancer. And I think we just need to learn more about their efficacy.

Joel T Nowak: [00:27:41] It's really interesting information, but I just to make it clear because a lot of men have heard about PSMA, but usually it's in reference to scans, which are breaking news.

We just got an approval for a PSMA scan and also there are theranostics using PSMA as a way to target therapy. And so, what you're actually talking about is even a third use of PSMA, and it's not a scan and it's not what we think of as theranostics.

Dr. Rana McKay: [00:28:14] Correct, it's not lutetium, it's not getting a scan. It's actually theranostics, basically linking a little bit of radiation to something that targets PSMA. And then the radiation gets delivered to PSMA specific cells. Here we're talking about how can we, one, get the immune system to attack PSMA cells as opposed to giving each PSMA cell a little bit of radiation. So, same target of PSMA, but a different method of attack.

Joel T Nowak: [00:28:48] I think I take one message out of that, between all that's going on with PSMA and the development of immune therapy for prostate cancer, we're hopeful. That's the word hopeful. I think it's really important. As you pointed out 10 years ago, when Provenge was first approved, the option was basically chemotherapy, but in the course of the 10 years, we have a slew of new drugs.

We are developing many more and most of these drugs will extend survival. They can improve the quality of life. So I find your message to be really hopeful. I thank you for that.

Dr. Rana McKay: [00:29:25] Of course. Yeah. I think it is hopeful. I think there's a lot of things that are on the horizon and a lot of new discoveries that are currently being tackled.

I want it say it's largely because of the contributions of patients who participate in clinical trials, who, contribute to us being able to learn more about this disease so that we can help patients live longer and live better.

That's all of our goal, but really, I think a lot of this work couldn't be done without patients contributing to the research.

Joel T Nowak: [00:29:55] I don't disagree with you, It's got to be a team effort and we all need to work together to get rid of this disease and to get rid of cancer.

Ultimately isn't that our goal to get rid of cancer?

Dr. Rana McKay: [00:30:06] Yes, that’s correct.

Joel T Nowak: [00:30:09] I really want to thank you for the time and most importantly, I really do wish to thank you for the work that you have done in helping men with prostate cancer.

And with that, I just want to say that this has been Joel Nowak along with Dr. Rana McKay. if you have any questions about Provenge or anything you've heard on this podcast today, you should email them to Joel, that's

joel@cancerabcs.org. We will try to get them answered. Perhaps, if Dr. McKay is willing, we can send some of them onto her. We're always going to try to answer any of your questions. With that, I want to say that everyone should take care, be safe. Again, thank you Dr. McKay for your time, your effort, your work, and for this podcast.

Dr. Rana McKay: [00:31:06] Thank you so much Joel.

So happy holidays, everyone, and be safe.

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