Prostate Cancer Podcast

New Therapies for Metastatic Castrate-Resistant Prostate Cancer: Radioligand Therapy and PSMA Biomarker-Based Imaging

Sandhya Srinivas, MD; Oliver Sartor, MD


September 21, 2023

This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.

Sandy Srinivas, MD: Hello. I'm Sandy Srinivas, host of the Medscape InDiscussion podcast series on prostate cancer. Today we'll discuss radioligand therapy (RLT) prostate-specific membrane antigen (PSMA)-617–lutetium-177 and PSMA biomarker-based imaging. This is a really important topic. This is a new therapeutic that's available to us for our patients with metastatic castrate-resistant prostate cancer (mCRPC).

It's my pleasure to introduce my guest, Dr Oliver Sartor. He's an internationally recognized expert in prostate cancer. He's the director of the Radiopharmaceutical Clinical Trials at Mayo Clinic in Rochester, Minnesota. Dr Sartor has led many pivotal phase 3 trials that have led to the FDA approval for patients with prostate cancer, including cabazitaxel, radium 223, and the newest kid on the block — PSMA-617–lutetium-177. It is a pleasure to have him as our guest. Welcome to the Medscape InDiscussion podcast, Dr Sartor. Before I start, I really wanted to learn a little bit about your journey into the world of urologic oncology. You have trained and mentored so many young physicians. What would you tell the people who are joining urologic oncology? Tell us about your journey into it.

Oliver Sartor, MD: Great question, Sandy. I think the thing that I was very lucky to have had was, first of all, some really good mentors early in my career. I actually started in endocrinology, but understanding the endocrinology and how it might apply to prostate cancer and the hormonal therapies we utilize was really interesting to me. When my career got underway, I think being involved with clinical trials and seeing how clinical trials could make a difference in the lives of patients by offering new therapies that change the landscape — it's addicting. And then, you want to do more. If you're young, get involved with something that you're passionate about. Get involved with something that you think is important and work really hard so our patients can benefit.

Srinivas: Wow, great message. I'm sure many of our listeners are going to benefit from that. Let's start off by talking a little bit about definitions. RLT is really a new terminology for our field. Give us your definition. How do you tell patients and community physicians about what RLT is?

Sartor: First of all, let's start with RLT. We can also use other terms, I think that they can also be appropriate. One of the terms that I like is molecularly targeted radiation (MTR) and then also the term theranostics. Basically, what we use is the idea of finding the cancer with an image, understanding the distribution and uptake of a particular biomarker, and then targeting that particular biomarker with the therapeutic. Within the PSMA-lutetium space, we actually identify the patients with a PSMA positron emission tomography (PET) scan and typically use either gallium-68 (68Ga) or F-18 (18F) as the PET imaging agent. We look, understand the distribution of the disease, make sure there's plenty of uptake, and then if the patient is eligible, we can follow it with the PSMA-lutetium. When I explain it to patients, I use simple terms: "We're going to see it, and we're going to treat it." That really synopsizes what theranostics and RLT are about. We see the disease, and then we treat what we see. It's intuitively obvious to patients. They get it quickly.

Srinivas: I love that simplistic explanation that you have. In this era of precision medicine, it really feels like we have a biomarker — PSMA being that biomarker. You briefly touched upon it. It's not just one imaging study that we have; we have a couple of FDA-approved imaging tools. Are they all the same? Do you have a preference for one vs the other?

Sartor: It's interesting. Within the VISION trial, the preferred imaging agent was one called PSMA-11 gallium 68 (68Ga). I think as we've gained more experience with one called DCFPyL 18F, that it turns out that selection using that particular isotope is just as good. Those are the two that we have experience with, and I think either one is fine.

Srinivas: I recall even as part of National Comprehensive Cancer Network (NCCN), this question came up because it's not just going to be one, we anticipate many more in this field. Broadly classifying them all as PSMA-based PET imaging seems very reasonable. Coming back to your baby child, the VISION trial, that was really a landmark trial presented in The New England Journal of Medicine and really changed for the first time ever for us to have a therapeutic agent. Talk a little about the VISION study that led to the approval.

Sartor: We ended up looking at this novel agent and thinking through where we might be able to get FDA approval. That was the goal of the study: to really get FDA approval. We had some preliminary data from both Germany and Australia to suggest that this could be an active agent. What we had to do was to devise eligibility criteria, and we decided to go late stage for this first study. By late stage, I mean individuals with mCRPC who've progressed despite a prior taxane and a novel hormone. You could even have two taxanes and two novel hormones. It wasn't really a third-line trial; it was often a fourth- or fifth- or even sixth-line trial, and we had to decide how to manage the control arm. We decided to let physicians do what they wanted to do with standard of care. We did exclude chemotherapy because we did not have safety data for the combination of PSMA-lutetium and the chemotherapies. The bottom line is we randomized the patients 2:1. We looked at two primary endpoints: radiographic progression-free survival (rPFS) as well as overall survival (OS). We hit both of them, had good safety signals, and got the FDA approval. Now, we're going to be moving it up. The bottom line is VISION is a nice positive trial for both rPFS and OS.

Srinivas: I would love to hear a little bit about your thoughts. You were also a key in the [ALSYMPCA trial] on radium-223, which was also a therapy that's intravenous, targeting more bone disease. One thing that I find really fascinating about lutetium-177 is that the benefit is not limited just to bone. We have soft tissue. Even patients with metastatic liver disease, which has been a challenge to take care of patients with prostate cancer, have had a benefit. Physicians and patients love to see that their prostate-specific antigen (PSA) dropped down. What was the approximate patients where we did see PSA dropdown? We talk about PSA 50, and perhaps even there were some patients who had a PSA 90 in this study.

Sartor: We did, and there are a couple ways that you can look at activity. I mentioned the OS and the rPFS. PSA decline rates confirmed by 50% or more. It was right about 46%, so almost 50% of patients. What was interesting, Sandy, is that we also had objective disease radiographic response in about 50% of patients. It turned out about 9% of the patients actually had complete remission, so their measurable disease all disappeared, and another 41% had partial responses by RECIST criteria. And by the way, there was health-related quality of life. We looked at OS, rPFS, objective responses, PSA declines, and quality of life. The trial was positive on every single endpoint.

Srinivas: That was incredible. As we talk about any therapy, we can't talk about the efficacy without talking about the toxicity. What do you tell patients and also physicians who are not familiar with this drug? What do you say are the three topmost side effects that one can expect from this drug?

Sartor: It's a little bit scary talking to patients because we're injecting a radioactive material that is going to circulate throughout their body and then somehow land on the cancer. It is a little bit of a scary concept. One of the things that's unique about this therapy, because PSMA PET is uptaking in the salivary glands, and the PSMA-lutetium will go to the salivary glands and give some radiation. Xerostomia, or dry mouth, is one of the things you have to watch out for. Another thing you have to watch out for is cytopenias. We didn't end up with a lot of cytopenias, but the fact is some degree of anemia and thrombocytopenia were present. Neutropenia was very rare, but we have to watch for it. It's not as bad as chemotherapy but nevertheless can be present. There can be some GI effects. The drug is excreted partially in the GI tract, predominantly through the kidney, but people can have some GI upset as well. We're telling people to watch out for the dry mouth, watch out for the blood counts, watch out for the GI side effects, and of course, communicate if there are any issues.

Srinivas: Unlike chemotherapy, the sequence, the timing of this drug is given every 6 weeks, which is a little bit easier on patients compared to, let's say, docetaxel or cabazitaxel, which is a common chemotherapy. How many treatments do you offer patients?

Sartor: What we started in the VISION trial and what we've been doing is we try to target at least four. If the patient is benefiting, then we have the option of giving two more. Over 50% of the patients in the VISION trial actually received six doses — one dose every 6 weeks. That's as far as we can go right now. It turns out that there's an interest in going further, particularly for the patients who relapse and then have a PSA rise. Could they be eligible for more of the PSMA-lutetium? The answer is we're not really sure. There have been some small studies done in Europe and Australia on repeated lutetium dosing, but right now, we don't really have the strict guidelines that allow us to do that, and they're not reimbursed in the US right now.

Srinivas: We spoke a little bit about the PSMA imaging. What fraction of patients end up having a positive PSMA scan? Is there any reader variability in terms of what is defined as being PSMA positive?

Sartor: Great question. I didn't want to drill down too far on the screening eligibility, but it's a really important question. Number one, the patient had to have PSMA PET-positive metastatic disease to determine whether or not there was enough PSMA PET uptake — we compared it to liver. Standardized uptake values (SUVs) can kind of be up and down. Other parameters could be up and down, but every patient served as their own control because we had liver uptake. The PSMA PET uptake in the metastatic disease had to be greater than liver. Now, interestingly, 87% of the patients whom we screened with PSMA PET were actually eligible. I was surprised it was that high. There was an additional component to the eligibility. If you had PSMA PET-positive metastatic disease, but you had a visceral lesion greater than 1 cm, that was PSMA PET negative; a lytic bone lesion 1 cm or greater that was PSMA PET negative; or a lymph node of 2.5 cm that was PSMA PET negative, then you were excluded from the trial. The totality of evidence indicated, as I stated, that 87% of the patients actually qualified. That was higher than I was expecting, and I think it's good news for patients. Most of the patients are going to be eligible.

Srinivas: Absolutely. That sounds like a wonderful option for our patients. You mentioned briefly that in the VISION study, patients were so heavily pretreated. We have a variety of options. If you look at NCCN guidelines for providers, there is docetaxel, there's cabazitaxel, and there are hormonal drugs. Now that PSMA-617–lutetium-177 is approved, how do we pick between giving somebody cabazitaxel vs lutetium 177? I know that there was a randomized trial between cabazitaxel and lutetium 177. Will you talk us through that trial and whether you use something like that to select who gets chemotherapy vs PSMA-617?

Sartor: Great question. The trial is called the TheraP Trial. It was run out of Australia, led by investigators at Peter MacCallum Cancer Centre in Melbourne, and they did a direct comparison: cabazitaxel vs the PSMA-lutetium. This was not a randomized phase 3, it was randomized phase 2, so it's a little bit underpowered, but the conclusions were pretty clear.

Conclusion number one: PSA response rate is higher, and that was their primary endpoint for the PSMA-lutetium. Point number two is the OS was actually quite similar. Remember, these are PSMA PET-selected patients. That underscores to me that cabazitaxel is actually a good option for these patients, and I've known about cabazitaxel a long time, going all the way back to the TROPIC trial. Patients do benefit from cabazitaxel, and we should remember it as an important option. Number three: If you looked at the tolerability of the therapy, the tolerance of the therapy, the quality of life favored the lutetium arm. Chemotherapy was a little more detrimental to quality of life, but the overall OS outcomes were similar, but PSA outcomes were better for the lutetium.

Srinivas: There were a lot of production issues with the availability of lutetium 177. During that time, I definitely used this exact strategy and all of the data that you've just outlined to highlight to our patients that cabazitaxel was a great option at that time. That, too, is systemic and gives patients an option in this highly refractory state. I appreciate you talking about cabazitaxel. In the VISION trial, it was incredible that there was only a 13% screen fail. In the therapy trial, they did use a fluorodeoxyglucose (FDG) PET scan. Are there other tools that you use in your practice to have a tighter selection of patients? Is that something that will be used in the US with FDG PET as well?

Sartor: Therapy actually used a double PET — they used a PSMA PET and an FDG PET. First of all, they had a higher cutoff than just greater than liver on the metastatic disease. They wanted to see more PET uptake and measured the standard uptake values (SUVs) that were 10 or higher in general. They also did the FDG PET looking for discordant lesions. We used the CAT scan to look for discordant lesions. They used the FDG PET, so if they ended up with patients who were FDG PET positive, PSMA PET negative, that was an excluded patient. They excluded almost one third of the patients, slightly less than a third, so they had much tighter criteria than we used in VISION. How do I do it here in the US? Well, the first thing is I do look and pay attention to how much uptake there is. We do know to some degree that those who have the most uptake are the best responders. We also have to be careful because in the VISION trial, even those with less-than-optimal PSMA PET uptake outperformed the control group. We are working on a manuscript detailing that right now. PSMA PET remains a good therapy option if you fulfill the VISION criteria. If you have even more hotness, more SUV on the PSMA PET, then you're likely to respond in a little more robust way.

Srinivas: It's great to get these insights for drugs that are relatively new from somebody like you who's had such tremendous experience. I know that the VISION trial had up to six cycles. If somebody were to not have a PSA drop after cycle one or cycle two, what's your advice for providers in terms of continuing beyond two cycles?

Sartor: That is a really good question, Sandy. At ASCO last year, we presented data on PSA decline in OS, and — not a surprise — those individuals who dropped their PSA the most by the 12-week point were the ones who did the best, and those people who had a rising PSA did the worst. However, I think there's a little more to consider other than just PSA, and I think we need to talk to the patient and understand how they're feeling and understand whether or not they may have had pain that was relieved.

There are clinical parameters that matter as well. If the patient is progressing clinically with a PSA rise after two cycles — and by after, I mean at a 12-week point — I am thinking about other therapy. Then you can have these discordant patients. Maybe the PSA is down, but the pain is worse, in which case maybe you consider something like external beam, if that would be an option. Or you could have the PSA is worse, and the patient is better. Under those circumstances, the clinical parameters drive me to continue therapy if I believe the improvement is attributable to the PSMA-lutetium.

Srinivas: Maybe we can briefly touch upon where you think PSMA-617-lutetium is going to eventually end up in prostate cancer. Right now, it's for heavily pretreated patients. What can we expect in the next year?

Sartor: Well, we already have a top-line report from the PSMAfore trial on mCRPC patients who are PSMA PET selected but no prior chemotherapy. These would be people who have advanced to more of the novel hormones — abiraterone, apalutamide, enzalutamide — but they've never seen chemotherapy. We already know it's a positive trial, and I'll simply say that we're hopefully going to have more results later this year.

Srinivas: Oliver, I always learn so much from you, and we appreciate what you have spoken about today. I'm going to give a few key takeaways. You have described the PSMA imaging as being a biomarker, the VISION study for patients with heavily refracted disease who have had responses both in rPFS as well as OS, and the excitement of moving this drug to earlier lines of therapy.

Thank you so much for tuning in. Please take a moment to download the Medscape app to listen and subscribe to the podcast series on prostate cancer. This is Sandy Srinivas for Medscape's InDiscussion podcast.


Lutetium-177-PSMA-617 for Metastatic Castration-resistant Prostate Cancer

Prostate Cancer Theranostics: PSMA Targeted Therapy

Piflufolastat F-18 (18F-DCFPyL) for PSMA PET Imaging in Prostate Cancer

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) in Prostate Cancer

German Multicenter Study Investigating 177Lu-PSMA-617 Radioligand Therapy in Advanced Prostate Cancer Patients

Results of a Prospective Phase 2 Pilot Trial of 177Lu-PSMA-617 Therapy for Metastatic Castration-resistant Prostate Cancer Including Imaging Predictors of Treatment Response and Patterns of Progression

Effect of Radium-223 Dichloride on Symptomatic Skeletal Events in Patients With Castration-resistant Prostate Cancer and Bone Metastases: Results From a Phase 3, Double-blind, Randomised Trial

Long-term Follow-up and Outcomes of Retreatment in an Expanded 50-patient Single-center Phase II Prospective Trial of 177Lu-PSMA-617 Theranostics in Metastatic Castration-resistant Prostate Cancer

[177Lu]Lu-PSMA-617 Versus Cabazitaxel in Patients With Metastatic Castration-resistant Prostate Cancer (TheraP): A Randomised, Open-label, Phase 2 Trial

Prednisone Plus Cabazitaxel or Mitoxantrone for Metastatic Castration-resistant Prostate Cancer Progressing After Docetaxel Treatment: A Randomised Open-label Trial

[177Lu]Lu-PSMA-617 in PSMA-positive Metastatic Castration-resistant Prostate Cancer: Prior and Concomitant Treatment Subgroup Analyses of the VISION Trial

PSMAfore: A Phase 3 Study to Compare 177Lu-PSMA-617 Treatment With a Change in Androgen Receptor Pathway Inhibitor in Taxane-naïve Patients With Metastatic Castration-resistant Prostate Cancer

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