Optimizing Lutetium PSMA Treatment Sequencing in Metastatic Prostate Cancer

Clinical Summary:

• Atish Choudhury, MD, PhD, examines the evolving role of lutetium PSMA in metastatic prostate cancer, including optimal treatment timing, patient selection, and sequencing relative to taxane chemotherapy and other treatment-intensification strategies.
• Earlier lutetium PSMA treatment has demonstrated progression-free survival benefits, although its optimal sequencing relative to chemotherapy remains uncertain. PSMA expression, disease burden, prior therapies, and treatment-related toxicities are important considerations when selecting patients for radioligand therapy.
• As lutetium PSMA moves into earlier treatment settings, individualized sequencing may help maximize clinical benefit, preserve subsequent treatment options, and balance efficacy with short- and long-term toxicity.

Atish Choudhury, MD, PhD, Dana-Farber Cancer Institute, Boston, Massachusetts, discusses the evolving role of lutetium PSMA radioligand therapy in metastatic prostate cancer and the clinical considerations surrounding earlier versus later treatment following his presentation at Great Debates in Solid Tumors in New York, New York.

Dr Choudhury reviews evidence comparing lutetium PSMA with taxane chemotherapy across castration-resistant and hormone-sensitive disease settings, highlighting how PSMA expression, disease burden, and patient characteristics influence treatment selection. He also discusses the importance of balancing efficacy, potential long-term toxicity, and access to subsequent therapies when determining the optimal treatment sequence.

Transcript: 

My name is Atish Choudhury, I'm a genitourinary medical oncologist at Dana-Farber Cancer Institute. Here at Great Debates, I gave a talk in a session debating earlier versus later use of lutetium PSMA.

When we think about the disease spaces where lutetium PSMA are approved, the initial approval was post-taxane in mCRPC. Then we got an approval that allowed for patients who are not candidates for taxane. And most recently, we got an approval in the hormone-sensitive space. In all three of these situations, there are patients who are probably most appropriate for lutetium PSMA, but then there are also patients who might be more appropriate for other treatments.

In that post-taxane mCRPC space, what we're really thinking about is lutetium versus cabazitaxel. The TheraP trial showed that there were more responses with lutetium compared to cabazitaxel, but the overall survival of the patients who received those two drugs in either order was really the same. It did seem that the patients who had the lowest SUV for PSMA expression might have actually had more benefit from cabazitaxel compared to lutetium PSMA.

So that's certainly an appropriate setting for patients who have PSMA-expressing disease, but patients who have lesions that are not PSMA-expressing would not be candidates, even in that disease setting.

When we think a bit earlier about chemo-naive mCRPC and we're deciding between lutetium PSMA and docetaxel, the only trial that compared them directly was a Canadian trial where patients were randomized to get lutetium followed by docetaxel versus the other direction. And interestingly, the patients who were randomized to get docetaxel first had prolonged overall survival, and that's primarily explained by the lack of crossover in the patients who got lutetium first– many of them didn't wind up actually getting docetaxel second.

This is something that we do see in our clinics, whether the patients are older or more frail, have some marrow suppression from their lutetium, or just decide they don't want the chemotherapy. So, for patients who are docetaxel candidates, I do think that there are advantages to giving the taxane first over the lutetium.

Here again, the PSMA expression might be helpful because patients who have high PSMA expression are the ones who are more likely to benefit from the lutetium. Patients with low PSMA expression or visceral disease might be the ones who benefit more from the taxane.

Now, if we think about that first line, in the initial hormone-sensitive space, this is a very different disease setting. Many of these patients actually will live for a very long time, even just when starting with hormone drugs, so here we really want to think about what the toxicities of the treatments are in relation to the potential benefits.

And what the PSMAddition trial showed with lutetium compared to ADT-ARPI alone was a progression-free survival advantage, but there was not a statistically significant overall survival advantage as of yet. Lutetium does have some toxicities, both short-term in terms of myelosuppression, dry mouth, fatigue, nausea, and things along those lines, but also potential late-term impacts on bone marrow and probably non-negligible rates of myelodysplastic syndrome and acute myeloid leukemia. So this is a treatment that we would use in the first line in a situation where we really think that a patient would benefit and really need it.

For patients with low-volume metastatic disease, this is probably not a really appropriate treatment option. But for patients with high-risk features and high-volume metastatic disease, where treatment intensification might be appropriate, we actually have several options. We have lutetium PSMA, we have docetaxel, capivacertib for P10 loss patients, PARP inhibitors for BRCA2-mutated patients as well.

And who's going to be most appropriate for one of those treatments really does depend on the biomarker. For lutetium, obviously, you need PSMA expression. But whether it's actually better than docetaxel in this setting, in terms of short-term and long-term quality of life, efficacy, and survival—they've never been compared head-to-head.

My personal inclination is that for patients with high-volume and aggressive disease, docetaxel has a long history of being an effective agent. It's completed after six cycles, so 18 weeks of treatment, and doesn't require maintenance. And also, there's not a worry about late-term risk of marrow toxicity.

But there are certainly patients who have baseline contraindications to docetaxel—for example, neuropathy—or just very elderly patients who might not tolerate it. And in that setting, where you have a patient who has high-volume metastatic disease, might not be a candidate for docetaxel, and is not in the population that is going to respond well to ADT and ARPI alone, I would certainly consider lutetium in that particular disease setting.

When we're thinking about the overall sequencing of agents in mCRPC, I do think that sequencing the agents that have a survival benefit is what's going to lead to the most prolonged overall survival. For patients who are progressing with an indolent pace of disease, I actually do still use Sipulus LT and radium-223 in my practice, even though they're not particularly cytoreductive, because each of those agents has demonstrated a survival advantage.

However, for patients with more rapidly progressing disease, I do think that there's evidence that both taxane and lutetium have good cytoreduction, at least in a proportion of patients. And those are the treatments that I might reach for next. If they do have more indolent progression later on, we can use one of these agents that might have less ability to cytoreduce.

So lutetium is a very, very important tool in our armamentarium. We use it quite a bit in our practice at Dana-Farber. But I think finding the appropriate patient at the appropriate time is going to be the real key in terms of adapting it to clinical practice in general.