The Evolving Treatment Landscape of Metastatic Castration-Resistant Prostate Cancer - Episode 8

Potential Role of Lu-PSMA-617 in mCRPC

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Expert perspectives on where Lu-PSMA-617 therapy may fit into the treatment paradigm for metastatic castration-resistant prostate cancer.


Oliver Sartor, MD: Salvage therapy is in the eyes of the beholder. I don’t always use the term salvage therapy to patients or in my own practice. I look at it as an additional line of therapy. In some ways, the novel hormones—I’ve mentioned abiraterone and enzalutamide, but I should also mention things like apalutamide and darolutamide—are quite nice and have all been shown to prolong survival in different settings for patients with advanced prostate cancer. The taxanes also unequivocally provide benefit; there’s no doubt in my mind that taxanes provide benefit. Here we are with another line of therapy that shows benefit in the majority of patients. It’s not everyone. Remember, only 87% of the patients were included because the PSMA [prostate-specific membrane antigen] PET [positron emission tomography] excluded about 13% of patients.

If we look at other active therapies—this is important to keep in mind—things like the PARP inhibitors, particularly olaparib, have been shown to prolong survival. Then we have agents like pembrolizumab that are appropriate in a small subset of patients. They have quite significant activity in those with MSI [microsatellite instability]–high mismatch repair deficiency or high tumor mutational burden. Overall, I’m not viewing this as salvage therapy. I’m viewing it as another option as we treat patients through the natural history of the disease using the agents that we have in our armamentarium.

In the VISION trial, we laid out some pretty good parameters, and we’ve generally been treating those with a performance status of 0 to 2. With regard to the location of metastatic disease, it doesn’t matter that much whether they have lymph node metastases, bone metastasis, both lymph node and bone, potentially liver, or visceral lesions, such as lung. We’re not excluding patients on the basis of any particular location. In the trial, we didn’t allow brain metastasis, but that’s a very small fraction of patients with prostate cancer.

We were looking for good hematologic reserve. It didn’t have to be great, but we were looking for adequate white blood cell count and adequate platelets. We were trying to get platelets at least above 100,000 per μL in order to be eligible, and even higher would probably be better. Neutrophils had to be essentially within the normal range. We weren’t treating people with an absolute neutrophil count of less than of 1500 per μL.

We were also looking for people who would ensure that they’d have adequate follow-up. The treatment is planned for at least 4 injections of the PSMA lutetium, but they can receive up to 6. You have to make sure the patient can make repeated trips into our center to receive these infusions. Simply stated, most of the patients who are PSMA positive and fulfill the criteria are very interested in receiving this therapy. We’ve had a lot of enthusiasm among patients who are seeking this therapy if they’ve had prior novel hormones and taxanes and have metastatic CRPC [castration-resistant prostate cancer].

Scott Tagawa, MD, MS, FACP: The VISION study was designed to be for when there’s nothing else available. The minimum entry criteria were at least 1 AR [androgen receptor] pathway inhibitor and at least 1 taxane chemotherapy. It was designed in spirit for patients who had nothing left, whether they had radium and a PARP inhibitor, 2 taxanes, and at least 1 AR pathway inhibitor. It took whatever standard of care can be pulled out within the limits of the trial for safety reasons, with or without lutetium-PSMA-617.

It’s a late-stage design. I’d expect that to be reflected in the label, assuming that this drug gets approved soon. I believe the initial use will be for patients who don’t have a lot of additional options and who are probably PSMA selected. Although, I’d argue [to treat those patients] in that particular setting when there’s no other option and maybe no clinical trial options, because PSMA is almost always there—it was 19 out of 20 in the VISION trial, with a few who also have PSMA-negative tumors. Plus the fact that the safety profile for the drug isn’t nothing. There are some important adverse events with the drug, but it’s reasonably clean in the setting of advanced prostate cancer. One could argue in a setting with no other options to just treat those patients. But it’s likely that because there are clinical trials and other drugs out there, at least in major centers, that we’ll initially look at patients with PSMA-positive disease by imaging who have had chemotherapy before, at least 1 line of chemotherapy, and certainly at least 1 AR pathway inhibitor.

There’s also the TheraP trial, which has a very highly selected patient population with extreme PSMA positivity and no discordance with FDG [fluorodeoxyglucose]. But in that setting, head-to-head against cabazitaxel chemotherapy, it was better in terms of the primary end point of overall response rate and biochemical progression-free survival, at least by PSA [prostate-specific antigen] metrics. It also had overall better tolerability vs chemotherapy. In that context, even though it wasn’t designed as a registration trial, initial use for the average patients is maybe after docetaxel but before cabazitaxel, assuming that those PSMA metrics are hit.

Then we have a number of different beta- and alpha-targeted PSMA drugs, lutetium-PSMA-617, plus 2 additional lutetium PSMA–targeted drugs, that are in phase 3 in the prechemotherapy setting, including 1 that’s in the noncastration-sensitive setting. I think that the initial use will be in heavily pretreated patients with metastatic CRPC. But because there’s a lower hazard of having PSMA-negative disease in earlier lines of therapy, and there are likely to be fewer radiation resistance mutations with less pretreated disease, the likely future is going to be in earlier lines of therapy.

Transcript edited for clarity.