LuPSMA Therapy in mCRPC: Managing Adverse Events

EP: 1.Overview of Prostate Cancer

EP: 2.Role of Imaging in Prostate Cancer

EP: 3.Treatment Options for Metastatic CRPC

EP: 4.Phase 3 VISION Trial in mCRPC

EP: 5.Clinical Implications From the VISION Trial in mCRPC

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EP: 6.LuPSMA Therapy in mCRPC: Managing Adverse Events

EP: 7.Remaining Questions for LuPSMA Therapy in mCRPC

EP: 8.Future Treatment Landscape of mCRPC

EP: 9.Clinical Pearls for the Management of mCRPC

Scott T. Tagawa, MD, FACP: As with all of our therapies, there are a number of adverse events that are associated with treatment. There are 2 randomized trials of lutetium-PSMA [prostate-specific membrane antigen]-617. We have the VISION trial, which includes lutetium-PSMA-617 in addition to standard of care vs standard of care alone, as well as some head-to-head data against cabazitaxel chemotherapy. What’s important to know is that both of these trials were positive. The duration of exposure and duration of looking closely at adverse events was much longer in those getting lutetium-PSMA-617 compared with the control arms. That being said, there are some somewhat generic adverse events that might occur. Then there are some that are specific to the agent.

The important ones are those that are specific to agents, because I suspect there are a number of clinicians out there, whether it’s a physician extender, a nurse, a patient, or the family members, who we need to understand that there’s some gamma emission. This isn’t true of all radionuclides, but it is true of lutetium-PSMA-617. Gamma emission can be dangerous to those around. It’s a low level overall, but it’s something we need to think about. The patient receives therapy, walks out the door, and is emitting to the public, but generally not enough to be dangerous. But for someone who’s in close proximity for a prolonged duration of time, it’s something to think about. That’s not part of general presentations or publications.

In terms of the adverse events commonly associated with lutetium-PSMA-617, there are some constitutional symptoms, such as fatigue. There’s fatigue with any type of generic administration of radiation, whether it’s localized or systemic. There was more fatigue in the VISION study with lutetium-PSMA-617 compared with standard of care. Generally speaking, it was low-grade fatigue, but high-grade was also more common than standard of care alone. There are some hematologic issues. All of the counts can be decreased. Thrombocytopenia stands out, not only from the VISION study, but because that was the cell type that was worse compared with cabazitaxel chemotherapy in the TheraP study. These generally aren’t high grade, but they can be. With any type of radiation that’s affecting the bone marrow, at least in theory, these could be of long duration or theoretically even permanent. That hasn’t been seen very often, but we’re mostly administering this in metastatic CRPC [castration-resistant prostate cancer], where not many people make it to 10 years, unfortunately. Hopefully that will change in the future.

There are certain areas that are on target in terms of PSMA-positive areas in the body, but off-tumor. For instance, the salivary glands as well as the lacrimal gland. We’re talking about the head and neck. In my personal experience, dry eye is not that common, but it can happen. Dry mouth is common, however, and possibly even underreported in the VISION study because in other studies with a lot of PSMA-specific investigators, they’re asking the questions on a daily or weekly basis. It’s a higher percentage who are affected. That being said, generally speaking, the average patient would have that for a defined duration of time, days or weeks, at a low grade.

There’s some nonspecific nausea that may occur, but there’s also some specific nausea with uptake into PSMA in the small bowel. Nausea stands out as more common with lutetium-PSMA-617, along with the other small molecules. We luckily haven’t seen a significant kidney toxicity signal, ie, in terms of renal failure. That being said, that may be a late effect, so it’s certainly something to keep in mind. When I put all of those together, like with any other treatment, I counsel my patients prior to the treatment, generally in the visit or visits that happen prior to the administration, and then usually I’ll quiz them and then remind them on the day of administration. We can do certain things, like having them hydrate well orally. This can also happen intravenously. That’s happened in some drug developments, particularly for alpha PSMA-targeted radionuclide therapy. But for someone who feels dehydrated, that can help. We have them drink more than usual for days or weeks following therapy. That might help protect the kidney, and may also combat dry mouth.

We also may administer prophylactic antiemetics. That was recommended in the VISION study, although not absolutely mandatory. Just like with chemotherapy, we have some patients who have very severe nausea. We have some who have absolutely none. But it’s one of the more common toxicities to occur. You can give a prophylactic administration of a 5-HT3 [receptor antagonist] with therapy, as well as making sure they have antiemetics at home for as needed use. I will generally follow up with them after therapy, certainly within 2 weeks. The VISION study had weekly follow-up. That doesn’t necessarily have to be in person. Whether that’s a phone follow-up or a telemedicine video visit, it depends on the individual practice. This isn’t so different from other drugs.

At the beginning, cycle 1, I’m more conscious and cognizant of what might happen because everyone is different. I’ll make sure I see them within 2 weeks, and often within 1 week. With subsequent cycles, that may be relaxed a bit as long as there’s counseling, “You need to call us if something happens.” Usually I’ll talk to their family or support system as well, just to have them give me a call if there are any issues that arise.

One thing I’ll mention that’s relatively new and not yet peer-reviewed, is that despite the higher incidence of adverse events in the lutetium-PSMA arm of VISION compared with standard of care alone, that didn’t translate into a major problem in terms of patient-reported outcomes. Karim Fizazi, [MD, PhD,] reported the secondary end points of patient-reported outcomes at ESMO [European Society for Medical Oncology Congress] 2021, and there was a significant improvement in time to deterioration of global quality of life as measured by FACT-P [Functional Assessment of Cancer Therapy–Prostate], time to deterioration of pain as measured by the Brief Pain Inventory, and time to first symptomatic skeletal event. This is despite the fact that there were more adverse events, partly because of longer follow-up. There are real toxicities that may happen with that. Despite that, likely because of a combination of not so severe and long-lasting, plus the impact on prostate cancer, these did translate into improvements in patient-reported outcomes.

Transcript Edited for Clarity