Radioligand Therapy 177Lu-PSMA-617 in Progressive PSMA-positive mCRPC - Episode 5

Safety Profile of LuPSMA Therapy in mCRPC

Dr Andrew J. Armstrong reviews the safety of LuPSMA therapy as compared to cabazitaxel as seen in the phase 2 TheraP trial and comments on sequencing strategies for patients with metastatic castration-resistant prostate cancer.

Andrew J. Armstrong, MD, MSc: We now have safety for over 800 patients to really talk about. The good news is that the safety reporting in the study was very complete, and demonstrated a very favorable safety profile. If you talk about all grades of toxicity, the most common side effect of PSMA [prostate-specific membrane antigen] lutetium was fatigue. About half the patients experienced some degree of fatigue. About 7% experienced more severe fatigue. That can result from bone marrow suppression, such as anemia, where about 13% develop the need for transfusions. Cytopenia and the bleeding risk that can happen with low platelet counts occurred in about 8% of patients to that severe degree. PSMA is expressed in the salivary glands and the lacrimal glands, so you do see some dry mouth and dry eyes. This occurs for about 30% to 40% percent of patients. You can see some mild nausea or vomiting. Very rarely can you see renal effects. PSMA can be expressed in the renal tubules. There is only a slightly higher risk of impaired renal function from PSMA lutetium, but it does illustrate the importance of monitoring the GI [gastrointestinal] system, the metabolic system, and bone marrow lab parameters when treating with PSMA lutetium. Despite this, there was no increased risk of infection or neutropenic fever, unlike how it was with cabazitaxel in the randomized phase 2 study, where this was a major side effect.

One clinical trial that has been reported—again, it is a small clinical trial—is called the TheraP study. It was just published in Lancet Oncology. This trial, led by Michael S. Hofman, MBBS,FRACP, FANNMS randomized patients between PSMA lutetium and cabazitaxel, all of whom had a potent AR [androgen receptor] inhibitor, and had a positive PSMA scan. We do see that adverse events really do differ between these 2 therapies as one might expect. For example, the rate of fatigue was very similar, but dry mouth was more common with PSMA lutetium. It was the same with dry eyes. Nausea and vomiting were more common, as was diarrhea, with cabazitaxel. Neuropathy was more common with cabazitaxel. Neutropenia and neutropenic fever were more common with cabazitaxel. There are differing side effects. In general, my experience with PSMA lutetium is that it leads patients to have very good quality of life. By the way, you can use these therapies sequentially. If you chose cabazitaxel first, you can still reasonably try PSMA lutetium as another treatment to improve the survival of your patients, and vice versa. If you started with PSMA lutetium, and a patient starts to progress, cabazitaxel is still an effective agent that can rescue many patients.

A common strategy for treating dry mouth would be chewing gum. This tends to be a mild side effect. Just the stimulation of saliva—the constant stimulation—is one of the tools that can overcome this. This is typically a transient, not durable, side effect because of the radiation that is delivered through the PSMA targeting in the salivary ducts. Certainly, artificial saliva can be used. It would be rare to ever need that. Maintaining hydration and good dental hygiene is critical in this setting; we need to prevent dental caries or other side effects that are dental in origin.

It is always good news to see a PSA [prostate-specific antigen] response, but that is not the whole aspect of treating a patient. For a patient to feel like they are entering remission, you would like to see radiographic and symptomatic responses. Of course, the PSA can go along with that. While it is important to have better PSA declines, it is much more important to have better survival rates, more durable remissions, and radiographic prevention of progression. There are some patients that can progress on imaging, even without a PSA that is rising. We do not want to rely too much just on PSA.

Right now, the VISION study did not have a head-to-head comparison against cabazitaxel. Nor did it have a head-to-head comparison against radium. Right now, we do not know the proper sequencing of PSMA with cabazitaxel or radium. Radium is still a reasonable option for men with bone-predominant disease who have symptomatic progression. Cabazitaxel is still a reasonable option, particularly for patients that have PSMA-negative disease or visceral disease who might not be expected to do as well with PSMA lutetium. There’s going to be a huge demand of PSMA lutetium, however, for the broad PSMA-positive population, due to its efficacy, improved survival rates, good quality of life, and relatively low toxicity, relative to chemotherapy. Many men have the goal of putting off chemotherapy as long as possible. This therapy will not completely replace all our existing therapies. It will add to them and keep our patients alive for much longer. It is giving us, as investigators, time to develop even better therapies that are targeting PSMA or other molecules. We can develop other immunotherapies, other precision medicine treatments, that can then come in afterwards. PSMA lutetium is not curing our patients, but it is prolonging remission, improving survival rates, and maintaining quality of life, which are all major goals of our patients.

Transcript edited for clarity.