PSMA-Targeted Radioligand Therapies in Advanced Prostate Cancer - Episode 3

The VISION Study in Metastatic CRPC

An overview of safety and efficacy data presented at ASCO 2021 from the phase III VISION study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer.

Scott T. Tagawa, MD, MS, FACP: The VISION trial was a study of patients with pretreated, metastatic, castration-resistant prostate cancer. The study was designed for patients who really had no other options. The minimum requirements for inclusion was treatment with 1 prior AR [androgen-receptor] -pathway inhibitor and 1 prior taxane chemotherapy, but it was really designed for everyone. To enroll, the patients had to be PSMA [prostate-specific membrane antigen] -positive. About 95% [of patients] had PSMA positivity defined by at least 1 lesion with uptake greater than the liver. However, approximately 8.7% of these patients were excluded, because besides that minimum of 1 positive lesion, they had at least 1 lesion that met criteria that did not have PSMA uptake. That is an implication about who was included in that trial. After the drug is FDA [US Food and Drug Administration] approved, we can think about whom we might treat. Because the PSA-positivity rate is so high in a patient with no other options, do we really need the PSMA PET [positron emission tomography]? That is an unanswered question, but as this type of approach moves earlier, that is a different setting with more options.

The study design [of the VISION trial] was essentially a 2-versus-1, so standard of care with limited options based on what we can safely combine. It was mostly hormonal therapy, and that was hormonal therapy with lutetium-177–PSMA-617 open label. The patients [who received] the active drug (ie, lutetium-177–PSMA-617) … had some benefits, so they were assessed much longer. There were more adverse events reported in that group. Most were absolutely expected, based upon both retrospective and prospective data sets. We would expect a systemic type of radiation, even though it is targeted, to have some associated fatigue that was generally lower grade, but there was more higher-grade fatigue in those [given] lutetium-177–PSMA-617. Low blood counts is an adverse event that is known. There is actually some data outside of the VISION trial with therapy in a direct head-to-head comparison with cabazitaxel chemotherapy, so thrombocytopenia stands out. Luckily, generally speaking, we are talking about low-grade thrombocytopenia without associated bleeding, but it is a clear toxicity that may happen, and [we] worry about a nadir approximately 3 weeks out. Leukopenia and anemia can happen also but [are less concerning], at least in the head-to-head setting versus cabazitaxel.

There was also GI [gastrointestinal] toxicity (ie, nausea). PSMA is expressed in the small intestine, so there was nausea in a systemic basis circulating in the blood. Although radium is excreted in the small bowel, there is also some systemic effect with that radiation. [Nausea] may be the systemic effect of circulating lutetium-177–PSMA-617 and excretion in the small bowel. Nausea can happen to a low-grade degree, typically within the week after administration.

Dry mouth can also be an issue. There is a relatively high level of PSMA expressed in the parotid and salivary glands, and lutetium-177–PSMA-617 is small enough to get into those glands, unlike some of the larger antibodies. Luckily, the beta radiation with lutetium-177–PSMA-617 was weak enough that it looks like it does not lead to permanent salivary-gland damage. Generally speaking, this is low grade and temporary.

The caveat of all of that is that follow-up is relatively short. Unfortunately, for this group of men, we do not have a lot of patients who live past 5 years. In assessing some of the longer term effects, particularly worrisome effects might impact the kidney, because there is PSMA targeting the proximal tubules with small molecules. The longer-term effect on the bone marrow and the possibility of secondary malignancies may be more of a worry as we move to earlier disease states.