Phase 3 VISION Trial in PSMA-Positive mCRPC

EP: 1.Standard of Care for PSMA-Positive mCRPC

EP: 2.Response to LuPSMA Therapy in mCRPC

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EP: 3.Phase 3 VISION Trial in PSMA-Positive mCRPC

EP: 4.Patient Selection of LuPSMA Therapy in mCRPC

EP: 5.Safety Profile of LuPSMA Therapy in mCRPC

Andrew J. Armstrong, MD, MSc: The VISION clinical trial was a phase 3 global study that looked at the safety and global efficacy of PSMA [prostate-specific membrane antigen] lutetium 177, which is a small molecule that binds to PSMA on the cell surface of prostate cancer cells, and delivers a beta emitter, called lutetium-177, that emits radiation selectively to PSMA-expressing tissues. This trial selectively enrolled patients with mCRPC [metastatic castration-resistant prostate cancer], who had failed with at least 1 prior AR [androgen receptor] inhibitor or ongoing androgen deprivation therapy [ADT] and had also progressed on at least 1 prior taxane, mostly docetaxel. Patients who were not considered fit or optimal for further chemotherapy, such as with cabazitaxel or with radium 223, were also enrolled. These patients underwent PET [positron emission tomography] imaging as part of their screening. If they had PSMA-positive disease and lacked PSMA-negative disease—which was, again, about 82% to 83% of all the randomized screened patients—then they would be eligible for the VISION study approach, in which patients were, again, randomized to the best supportive care, standard of care, that they could receive, provided that was an oral agent, such as a steroid or a second AR inhibitor. Alternatively, they could receive the best supportive hormonal therapy, with ongoing ADT, with up to 6 cycles every 6 weeks of PSMA lutetium. The final sample size for this trial was over 800 patients, specifically 831 patients. The primary end point of this trial was radiographic progression-free survival, but the most impressive results occurred in reference to—and a key co-primary end point was—overall survival. Both end points were met in this study.

All these patients were heavily pretreated. Most patients had already had, again, an AR inhibitor. All patients had a taxane regimen, but some patients had several taxane regimens. And many patients had already had multiple AR pathway inhibitors. The topline results for overall survival demonstrated that PSMA lutetium plus the standard of care improved overall survival, over standard of care alone, by about 4 months. The hazard ratio was .62, with a very significant P value that was less than .001. This met the primary analysis for all the randomized patients. This was also held up in an analysis set that was restricted to just those patients that were evaluable for a key primary end point of radiographic progression-free survival. In both subsets of patients, including the overall group of patients, overall survival was significantly improved by about 40%.

PSA [prostate-specific antigen] is one of the proteins made by prostate cancer. PSMA is expressed on the cell surface. PSA is a secreted protein. We often use PSA declines with hormonal therapies and chemotherapies to update the prognosis of our patients, and to reassure them that they are doing very well with the therapy that they are on, that they are having a robust response to treatment. We can follow PSA over time, to detect the time until PSA progression, for example. Other aspects of the disease that are important are objective and soft tissue responses. Let me start with PSA declines. When we characterize PSA declines, there is really a continuum. The lower the PSA drops, the better the prognosis of a patient. With PSMA lutetium in the VISION study, we observed a confirmed 50% or greater drop from baseline in nearly half of the patients, or 46%.

With the standard of care, it was only 7%, illustrating that this is having an on-target effect. It is reducing PSA, and many more patients had a very robust decline, to 80% or more. A third of the patients had an 80% or more decline that was confirmed, as compared to only 2% of patients receiving standard of care alone. On imaging, which is equally important to PSA declines, you see 9% of patients had complete remissions and 41% had partial remissions. This was very rare with supportive care or the standard of care alone. Only about 13% of patients did not respond to PSMA lutetium, where their best response was progressive disease. Nearly half the patients treated with this standard of care alone had a best response of progressive disease, illustrating that this treatment is very effective in establishing disease control. The radiographic progression-free survival was substantially improved for these patients with an improvement of about 5 months over standard of care.

Transcript edited for clarity.