Metastatic castrate resistant prostate cancer (mCRPC) is a heterogeneous disease for which several treatments are already available. These include systemic chemotherapies, a variety of androgen receptor pathway inhibitors, radionuclide agent (Radium-223) and drug therapies that target specific genomic aberrations (HRD pathway). All of these are administered with palliative intent, are FDA approved, and help in slowing down disease progression.
In the therapeutic mix of 10 existing FDA approved drug treatments for mCRPC state, the “VISION” trial was presented at the plenary session of ASCO 2021 in a Late Breaking Abstract, “Phase III study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION).”
This study was an open label 2:1 randomized study which used a new agent 177Lu-PSMA-617 (LuPSMA), a form of targeted radioligand therapy that delivers beta radiation to cancer cells after zeroing to and attaching to the prostate specific membrane antigen (PSMA) receptor on prostate cancer cells, followed by internalizing of the radioactive payload into the cell that then delivers the radiation to destroy the tumor cell. LuPSMA is administered intravenously and in this study between four to six treatments were compared to standard of care (SOC) treatments in mCRPC patients who had either failed 1–2 standard of care chemotherapies and at least one androgen receptor pathway inhibitor drug therapy. As part of the eligibility, all the mCRPC patients were screened for PSMA positive metastases using a 68Ga-PSMA-11 PET scan and patients were enrolled if they met a very “liberal” criteria of being positive or avid for the PSMA-based metastasis on imaging. The co-primary end points of the trial were overall survival (OS) and radiographic progression-free survival (rPFS).
After a median study follow-up of 20.9 months, the addition of LuPSMA to SOC was observed to have a 40% reduction in the risk of death with a 4-month improvement in the median OS to15.3 months from 11.3 months (HR, 0.62) and a 5.3-month improvement in median rPFS for patients who received LuPSMA along with SOC treatments.
Most common adverse effects associated with higher rates for LuPSMA included fatigue (49.1% vs 29.3% in the SOC alone), bone marrow suppression (47.4% vs 17.6%, respectively), dry mouth (39.3% vs 1%), nausea/vomiting (39.3% vs 17.1%). There were also an increased need for blood transfusions in the active treatment arm patients who received LuPSMA compared to SOC. While the results show a statistical and possibly clinically meaningful benefit, there are several relevant pieces of information that are needed to be further clarified.
As part of the study, individual investigators determined the “SOC” treatments that enrolled patients would receive, but investigators were specifically not allowed to administer radium-223 (Xofigo) and cytotoxic chemotherapy after patients were enrolled on the study, which are FDA approved treatments in this state. Study investigators justified this on the basis of unknown toxicity that could occur from the combination of LuPSMA with Radium-223 or cytotoxic chemotherapy should these approved drugs be allowed during the study. Under these circumstances it would appear that LuPSMA drug was compared to relatively non-“SOC” treatments to demonstrate a survival advantage. In fact, the abstract presenter and lead principal investigator mentioned that several patients received only oral glucocorticoids as part of the “SOC.” It will be critical to learn more in the publication as to how many patients truly received SOC drug regimens, so that a better understanding of how to use this drug and which type of advanced prostate cancer patients may have a greater degree of benefit from it. This in fact is the essential bridge between “efficacy” seen on trials to “effectiveness” of a drug treatment in clinical practice in the real world.
There was also a relevant discussion on what constitutes PSMA-PET positivity to qualify and receive the LuPSMA drug. In this trial all patient underwent a PSMA-PET scan and the investigators used a very liberal criteria to call the PET scan positive. It is so far not clear from the results presented that in future all patients who are candidates for this study drug have to undergo an expensive modality PSMA-PET scan and if it has to be positive before undergoing treatments. These type of PET scans are expensive and are typically being restricted while getting insurance approvals/clearance, as well as the fact that there also are limitations in its availability because cyclotrons that produce the specific radioactive imaging dye to be used are not widely available yet.
These issues are relevant and most likely will be discussed in the FDA committee that will have to evaluate this novel agent for drug approval, so the final verdict therefore remains to be seen.
Separately of note, LuPSMA is being extensively evaluated in metastatic hormone sensitive and metastatic castration resistant prostate cancer states in a number of clinical trials both in the U.S. and globally.
Dr. Kohli has no conflicts of interest to report.