The PSMAddition study expands upon what we know about the 177Lu-PSMA-617 drug that was first approved based upon the VISION study that was in the post-chemotherapy, post-ARPI setting with an overall survival and radiographic progression free survival benefit as well as the PSMAfore study in the post-ARPI, pre-chemo setting. Both of those were in the setting of hormone resistance and we know in the hormone resistant setting there’s a higher hazard of having PSMA low disease as well as a higher chance of having radioresistant clones. So it made sense, we always want to move drugs up in terms of the number of the lines of therapy and it also made scientific sense to go into the patient population where there, we think, is the highest amount of PSMA in terms of the target in a more homogeneous fashion as well as less radioresistance.
This was also a combination study so it’s with hormonal therapy and we know that hormonal therapy can, number one, increase the target of PSMA as well as radiosensitise. So all that together led to the study.
This enrolled patients with either de novo or recurrent metastatic disease, that was metastatic disease on CT, MRI or bone scan, and they had PSMA positive disease by a screening Gallium PSMA-11 PET CT where they had to have at least one lesion that was brighter than the liver to get in.
Patients in the study were randomised 1:1 to either the standard of care backbone of ADT plus ARPI of physician’s choice, or whatever was approved in that jurisdiction, with or without up to six cycles of 177Lu-PSMA-617 administered at the standard 7.4GBq every six weeks times up to six. The primary endpoint was radiographic progression free survival. The patients that were in the control arm, after they had confirmed radiographic progression they were allowed to cross over to the 177Lu-PSMA-617 and, in fact, about 60% of those in the control arm that had radiographic progression at the time of this analysis did cross over.
What results were you presenting?
The primary endpoint was radiographic progression free survival and at the first efficacy interim analysis there happened to be a positive result. So there was a 28% improvement in radiographic progression or death and that was statistically significant based upon the statistical analysis plan. There were several other efficacy secondary endpoints that also favoured the 177Lu-PSMA-617 arm and they included a trend for overall survival, the hazard ratio was less than 1.0 although the confidence intervals did cross 1.0, and RECIST response for that subset that had measurable disease, PSAs including PSA less than 0.2, as well as time to SSE and castration resistance were also positive.
There were more adverse events in those that got 177Lu-PSMA-617, so not surprising to me that three drugs have more AEs than two drugs. However, the types of AEs were not of any surprise – they were related to the components of the treatment – ADT, ARPI, or 177Lu-PSMA-617. Those that were expected for 177Lu-PSMA-617 included fatigue and others that were at least partly related to areas of normal PSMA expression in the body such as the salivary and lacrimal glands, so dry eye, dry mouth, dry mouth was the most common, as well as the small intestine which can lead to nausea, vomiting, diarrhoea or constipation. So those were not surprising. There was also more myelosuppression, cytopenias, with the 177Lu-PSMA-617 arm. Fortunately either neutropenia, thrombocytopenia or anaemia, none of them had a grade 3 or higher rate that was more than 5%. So we’re talking about single digits in terms of the high grade adverse events. So that’s fortunately so far. Despite the higher number of adverse events, there was not a major detriment in quality of life, at least as assessed by the FACT-P or BPI short form in terms of the patient-reported outcome surveys.
We hope to have more details in terms of the patient-reported outcomes as well as some of the other qualitative analyses such as the PSMA-PET data, we collected blood as well as tissue, but those should be coming in the future.
What could be the implications of these findings?
It’s nice to have some demonstrated benefit with what appears to be acceptable safety in this patient population. The nice thing is that we know that, in part, because they may do better at the beginning but also because we know that fewer number of patients, or percentage of patients, receive each line of therapy, so to allow patients to have this up front, essentially at the time of diagnosis, hopefully will be wonderful for our patients. Right now we have the ability to add docetaxel, it’s unclear how much docetaxel adds to the ADT/ARPI backbone but that is available. There may be a PARP inhibitor or PARP inhibitors coming in that patient setting, there may be an AKT inhibitor, but it will be nice to have multiple options though likely to be some clinical criteria that we use to assess if a patient is appropriate and also biomarkers. So at least there will be PSMA PET for 177Lu-PSMA-617 and maybe even more.
