Negative trial results of custirsen for metastatic prostate cancer
Prof Karim Fizazi - Cancer Medicine at the Institut Gustave Roussy, Villejuif, France
This is a phase III trial testing a new compound called custirsen together with chemotherapy used for second line metastatic prostate cancer that has resistance already to not only hormonal therapy but also to first line docetaxel chemotherapy. As probably you will know, prostate cancer is a very frequent disease, it is being treated mostly by hormonal therapy as a first line treatment when we need systemic treatment and hormonal treatment works very nicely in almost all men who suffer from this disease but it doesn’t necessarily work very long. Depending on after one or two years, perhaps sometimes longer, the disease tends to resist and until recently we didn’t have many, many options to propose to these patients.
The very good news from the last five years is that a series of compounds that could be shown to increase overall survival in this situation of what we call castration resistant prostate cancer – two chemotherapy agents, docetaxel and cabazitaxel, two androgen receptor axis targeting drugs, abiraterone and enzalutamide, and one bone targeting agent, radium, and this is because metastatic prostate cancer is a bone disease. Having said that, none of these compounds is able to achieve a cure in patients with metastatic disease so we still need more treatment and we need treatment that can reverse or prevent the resistance to these drugs.
Clusterin, that is shown here, is a cytoprotective protein, so every time a cell, a cancer cell, will be attacked by either hormonal therapy or chemotherapy, clusterin will be expressed and it will try to protect the cells against the harming from the treatments we are using. It pretty much gives a time for the cells to survive, if you will, by various means and I won’t go into too much depth. It really prevents the apoptosis that we are trying to achieve with hormonal treatment or again chemotherapy. So custirsen, which is shown here, which is the drug I’m going to talk about is an antisense that is really preventing the making of a protein. So by combining chemotherapy plus custirsen the goal is really to achieve a better job than chemotherapy alone.
So the rationale was based on multiple experiments in the last fifteen years in vitro and in animal models mostly conducted in Vancouver by Martin Gleave’s group suggesting again a strong biological effect of clusterin and an inhibitory effect of custirsen. Then we moved to a clinical development with custirsen and a randomised phase II trial was conducted and reported some years ago suggesting that, indeed, combining custirsen together with chemotherapy can achieve a better job with approximately a 40% reduction in the risk of death in this randomised phase II trial, again in metastatic castration resistant prostate cancer.
So we designed the AFFINITY phase III trial, the large phase III trial in the second line setting, so in very advanced patients. They had all failed not only hormonal therapy but also chemotherapy with first line docetaxel and it was a quite straightforward randomisation of a standard of care, cabazitaxel, prednisone plus or minus custirsen which is an IV drug that we give in a weekly fashion after a loading dose. Patients continued treatment until progression, cancer progression, toxicity or completion of ten cycles and the primary endpoint was survival.
This is the main results of the trial and unfortunately by intent to treat analysis there was no superiority of custirsen when added to chemotherapy. We looked at different subgroups, perhaps it was a little more active in what we call poor prognosis patients but still no overall survival benefit. Having said that, we’ve tried to look at what happened to serum clusterin and was that because clusterin finally is not a good enough target or was that because the drug is not good enough to target clusterin? Actually in the control arm you don’t see much effect whether clusterin is being lowered or not by chemotherapy. In the experimental arm it’s another story – as you can see here, those patients who achieve a marked decline in clusterin while on custirsen do much better as compared to those who do not achieve this effect. So, again, a decline in clusterin seems to have an effect but again perhaps the drug is simply not potent enough to have a biological effect being translated into overall survival improvement.
So, in conclusion, addition of custirsen to second line chemotherapy with cabazitaxel did not significantly improve overall survival. There was no new safety signal and generally speaking this is very well tolerated as an add-on to chemo. No imbalance of active drugs beyond progression can explain the lack of overall survival benefit, we looked at that because we have now again many drugs that can postpone death and it was well balanced between the two arms. So again two possible questions or answers, either clusterin is not relevant enough as a target in this disease or, and perhaps more likely, the target was not inhibited enough with the compound we have at the moment.
The second and last conclusion that I have is really about the pre-requirement that we need for the future when designing a new phase III trial because in this trial we had a strong biological rationale, we also had a strong clinical signal – again overall survival was improved or apparently approved in randomised phase II but didn’t really select all the patients based on biomarker. There was no molecular certification and I think this is what we need to achieve now for future development in prostate cancer. Thank you very much.