DR BEER: Custirsen is an agent that inhibits the expression of clusterin. Clusterin is a chaperone protein that is induced by various interventions, including chemotherapy, and appears to mediate resistance to treatment. So it’s an interesting target, because it appears to be an inducible resistance mechanism for chemotherapy and, potentially, for hormonal therapy.
Custirsen is also an interesting agent by virtue of the type of agent that it is. It is an antisense oligonucleotide, so it targets the expression of clusterin at the level of nucleic acid, so not protein. We don’t have any drugs like that on the market, so it’s a new kind of drug and a new kind of target.
DR LOVE: Could you just elaborate a little bit more on that in terms of what antisense is?
DR BEER: So antisense oligonucleotides are short sequences of nucleic acids that bind to RNA and prevent the translation of that RNA into active proteins. So it’s kind of like, you could call it, in a manner of speaking, gene therapy. It’s not really gene therapy in the full sense of the word. Classic gene therapy would mean inserting a healthy gene where a gene’s been damaged or is absent. But this is trying to shut down a target at the level of its genetic expression. One of the really innovative things about how it was developed was that the agent was given prior to prostatectomy. And its concentration and its biologic effects were actually measured in the prostatic tissue. So we have very good documentation that the drug gets into tumor and shuts down its target in a dose-dependent fashion. And for most targeted agents, we don’t have those kind of data.
Next it was studied in combination with chemotherapies used in prostate cancer. The study that we were highlighting in this meeting was a Phase II study of docetaxel or mitoxantrone — it was a randomized Phase II — in patients who’d been previously exposed to docetaxel. So this is a study that was done before cabazitaxel was available, before abiraterone was available, where docetaxel re-treatment or mitoxantrone were the 2 most commonly used treatments for patients with metastatic castration-resistant disease who’ve been through a round of docetaxel chemotherapy.
And in this study, which included around 40 patients, half of them got docetaxel plus custirsen and the other half got mitoxantrone plus this agent.
The result that got the most attention was the pain relief rate, which was 77% in the custirsen plus docetaxel group and 46% in the mitoxantrone plus custirsen group, which is higher than you’d expect, even from chemotherapy in the front-line setting.
The other interesting result from this study was that there is a pharmacodynamic marker of the targeted drug, serum clusterin levels. And those patients in whom serum clusterin levels were lowered with therapy lived quite a bit longer than those patients who did not have a lowering of clusterin. Now, an uncontrolled study. We didn’t have a noncustirsen control arm. So this is a hypothesis-generating finding, but it is interesting to see that a target that you think is important appears to at least correlate with better outcomes.
So, on the basis of this and other data, there are 2 Phase III studies that have been launched: 1 in the front-line chemotherapy setting, where custirsen is being combined with docetaxel in a randomized study with overall survival as the primary endpoint, and a second study in the second-line setting, which started out as a short-lived effort to look at docetaxel re-treatment and, with the approval of cabazitaxel, was redesigned and relaunched as a cabazitaxel plus or minus custirsen Phase III trial, which literally was just activated. It’s open at 2 sites and is being activated as we speak at a variety of sites.
DR LOVE: So Oliver, any thoughts, excited, bored, in between?
DR SARTOR: Interested. We have a whole new class of action for this particular novel agent. I think there’s been some nice work in making the target appear attractive. It’s an agent that I think deserves to be explored in Phase III, and I’ll eagerly await the results.
DR LOVE: I’m trying to think of any other agent with a similar mechanism of action. Is there one?
DR SARTOR: Well, there have been some trials in the past for antisense, which have not succeeded. It turns out this particular way of synthesizing the antisense, I think, is a good one. And there is clinical data involved in the neoadjuvant studies that demonstrate you actually could hit the target and downregulate the clusterin. So I think there’s good science behind this. But just because it’s good science doesn’t mean it’s good medicine, and so we’ve just got to wait and see.
DR BEER: Yes. I mean, I think of it as a high-risk/high-reward situation. So it’s a very interesting target that, in preclinical systems, looks to be compelling. It’s a unique target. It’s important in many tumor types. It’s a unique drug. So if the trials are positive, this could potentially be important across many tumor types. The high-risk part comes from the fact that this is not the androgen receptor. If you develop a new drug for the androgen receptor, you have 60 years of data that it’s a solid target and many drugs that have already been developed for that target. This is a brand-new target. And it’s a completely new technology. If this were a monoclonal antibody, we’ve got a dozen drugs on the market that are monoclonal antibodies. If it was a small molecule, we’ve got 50 drugs that are small molecules. This would be the first ASO. So there’s a new type of drug and a new target, which make it, I think, very exciting, but certainly we need to see the data. It’s hard to make a bet one way or another on this one.
DR PETRYLAK: I think the key to this study is the clinical trial that Oliver mentioned, which is, in fact, that they saw downregulation of clusterin in radical prostatectomy specimens. I think if it wasn’t for that trial, I would be extremely skeptical. Remember, there was an antisense compound to Bcl-2 a number of years ago that never demonstrated a tissue correlate that showed downregulation. So I think the keys are downregulation and the different antisense preparation that’s been used here. Antisenses have never worked in any solid tumor type before. Now I think we’re seeing, with the modification, this has a good chance to work.
DR BEER: And I want to say one more thing. When I say “high risk/high reward,” I don’t mean for the patient. I think we’ve got good safety data with this drug. I’m thinking more about the field.
DR LOVE: High risk that it may not work.
DR BEER: This is not a drug that today I can say I think there’s an 80% chance these studies will be successful, whereas I think I could have said that, frankly, for abiraterone and enzalutamide. But if they are successful, I think the applications are potentially much broader than androgen agents, and it could really have a substantial contribution to the management of cancer overall.