Hi. I'm Tom Beer. I'm professor of medicine at Oregon Health and Science University, Knight Cancer Institute. And I'm very happy to be here with you to offer a few comments about the results presented at this year's virtual ASCO meeting from three large randomized clinical trials, ARAMIS, PROSPER, and SPARTAN, that reported on the results of treatment with highly-active androgen receptor inhibitors enzalutamide, darolutamide, and apalutamide in non-metastatic castration-resistant prostate cancer. We'd previously known that these agents produce a significant improvement in metastasis-free survival.
So as you recall, these are patients who are already being treated with hormonal therapy. They're in a castrate state. They now have a rising PSA. But by conventional imaging, we don't see any metastases.
And so these drugs have been studied in that context to determine if they can delay the development of metastasis, and they can. And at this meeting we heard about the overall survival results from those three trials. And gratifyingly, all three trials reported positive results.
PROSPER, which studied enzalutamide and SPARTAN, which studied apalutamide, had longer follow-up, median follow-up of 47 months for PROSPER and 52 months for SPARTAN. And so they were able to estimate the median difference in overall survival, which came in at about a year or so for the two trials. ARAMIS was a little less mature with regard to survival data. It had a follow-up of 29 months. And so the investigators were able to report the hazard ratio for OS at 0.69 but weren't yet able to estimate the median.
So what we've learned from this are several things. First that early intervention with potent androgen receptor inhibitors, not only delays disease progression, but translates into an overall survival advantage. And that's really good news for patients.
We've also learned that survival advantage appears a little bit longer in absolute terms than what you'd be able to get if you use these drugs in the metastatic CRPC setting. So although, the hazard ratio, the ratio between the risk of death in treated versus placebo patients is pretty similar to what we see in more advanced disease, because these drugs are being deployed earlier, where patients live much longer in absolute terms, we seem to be seeing greater gains in overall survival which is also great news. I would note that the trials-- all three trials are not completely mature for overall survival. And the medians are estimates. And so I'd caution folks not to get overly focused on the median number.
Remember, even in PROSPER and SPARTAN, which have a much longer follow-up, only about a third of patients had actually died. So an actual median has not been reached yet. So these are all estimates likely to change a little bit as more follow-up occurs.
In terms of differences between the study other than follow-up studies, other than follow-up being a little bit shorter for ARAMIS. One of the things that appears to be emerging from these data, and we've heard about this before, is that in the darolutamide study, there does not appear to be much of an increase in fatigue and falls, cognitive impairment, and other similar toxicities. Now it's hard to know for sure what to make of that, when we're comparing across studies. That's not really the way we should be looking at data. And when we're looking at agents that are generally quite well-tolerated across the board and looking at just a subset of side effects, that can be a little bit misleading.
So I would view these data as intriguing and worthy of additional investigation. And point of fact, we have a clinical trial launching as soon as the coronavirus crisis allows that is going to enroll patients to enzalutamide or darolutamide, and carefully assess their physical function and their cognitive function to see if there is actually an advantage to one drug or another there.
I think it's also worth recognizing that there are a couple of caveats about the non-metastatic CRPC population. First of all, we know that if we imaged these folks with more sensitive techniques, such as PSMA PET/ CT, or similar high-sensitivity imaging, we almost always will find some locoregional or metastatic lesions.
So some would say, well, non-metastatic CRPC, does that disease state really exist with better imaging? And my answer to that would be, it really kind of doesn't matter from a patient management perspective. It does matter from a research perspective and helping us figure out how we build on these results. But from a patient management perspective, we should be guided by these data as they were gathered. And patients who are free of metastases by conventional imaging should be treated guided based on the results from these trials.
Another question, caveat that might be worth mentioning is that, although, overall there is a survival advantage, treatment with these agents is associated with some side effects, including an increase in cardiovascular side effects. And so I think we need to be thoughtful about patient selection. We likely should stick with treating people with PSA is going up at a relatively rapid rate, a PSA doubling time of less than 10 months, which is what was studied in these clinical trials. And we should be thoughtful within each individual patient about their personal risk of side effects, as well as the personal potential for benefit from therapy as we recommend or forego this treatment in individual patients.
Finally, I think people might wonder how to choose between these agents. And really at this point, there is not a clear guidance on that question. We have three agents. They're all active. They're all quite well-tolerated.
They're all producing significant metastasis-free and overall survival benefit. And I think clinicians and patients can choose amongst any of these three agents and will make those choices based on local preference, experience, and comfort with each agent. There's really not a right and a wrong answer here.
The issue of sequential use or what you do after one progresses on these agents is obviously of interest, because you need to know what to do next. Unfortunately, with these high-potency androgen signaling inhibitors, the first agent is by far the most impactful. And then there have been studies that have looked at abiraterone, which inhibits the synthesis of androgens, and enzalutamide, the first of the androgen receptor inhibitors.
And we've learned from those studies that the activity of one drug after the other is not nearly as impressive as it is on the first go around, if you will. And in particular, abiraterone after enzalutamide has a response rate of somewhere between 10% and 20%. And the responses tend not to be durable.
Enzalutamide after abi is a little bit better than that, but honestly, not nearly as effective as it performs upfront. These agents are all androgen receptor inhibitors. They all bind in the ligand binding domain. I have not seen any evidence that there's clinically meaningful activity with one agent after the other. There may be some opportunities to take a break from these kinds of therapies and then try them again.
The Hopkins group presented some intriguing results from something they called BAT therapy, which is Bipolar Androgen Therapy, where they're trying high doses of intermittent testosterone injections-- which seems a bit counter-intuitive-- and seeing some meaningful responses in patients to that sort of therapy and also seeing some preliminary evidence of re-sensitizing patients to drugs like enzalutamide with a course of androgen-based intermittent therapy. Now that is not a standard of care and has to be used with caution.
In some patients, antigens can cause a flare of the disease. So I wouldn't recommend that. I'm just citing that as an example of perhaps not immediately but after a period of time and with something in between. These agents might have an opportunity for a second prescription, but we really need to study that question.