Jiangsu Hengrui Medicine, a Chinese pharmaceutical manufacturer, published impressive results for its new drug Rezvilutamide. They randomized patients with 4 or more bone metastases to Rezvilutamide+ADT or Casodex+ADT. It increased 2-year radiographic progression-free survival by 56% and 2-year overall survival by 42%. It also significantly increased time to castration resistance by 79%.
Like Nubeqa, Rezvilutamide doesn't appreciably penetrate the blood-brain barrier. There weren't any large differences in side effects.
With Zytiga (abiraterone), Xtandi (enzalutamide), and Erleada (apalutamide) and docetaxel already approved for this purpose, I don't know whether Jiangsu Hengrui will be able to make significant inroads into the market, unless they are able to compete on price. It will probably take 1-2 years to get FDA approval.
Thank you so much for posting this exciting news. It appears that the new drug is slightly better than the ones currently available in the US market (e.g. Erleada+ADT). Is the new drug approved by the Chinese health authorities?
Rezvilutamide significantly improved radiographic progression-free survival compared with bicalutamide (median radiographic progression-free survival not reached [95% CI not reached–not reached] vs 25·1 months [95% CI 15·7–not reached]; hazard ratio [HR] 0·44 [95% CI 0·33–0·58]; p<0·0001). At the preplanned interim analysis for overall survival (data cutoff Feb 28, 2022), the median follow-up duration was 29·3 months (IQR 21·0–33·3). Rezvilutamide significantly improved overall survival compared with bicalutamide (HR 0·58 [95% CI 0·44–0·77]; p=0·0001; median overall survival was not reached [95% CI not reached–not reached] vs not reached [36·2–not reached]). The most common grade 3 or worse adverse events of any cause in the safety"; and
You said:
"It increased 2-year radiographic progression-free survival by 56% and 2-year overall survival by 42%. It also significantly increased time to castration resistance by 79%."
Yes, you are missing "compared with bicalutamide." That is NOT a drug used in the US for high-volume metastatic men.
So no, it does NOT appear "slightly better than the ones currently available in the US market." At least not the ones used in the US for high-volume metastatic men.
See my post below. I think this is a crappy, unethical study.
As a new entrant into a high margin market, they will most certainly compete on price.
But no more than necessary to take a proportionate share of the market.
Assuming it has pretty much the same levels of benefits and side effects of competitors, I would expect them to price at about a 1/3 discount to the competition.
Now that medicare can negotiate pricing, if the negotiators are reasonably competent, the price for Medicare beneficiaries should be far greater.
Wait... why are they comparing their drug to an inferior first-gen AA like Casodex, that isn't even used in the US anymore in the setting of metastatic disease? (Except for, you know, fools like myself.) Shouldn't they be comparing their drug to enzalutamide or apalutamide or daralutamide or zytiga, or anything close to our actual standard of care?
Oh, of course... they wanted their drug to really LOOK good, by comparing it to the most inferior competitor. But is it ethical to put high-volume metastatic men in a Casodex + ADT control arm without informing them they are getting a treatment that is inferior to the US standard of care?
Maybe not in hospitals in China, Poland, Czech Republic, and Bulgaria. Still... why would the FDA approve that new AA specifically for metastatic disease simply because it beat out Casodex, of all things? In the US, we would want to know if it could beat out things WE ACTUALLY USE for high-volume metastatic men!
For men in the US, the study shows rezvilutamide plus ADT significantly improved radiographic progression-free survival and overall survival when compared with AN INFERIOR TREATMENT NEVER USED HERE, in patients with high-volume, metastatic, hormone-sensitive prostate cancer.
Two thumbs down. Especially this: "Patients who ... intended to use second-generation androgen-receptor inhibitors, ketoconazole, abiraterone acetate, or other investigational agents that inhibit androgen synthesis were excluded."
Translation: we only want [economically disadvantaged] patients who themselves, or whose docs, do not intend on pursuing more aggressive and effective [and expensive] treatments for their metastatic disease??
This trial was primarily done in China, with some in Poland, Czechia, and Bulgaria, beginning in 2018. Ethics requires they compare it to the standard of care available there and then. That's what they did.
ARCHES, a similar study, done in 2016-2018, compared enzalutamide+ADT to placebo+ADT. The FDA didn't approve Xtandi until 2019. 18% had prior docetaxel.
A similar trial, ENZAMET, comparing enzalutamide+ADT to a first generation antiandrogen (flutamide, bicalutamide or nilutamide)+ADT. ENZAMET provided its first results in 2019. ENZAMET specifically excluded patients who used abiraterone. Up to 2 cycles of docetaxel was allowed.
TITAN, a trial comparing apalutamide+ADT to placebo +ADT, also excluded patients with prior use of abiraterone or second-gen antiandrogens. 11% had prior docetaxel.
Nothing was unethical about this study.
However, with the success of triplet therapy in PEACE1 and ARASENS, the question is whether couplets will continue to be standard of care going forward. That will impact future trial design.
Why would the FDA approve a drug based on studies using inferior (non-USA) standards of care?
If a (no doubt highly expensive) new drug is to be marketed in the USA, presumably to become part of our standard of care, would it not make sense to test the drug in the context of that standard of care rather than some other (lesser) one?
If this trial was conducted in the USA, would you still think it ethical? I think the answer is, it could NOT be conducted in the USA, because it would not be.
The bottom line is, the FDA will be asked to approve a drug for use in the USA that has been shown superior to a therapy that does not exist in the USA. So WHO CARES if this drug is better than one that is never used here?
Will the FDA demand that the drug be shown to be NOT inferior to the actual standards of care that DO exist in the USA for high-volume metastatic?
Something tells me: no.
Note that the first person to reply to this thread was fooled into thinking this drug was shown superior, by the way the study was framed, when for all we know the drug is actually inferior to our current standard of care. Perhaps one goal of the study is to fool MANY men (including prescribing doctors).
They say their "results support the use of rezvilutamide plus ADT as frontline treatment for patients with high-volume, metastatic, hormone-sensitive prostate cancer."
What the results show is that the use of rezvilutamide plus ADT for patients with high-volume, metastatic, hormone-sensitive prostate cancer is better than the use of bicalutamide plus ADT for such patients.
Who in the developed world uses bicalutamide plus ADT for such patients? Nobody, because there are better treatments. So what do the results support? A potentially inferior treatment to existing treatments for patients with high-volume, metastatic, hormone-sensitive prostate cancer. This is good news for who, exactly?
None of the patients who got rezvilutamide in China, Poland, Czech Republic, and Bulgaria would normally get this treatment, because if they would, they would ALREADY be getting the existing 2nd gen hormonals that are cheaper and generic. Assuming approval by the FDA based just on this trial, none of the patients who get rezvilutamide in the more-developed West SHOULD get this treatment, because no trials have been conducted to prove it is non-inferior to the existing 2nd gen hormonals and/or chemo that men currently get for high-volume, metastatic, hormone-sensitive prostate cancer.
"Being approved by the FDA" is different from "being approved by the FDA for high-volume, metastatic, hormone-sensitive prostate cancer." On what basis should the FDA approve this drug for that use? That it works better than the treatment that is never used?
A doctor who prescribed ADT+rezvilutamide as a first approach for high-volume, metastatic, hormone-sensitive prostate cancer (based on an approval via this trial) would be experimenting with his patient.
Do you feel the same way about ARCHES, ENZAMET and TITAN? I guess you wouldn't use Xtandi or Erleada, which were approved based on exactly this kind of trial.
I'm saying I wouldn't enter a trial that gave me a choice between a therapy with unknown effectiveness or a therapy with PROVEN inferiority to existing standards of care in the US. Would you?
If I lived in China and I didn't have access to those other drugs, I imagine it would be because I was poor. Abi is certainly available in China, and its cost has come down considerably.
"Patients who ... intended to use second-generation androgen-receptor inhibitors, ketoconazole, abiraterone acetate, or other investigational agents that inhibit androgen synthesis were excluded."
I read that as, men who could afford a higher standard of care need not apply for an inferior one
In China, "the addition of docetaxel or abiraterone acetate plus prednisone to ADT has been recommended for patients with newly diagnosed mHSPC" according to an article I found. In other words, professionals in China already know that ADT plus Casodex is NOT an appropriate standard of care... unless you are poor.
This clinical trial was obviously run in countries where some men could only afford inferior standards of care, because it could not attract willing participants in richer countries. Where will the new drug be used? In those richer countries,
Exactly. The market is big. In Canada casodex is still used. Here in Sydney my professor Anthony Joshua proposed to put me on casodex after I reach PSA 1. My understanding is that it is still a standard practice in Canada.
I was diagnosed with 15 mets in my spine and one is just under my skull. I had a painful sciatica nerve pain wich disappeared 7 days after starting Degarelix ADT.
It's not that Casodex has no applications. I actually chose it as monotherapy at 150 mg, asymptomatic with Gleason 3+4 and two probable spinal mets. But I KNEW I was choosing something outside SOC that would likely fail, and I would then proceed to ADT and/or 2nd gen drugs and/or chemo.
It seems that "high-volume, metastatic, hormone-sensitive prostate cancer" often gets treated with ADT alone for starters, but there was never really good evidence that adding Casodex at 50 mg did anything more than prevent T flare. That is why it is only used in the US for that.
As for Casodex at 150mg, that was never approved in the US even though it was widely used elsewhere. What is the dosing used in Australia and Canada, and for what patient groups?
Men can use any drug they choose. I'm saying I don't know WHY they (or their docs) would choose this new one rather than the tried-and-true 2nd gens already on market. This study give them no reason to do so.
I chose a drug based on its side effect profile, not based on its higher chance of efficacy. I knew it was statistically inferior. But yes, there is evidence that 150 mg bicalutamide monotherapy can be effective (Tyrell), even if LESS effective. You already know this from prior discussions...
"Casodex' 150 mg was found to be less effective than castration in patients with metastatic disease [but] was associated with a statistically significant improvement in subjective response [with] an advantage in sexual interest and physical capacity, a substantially lower incidence of hot flushes. [It has] a benefit in terms of quality of life and subjective response when compared to castration and has an acceptable tolerability profile. Thus 150 mg monotherapy is an option for patients with M1 prostate cancer for whom castration is not acceptable."
This drug, like Nubeqa, has minimal penetration through the blood brain barrier. There are no clinical trial results for Nubeqa among mHSPC, and it is not approved for that indication. Side effects may preclude one medicine or another in certain patients, so it can't hurt to have options. I hope that if they do get it approved and marketed in the US, it will drive prices down, as competition often does.
You decided to forgo survival to get improved QOL for about 3 years. Not everyone would make that choice.
I didn't actually "forgo survival." I chose the statistically less likely treatment mode to lengthen survival. I switched to ADT when the Casodex failed (I only got six months of PSA decline). If you can tell me that exact amount of time I had my life shortened by way of that delay, then I will tell you if it was worth it.
We only have statistics, which only can tell us what would happen if you are average. If you are similar to the average man, choosing 150mg Casodex/day rather than castration, shortened your expected survival by 30%. You may be an outlier from the population, but that is a bad bet.
Please provide a reference for the 30%. I find it hard to imagine that number holds for men who fail 150mg with different disease states over different time frames. In other words, "the average man" does not really exist, because two groups of ten men whose survival is shortened by about 10% and 50%, respectively, will be claimed to ALL have their lives shortened by 30%.
Statistics do NOT tell us about "the average man." Rather they lump all heterogenous men into an aggregate and render them equal, which they are not. What statistics tell us are probabilities. When "the average man" makes a sports bet, he does not break even... he either wins or loses. The sum of all wins and losses that balances to zero tells us little about how much the "the average man" wagered and lost or wagered and won. If we took that zero-sum at face value, we might assume "the average man" broke even when in fact not a single man broke even!
There were 1,453 men in that trial. Statistics depend on large numbers like that to provide a normal distribution (a bell shaped curve). When sample size is large enough, 95% of the people fall within 2 standard deviations of the mean, and 68% within 1 standard deviation. I hope, for your sake, that you were an outlier. If you distrust statistics, there is no ground on which to base any medical decision- you might as well consult a crystal ball.
I wish everyone would take a course in statistics!
You are referring to a binary outcome - win or lose, heads or tails, pass or fail, etc. The frequency distribution is just a two-bar bar chart. The average would not be meaningful, only the relative height of the 2 bars is meaningful.
Time to death is a continuous variable. The frequency distribution is a normal curve, or in this case, a bar chart with 1,453 bars, which approximates a normal curve.
Here's what Tyrell and Iverson wrote in 2001: "... bicalutamide has been compared with castration in large, controlled, randomised, Phase III trials in M1 patients. A post-hoc analysis of these studies indicated that bicalutamide 150 mg/day monotherapy may be of benefit to M1 patients with a prostate specific antigen (PSA) level ≤400 ng/ml. Patients with a higher disease burden (PSA >400 ng/ml) may decide that quality of life and symptomatic benefits outweigh the slight survival disadvantage seen in clinical trials..."
Why would these researchers characterize a supposed 30% shortening of expected survival as "a slight survival disadvantage ?"
I think what they are referring to in 2001 (before almost all the medicines we now have) is that if your PSA is greater than 400 ng/ml, you were going to die soon anyway.
With a Gleason 3+4 I’ve been using this protocol for 20 yrs blocking T than stopping T with combining adt. Now with Nubeua mono. failing will combine orgovyx (rellugolix)
I might add that I titrated 50 to 150 casodex and Psa got low from time to time took vacations. Less is best for low Gleason I think. Hope I get undetectable with relugolix to get short vacation because T recovers faster
A very interesting contribution to this thread leading me to wonder when I read of men post treatment deciding to take a ADT holiday why they don’t at least take casodex 150 with its lower side effect profile rather than take the holiday. And has their been any trials of casodex plus advanced hormone v ADT plus advanced hormone. QOL is not unimportant of course.
Adding Casodex to a 2nd gen hormonal is like adding a drop of water to a gallon. There are trials of abiraterone or darolutide monotherapies (without ADT).
Many men with recurrences after RP or RT, use Casodex either continuously or intermittently. Alternating with ADT defeats the purpose of iADT, which is to have a vacation from no testosterone.
Sorry, but I don't understand this. Can you better explain why is the use of casodex monotherapy not good if it provides high testosterone levels for men? Maybe i don't understand something correctly?
When men are using casodex mono therapy he enjoys his testosterone levels fully? Only the cancer dont get that testosterone? Am I confused?
You wrote:
"Many men with recurrences after RP or RT, use Casodex either continuously or intermittently. Alternating with ADT defeats the purpose of iADT, which is to have a vacation from no testosterone."
Casodex blocks the testosterone receptors at all sites, not just cancer. So you have all the same symptoms of having no testosterone, but because it's a weak anti-androgen, symptoms are milder.
All of the systemic medicines used for mHSPC (docetaxel, abiraterone, enzalutamide, and apalutamide) were tested along with ADT compared to either ADT alone in the control group or ADT+1st gen antiandrogen.
While I would love to see every systemic therapy tested against every other systemic therapy, that will not happen (who would pay for that?). STAMPEDE did a subgroup trial where patients were randomized to Zytiga or Xtandi. There was no difference.
If Xtandi permeates the blood brain barrier is that a bad thing.? What does it mean long term? I feel weak much of the time. It's been 7 to 8 years on Xtandi and Lupron, I feel exhausted much of the time.
i believe that it could be good for me as I have a bone met in my neck just under my skull. Again, Nubequa would be probably better for us, but you can't really complain as the results are good.
In my case I could switch to cabasitaxel chemotherapy as it also crossing the blood brain barrier. I am personally afraid of brain mets. It looks that they usually come later in a deases progression.
It depends on the person. My dad was on Xtandi for 3 months and it almost killed him for that reason, he stopped eating, had massive cognitive impairment (even though it worked against his cancer) . He was switched to Zytiga and the next 4 years were fine - just the usual symptoms of ADT. For a small minority of people, Xtandi seems to cause unbearable side effects and must be switched to another drug.
Some say that you should not have previous symptoms of tremor or shakiness (maybe I am wrong) in this people Xtandi is contraindicated. Otherwise you could half the dose of the Xtandi if you experiance side effects according to the Xtandi website.
The soft tissue of the brain is seldom a metastatic site for prostate cancer. Some people are prone to seizures from medications that affect the brain. Fatigue is principally from the lack of testosterone on ADT. Xtandi and Erleada activate GABAA receptors, which adds to the tiredness. Nubeqa, less so. I don't know if this new drug activates GABAA receptors.
I think you meant to write that QOL for 2 years is more important to you than increasing survival by 30%. I'm not arguing - it's a personal decision - but I wanted to clarify the trade-off for others reading your post.
While outcomes are never certain for any treatment I did review a study that outlined anti-androgen monotherapy vs ADT to bring psa in line; the divide of survival was not as substantial at 30% but yes QOL was pretty important in my decision.
Results: At a median follow-up period of approximately 100 weeks for both studies, ‘Casodex’ 150 mg was found to be less effective than castration in patients with metastatic disease (M1) at entry (hazard ratio of 1.30 for time to death) with a difference in median survival of 6 weeks.
You misunderstand. The study only had 100 weeks of follow-up because that's all that was needed. In that 1998 trial (before docetaxel or any advanced hormonals were available), median survival was reached in both groups of metastatic men within the two year study period. The men who used castration lived 30% longer.
So you would not be getting 6 weeks of extra survival with all the medicines available now, you would be getting 30% more.
Tall_Allen - Does Rezvilutamide also feeds the cancer on term use like bicalutamide ? i think i was reading online that bicalutamide can feeds the cancer if use for longer term. Rezvilutamide content mostly compare reason with bicalutamide. I am sorry if I am 100% wrong here.
Question is does Rezvilutamide feeds the cancer if use for longer term
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High Gleason low PSA - quit ADT? 
Changes in conditional net survival and dynamic prognostic factors in patients with newly diagnosed metastatic prostate cancer 
