is Darolutamide significantly different than Zytiga ?
should I make a switch or maybe do one year of each?
Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer
List of authors.
Matthew R. Smith, M.D., Ph.D., Maha Hussain, M.D., Fred Saad, M.D., Karim Fizazi, M.D., Ph.D., Cora N. Sternberg, M.D., E. David Crawford, M.D., Evgeny Kopyltsov, M.D., Chandler H. Park, M.D., Boris Alekseev, M.D., Álvaro Montesa-Pino, M.D., Dingwei Ye, M.D., Francis Parnis, M.B., B.S., et al., for the ARASENS Trial Investigators*
Abstract
BACKGROUND
Darolutamide is a potent androgen-receptor inhibitor that has been associated with increased overall survival among patients with nonmetastatic, castration-resistant prostate cancer. Whether a combination of darolutamide, androgen-deprivation therapy, and docetaxel would increase survival among patients with metastatic, hormone-sensitive prostate cancer is unknown.
METHODS
In this international, phase 3 trial, we randomly assigned patients with metastatic, hormone-sensitive prostate cancer in a 1:1 ratio to receive darolutamide (at a dose of 600 mg [two 300-mg tablets] twice daily) or matching placebo, both in combination with androgen-deprivation therapy and docetaxel. The primary end point was overall survival.
RESULTS
The primary analysis involved 1306 patients (651 in the darolutamide group and 655 in the placebo group); 86.1% of the patients had disease that was metastatic at the time of the initial diagnosis. At the data cutoff date for the primary analysis (October 25, 2021), the risk of death was significantly lower, by 32.5%, in the darolutamide group than in the placebo group (hazard ratio 0.68; 95% confidence interval, 0.57 to 0.80; P<0.001). Darolutamide was also associated with consistent benefits with respect to the secondary end points and prespecified subgroups. Adverse events were similar in the two groups, and the incidences of the most common adverse events (occurring in ≥10% of the patients) were highest during the overlapping docetaxel treatment period in both groups. The frequency of grade 3 or 4 adverse events was 66.1% in the darolutamide group and 63.5% in the placebo group; neutropenia was the most common grade 3 or 4 adverse event (in 33.7% and 34.2%, respectively).
CONCLUSIONS
In this trial involving patients with metastatic, hormone-sensitive prostate cancer, overall survival was significantly longer with the combination of darolutamide, androgen-deprivation therapy, and docetaxel than with placebo plus androgen-deprivation therapy and docetaxel, and the addition of darolutamide led to improvement in key secondary end points. The frequency of adverse events was similar in the two groups. (Funded by Bayer and Orion Pharma; ARASENS ClinicalTrials.gov number, NCT02799602. opens in new tab.)
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I believe the biological and the mathematical science supports hitting it hard upfront, including the use of chemo like docetaxel.
It was not that long ago that it was accepted practice to slowly escalate through various treatments.
The mathematical theory is that hitting the cancer with an early "shock and awe" campaign decreases the opportunity for the cancer to adapt by developing variants. The trials apparently prove this out.
This situation is not unlike the issue with our covid response. Our initial government response was so weak and unfocused that it gave Covid the opportunity to develop troublesome variants, and to embed itself well enough to become endemic,
Your cancer will eventually adapt. But it will take longer for it do to as it gets fewer times at-bat to try.
But chemo can do nerve damage and have other side effects not to be taken lightly.
Re Chemo This whole exercise is a balancing act between attacking the cancer while doing the least amount of damage to your body and QOL.I have not had a chance to do any research on Chemo but the recent discussion on melatonin and its ability to negate some of the effects of radiation and chemo are interesting.
There is a very recent post that I thought you were participating in. Anyway the message is docetaxel up front with adt is the way to go but if you have been on adt for awhile and did not receive docetaxel then don’t start now as you will get all the toxicity with no killing of the cancer because the long term adt you’ve been on renders the cancer insensitively to the docetaxel.
I do remember that, thanks. It should have been done upfront.The one side effect that Coco tells me I am experiencing from Lupron is a poorer short term memory.
Memory issues are a side effect of zero T. I did estrogen patch ADT and my short-term memory sucked. I'd test it every day and it got worse and worse. When I went off ADT and started doing high testosterone my short-term memory came back also immediately.
Darolutamide is an AR inhibitor. I think it's mainly used for CRPC.
Zytiga can be used for CRPC and also HS. It inhibits CYP17 so reduces T production from adrenals and cancer.
I'm planning on asking my MO next month if I should switch to Darolutamide or add it in with Zytiga on the low T phase of BAT. I'm 99% certain her response will be no.
Also, I asked about docetaxel but my MO was firmly against it for me. She said that there is no need right now but I'd just get side effects (cancer is too small to worry about yet). I think her logic is sound. Don't kill yourself until you need to. Chemo can destroy your gut biome, your immunity, your hair, your libido, your teeth, your energy... Hurts cancer but at what cost?
If you consider chemo or radiation, my research and my MO indicate that short-term fasting should be done. As well as a statin and possibly metformin. And of course, ADT while doing radiation. And Zytiga while doing ADT for either. And a low-dose estrogen patch while doing ADT.
In general, my MO balances more to the side of fewer side effects the better your life. So she doesn't want to hit it hard with multiple drugs. I am undecided. Seems like hitting it hard for a short duration wouldn't be bad.
May I offer this. It's something I have to remind myself of as I sometimes want to do more as my progression is stable I feel I should hit it some more while it is down.
You have probably heard this before. Chemo acts on cells that are replicating.
When you are stable or low PSA etc. there are no or few cells to target. No replicating cells to attack so you just get the SE's of chemo.
Acting on replicating cells is why hair falls out, finger and toe nails degrade as they are visible parts of our body where cell replication takes place rather fast.
I think but of course I could be wrong that in your case you don't have huge metastatic burden therefore chemo isn't necessarily indicated (you said your MO said cancer is too small to worry about yet).
I am extremely thankful chemo was offered to me. I would have been dead about 1 to 1 1/2 years ago without it.
As I recall you never had salvage RT following BCR after your RP? If “scans are clean” including PSMA PET, then that would be your best option by far, with or without your complex cyclic hormonal program. The only last chance for a possible true “cure”. Consult with an RO about this if that is the situation. It is outside the wheelhouse of your MO, perhaps. Your brother in arms, Paul
Thanks Paul! Those are my thoughts too but my MO doesn't agree. I consulted with an RO last year and he was all for radiation. I'm not sure how I would get an unbiased opinion. Guess it's up to me to decide...
Would not take MO opinion over RT when it comes to RT issues sounds like she (MO) is behind the knowledge curve on this. I would not accept that. Go to the best available RT, you don’t need they “best in the country”, just someone very good and conscientious. Please don’t put it off. It is not that hard and the current IMRT targeting is excellent and precise. Get the consult. Get the planning CT and PSMA PET. Then go over the images and the plan for treatment with the RO.Lu-PSMA is not for now. It is for when you PSMA avid Mets outside the pelvis. Let’s hope you never get there, amigo.
The company I had been with for 23 years shut its doors about 2 years prior to my dx. I started a small work from home business (meaning low income lol). Thank god for Obama Care (American Health Care Act).
I turned 65 end of last year so I am now part of the Medicare and supplemental world lol.
OBC helped me out a lot also. Made it possible for me to retire at 53 to spend time with my son. Budgeting and I are good friends... Well, it likes me more than I like it.
Yes, after buying private insurance, 63 and 64 are the only years of your life where you want to get even older! Those were brutal years indeed. Of course, the wrong Rx med could still do serious damage, but I've avoided it so far.
" And a low-dose estrogen patch while doing ADT. " Apparently high dose estrogen patch can accomplish the same as conventional ADT.....PATCH trial? Low dose doesn't inhibit the Lupron T reduction? Did a Doc approve of this use for E patch? I assume to reduce SEs of ADT? Thanks.....currently deciding re radiation + 24 mo. ADT for high risk PCa? Terrified of ADT, not so much radiation.
Low dose while doing Lupron or Orgovyx or other. Exactly, reduce the side effects. My MO and my urologist both support it. My urologist is old school so I had to interrogate him before he admitted that it shouldn't interfere with T (Lol! If anything it would help). My MO was on board right away.
0.3-0.4 mg/day is what I used for my estrogen-ADT back in 2019. My MO was 100% against this... at first. But then she saw my labs. Undetectable PSA and undetectable T for the entire duration (except when I reduced my E patches to 0.2 - I was testing it out). The upside is that after that experience she seems to trust me.
ADT can be horrible. The first time I did it I lost half my muscle mass in 3 weeks and in 5 months I had the body of a prepubescent girl. I found some muscle/bone tweaks and my current ADT is nothing at all like my last one, My MO is onboard since my PSA dropped to zero. She told me to continue what I'm doing and seemed even more convinced in the efficacy than I am.
RSH1 thank you for your posts. I'm not down the path of adaptive BAT but am curious as to how the adjuvant use of the E-patch impacted the side effects of ADT. I'm currently on Lupron and have been since June of 2020. Which side effects did it help diminish please? Libido is not my concern at this point. Hot Flashes are minimal and tolerable. Weight swings are not and it is indeed hard to walk here in the winter. Loss of muscle mass of course is also an issue. Gyms are high risk for me but winter is nearing an end. I have been PSA undetectable (<0.05) since May of 2020. I would appreciate any input you can provide would be appreciated. I Read your book in progress - what is the emoji for over my head? If you have a specific thread addressing how it minimized your ADT SE's, you could just point me to that. If not, I think it's use is worthy of a stand alone post. Thank you
The main mitigation for me was bone loss. Instead of the typical bone loss while on Lupron I gained bone mass when I did estrogen-ADT. A low dose isn't going to cause gain but it should reduce the loss considerably. It is also cardiac protective in the long term.
It reduces hot flashes but you're not affected by them. Supposedly they might prevent depression. No change in libido, and unfortunately, no change in muscle loss. For the muscle I do SARMs. I took a low dose and there was no change in my PSA or T. So I started increasing, and increasing, and increasing. I finally stopped going up when I was taking four times as much as what I intended (I like to test things until they break but I wasn't able to break my therapy - in this instance, great!). I talked to my MO and showed her my labs and now she is all for the SARMs.
Good suggestion. I'll make a post with references.
Next, I plan on testing nandrolone phenylpropionate (NPP) during the low ADT phase of BAT. NPP is an injectable steroid. I never anticipated that I would be messing with steroids at my age. But life took a turn and I have to turn with it. As far as I know, nandrolone is the only FDA-approved anabolic steroid. I'm going to use a low dose and only inject once a month. That should keep the sides away. NPP doesn't have as many side effects as typical anabolic steroids. I've used a moderate dose a few times in the last year but only on high cycles of BAT. My liver enzymes actually got better! (I assume total coincidence - I've never heard anything, ever, about steroids helping the liver).
I showed my labs to my MO and now she's pro-NPP. Awesome lady. She'd rather see hard data in front of her rather than look at studies to determine what is right for a particular person at a particular time. And she is big on QoL. I probably don't need to tell you that QoL seems to be a non-issue for some doctors.
MateoBeach also replied and my response to both of you is - Thanks Mates. I broached this with Kwon today and he just said "no we don't do that here". I will pursue it elsewhere. If I'm going to be on Lupron I need some relief.
I am guessing this is in your book but my ST memory sucks
The main mitigation for me was bone loss. Instead of the typical bone loss while on Lupron I gained bone mass when I did estrogen-ADT. A low dose isn't going to cause gain but it should reduce the loss considerably. It is also cardiac protective in the long term.
It reduces hot flashes but you're not affected by them. Supposedly they might prevent depression. No change in libido, and unfortunately, no change in muscle loss. For the muscle I do SARMs. I took a low dose and there was no change in my PSA or T. So I started increasing, and increasing, and increasing. I finally stopped going up when I was taking four times as much as what I intended (I like to test things until they break but I wasn't able to break my therapy - in this instance, great!). I talked to my MO and showed her my labs and now she is all for the SARMs.
Thinking I should be doing estrogen/SARMs during my current round of ADT/Zytiga before I get into BAT
Then introduce SARMs - 5 mg of Rad-140 and 10 mg of Ostarine. Check it in a couple of weeks. Make sure to cycle them to allow your HDLs to go back to normal (HDL is the only blood metric that I saw change on the SARMs). 8 weeks on/8 weeks off.
If no issue, add a low dose estrogen patch (0.25 mg/day - I like the weekly Climara patch but have used others and they are just as good). Then check it again after a couple of weeks.
Make sure there aren't any problems with the PSA. And then I would do a sensitive estrodiol test (men's test needed - women's is too inaccurate because they have a lot of estrogen). And a total testosterone test and also SHBG and CMP/CBC. SHBG, CMP and total test give you good info and also let you calculate free and bioavailable test instead of paying a company for them. I've checked mine with calculation vs lab tests and the calculations are spot on.
In a few weeks I'm going to test cardarine (myostatin inhibitor and supposedly will help with bone loss and also increases muscle but is completely nonandrogenic). And I'm going to check out nandrolone to see how my PSA reacts. Nandrolone is a weak androgen so I'm going to take bicalutamide with it.
No. If you did go for a blood test, get testosterone tested (total is fine). But I wouldn't wait on that test. You can fill in the blanks later if you need to.
I also have some improvements for radiation/ADT. I ran a few of them by my MO and she said that they are data-backed and in her opinion should improve my results (off the record).
Are you metastatic "M1" or is there only evidence to LNs, N1? Sorry I briefly read your profile but did not see your official stage. TxNxMx. Sorry if I missed it.
Got it. I believe the stage is still determined by Bone/CT Scan but may have changed. I am T3N1M0 so similar to you I believe. In 2019 I was denied the Axumin scan by insurance but consensus of my 3 oncologists was it would not change my treatment so I decided against paying out of pocket for one. I see no need to change between drugs that do the same thing unless one fails. If that's the case then you may very well have bigger issues. At that time chemo may be a consideration. Aren't you still planning radiation as your initial treatment + ADT + Zytiga (abiraterone)? That would be NCCN Guidelines/SOC for you as it was for me though my MO said abiraterone was added to the guidelines after I started it. It came up when I asked him if he was a straight SOC guy or if he offered out of the box options once is awhile. I wasn't sure if you are mentioning this particular trial out of interest for yourself or for general discussion though I suspected the latter.
I was not, and it did not appear on NCCN at the time of my first MO consult for my dx of high risk, regional disease. I did not find this forum until I was doing radiation so I was aware of it but only in a context of available options. I hadn't wrapped my head around my disease at the time. The old if I knew than what I know now in which case I would have inquired but I am not at a Center of Excellance and I doubt I would have found somebody nearby to do it. As we all know there's a lot going on when we get those words, you have cancer. Those that find this forum are both lucky and bombarded by more options. Many that do not apply to their disease. Even after finding the forum it took me months to learn to decipher which applied to me, other than the alternative options of course. And those are still not clear. We have a lot of very intelligent people here with some seemingly very different ideas.
Go get the PSMA PET scan now and quit fooling around with various end stage treatments please Scout. If nothing outside the PLNs then consult a good RO and go for definitive rescue treatment. It is a window of opportunity.
My next stop for Radiation consultation is ViewRay, seems like the most advanced machine. I may have to go out to UCLA to find the best practitioner.I have also been thinking that if I can find some one to treat me with LU-177 that it may be just as effective as conventional radiation with none of the side-effects. I know this may not be ready for prime time in my personal time frame to get radiation ( next 6 months) but it is intriguing.
Would not take MO opinion over RT when it comes to RT issues sounds like she (MO) is behind the knowledge curve on this. I would not accept that. Go to the best available RT, you don’t need they “best in the country”, just someone very good and conscientious. Please don’t put it off. It is not that hard and the current IMRT targeting is excellent and precise. Get the consult. Get the planning CT and PSMA PET. Then go over the images and the plan for treatment with the RO.Lu-PSMA is not for now. It is for when you PSMA avid Mets outside the pelvis. Let’s hope you never get there, amigo.
agree with mateobeach above but maybe brachy boost , and of course whole pelvic...other stuuf will still be there if recurrent! Also, IMHO, there is no "best"...how would anyone know anyway???
I have been told by multiple ROs that I am not a candidate for brachy because of the location of my tumors, I am going to have whole pelvic
I am looking into Viewray radiation because it is real time MRI guided, no need for fiducials as organ movements are tracked in real time, 2mm margins vs. 10mm for IMRT and Proton. It has an auto shut off if the target moves. Side effect profile should be better than IMRT which is also very good. I want to take advantage of every edge I can get. As a former floor trader on the option exchange I know how important getting an edge is, on the ultimate outcome.
I have lived my life looking for an edge when ever there is risk involved. Old habits die hard.
Sounds like you're good to go................... Viewray sounds like a good idea.....I think I recently saw somewhere a recent smaller study of SE statistics for a group of Viewray patients...I think it was favorable, and if that holds for larger group for a longer time, seems would become SOC preference. I have had a great deal of trouble lying for so long , approx 45 minutes, for prostate MRI. I've read radiation session time could also last that long. 5 sessions only is so attractive !! Only 1 hospital in Portland has MRI real-time RT, and it is not Kaiser. Some wealthy family donated the funding to Providence hospital here. I don't know if they are yet using for PCa. As far as I know, even med school here doesn't own one.
Hey scout . I was t-4 no surgery . I did imrt plus double adt . It knocked my aggressive pc into the abyss for six years . I wish you the same . It all takes a toll buddy . My mo told me that imrt would be my nail in the coffin ,for no mo erections ever again . He was wrong ..I’ve was given 36 months at best .And now m sitting on 80 months now w/ no signs of pc . 🙏
Darolutamide (Nubeqa) was used in the ARASENS trial. Abiraterone (Zytiga) was used in the PEACE1 trial. They could probably have demonstrated the same success of triplet therapy using apalutamide (Erleada) or enzalutamide (Xtandi). The point was that a triplet - ADT+chemo+an advanced hormonal provides superior results. There are no data showing that one advanced hormonal works any better than any other.
I Know nothing about it! What I do know is this photo is love extraordinaire! If you two dance like you eat lunch? I’m sure everybody sees the love in the room. Bravo Scout! You’ll figure out treatment. Just keep the love alive ❤️
Dr Luke told us not to stop abiraterone until progression is seen on scan. He added darolutamide to abi which dropped and temporarily halted the PSA rise. Progression was seen to bones so chemo offered.
Our local MO stopped both products for 2 weeks prior to starting Taxotere next week.
I like Nubeqa because of its low side effect profile. I am castrate resistant and metastatic, and the combo of Nubeqa and Orgovyx seems to be working . I recently tried Nubeqa as a monotherapy in my own personal trial, and it only worked for about 3 months before PSA started rising again. I had pretty bad Heart toxicity and cognitive problems a couple years ago when I was on Firmagon and Xtandi. I’m hoping to not repeat all that now that I am on Nubeqa and Orgovyx
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