"Enzalutamide is an important drug in the treatment of prostate cancer. Standard dosing often requires dose reduction because of side effects. There is no information on survival outcomes with lower doses. We investigated the impact of starting enzalutamide at ≤ 50% dose on metastatic prostate cancer outcomes including patients' longevity."
"Of 111 patients treated, 32 received a low-dose and 79 the standard-dose."
"Patients on low-dose had a better longevity with significantly longer RMAA, 89.1 years, versus standard-dose RMAA of 83.8 years"
{Note: RMAA (restricted mean survival time) is "an alternative to the hazard ratio for the design and analysis of randomized trials with a time-to-event outcome."}
"In a subgroup analysis by age at start of enzalutamide, <75 versus ≥75 years old, longevity was also better with low-dose in younger patients".
"Conclusion: The longevity advantage and reduced adverse events seen in patients with prostate cancer treated with low-dose enzalutamide warrants further investigation."
3 Centre National Hospitalier Universitaire Hubert K. MAGA, Cotonou, Benin.
4 Département de radiothérapie, Institut Bergonié, Bordeaux, France.
5 Ohio State University Comprehensive Cancer Center, Columbus, OH.
6 Howard University, Washington, DC.
7 Ohio State University Comprehensive Cancer Center, Columbus, OH. Electronic address: claire.verschraegen@osumc.edu.
PMID: 35778336 DOI: 10.1016/j.clgc.2022.05.012
Abstract
Background: Enzalutamide is an important drug in the treatment of prostate cancer. Standard dosing often requires dose reduction because of side effects. There is no information on survival outcomes with lower doses. We investigated the impact of starting enzalutamide at ≤ 50% dose on metastatic prostate cancer outcomes including patients' longevity.
Patients and methods: Records of metastatic prostate cancer patients treated with enzalutamide at one center were retrospectively reviewed. Low-dose enzalutamide (≤80 mg/day) was compared with standard-dose (160 mg/day). The primary objective was to compute the restricted mean survival time (RMST - time scale) and restricted mean attained age (RMAA - age scale) using the Irwin method. Secondary objectives included overall survival (OS), progression-free survival (PFS), and PSA progression per PCWG3 criteria (PSA PFS). We used the logrank test and the ∆ difference between RMSTs for comparison.
Results: Of 111 patients treated, 32 received a low-dose and 79 the standard-dose. Low-dose patients had less prior abiraterone or chemotherapy (28.1% vs. 65.8%, P < .001); more testosterone assessment (65.6% vs. 40.5%, P = .016); poorer ECOG performance status (48.3% score ≥2 vs. 26.6%; P = .040), more comorbidities (75.9% vs. 46.3%; P = .010)) including increased cardiovascular disease (51.7% vs. 21.4%, P = .004). Baseline PSA value and doubling time at start of enzalutamide and distribution of metastases were similar between the groups. OS and PFS did not differ between low-dose and standard-dose. Patients on low-dose had a better longevity with significantly longer RMAA, 89.1 years, versus standard-dose RMAA of 83.8 years (∆ = 5.3 years, P = .003, logrank P = .025). In a subgroup analysis by age at start of enzalutamide, <75 versus ≥75 years old, longevity was also better with low-dose in younger patients (∆ = 2.9 years, P = .034, and older, ∆ = 3.3 years, P = .011).
Conclusion: The longevity advantage and reduced adverse events seen in patients with prostate cancer treated with low-dose enzalutamide warrants further investigation.
Keywords: Aging; Life table methods; Lifespan; MDV 3100; Prostatic neoplasms.
Very interesting, but the math at one point confuses me. The difference in longevity was 8.9 years overall, but dividing into two subgroups gave differences of 2.9 and 3.3 years in the two groups. Is RMAA confusing me?
No, the difference in RMAA was 5.3 years in the entire cohort. So the subgroups still don’t explain it. But less of a difference. But indeed it is not clear why the total would be higher than either. 🤔
Thank you. Well, so my math is bad, but at least the logic part of my brain is semi-functional. No idea where 8.9 came from. I blame Patrick, he is far too smart for the rest of us.
Doses should be individually adjusted to achieve sought results. Try to drive your car at a fixed throttle setup and tell me how far you will go. Medicine is still in the era when horses were used as power drives. Needed more power, a second, third or fourth horse were harnessed together.
Started at full dose, maybe 2-3 months in switched to 1/2 dose, following instructions on the Xtandi website and MO (Adverse events at full dose - swelling lower legs and feet, extreme overall weakness, QOL... )
They always test maximum tolerated doses from Phase 1 trials when it comes to Phase 3, to avoid risk of inadequate dose-response and failure. This means the approved dosing tells us nothing about minimum effective dose.
Great post! Makes one think outside the box.For example regarding initial dose and maintenance dose.
Seems to me I recall taking medication re: antibiotics at a high dose at the beginning and then 50% of the initial dose. Or diabetes drugs and then tapering off in a maintenance dose.
Another thought comes to mind Aspirin. Baby dose for maintenance of anti clotting. Less is more. Could it be possible that 20mg of Enzalutamide be the perfect maintenance dose? After 6 months to a year with undetectable PSA someone might be a good candidate to try the maintenance dose.
Less might be more. Then again the makers of Enzalutamide
Thank you Patrick as ever. I might mention this at my next appointment. I'm 23 months in on Enzalutamide, full dose of 4 tablets. It's working which is great but the key I know is to try and keep it working for as long as is possible. As I had extensive Mets and lymph nodes involvement at diagnosis, my understanding is that BAT itself will be too painful. To stick or twist, it's really difficult.
Xtandi worked well for me, but had to stop due to cognitive and cardio side effects. Nubeqa is starting to fail, so may have to give Xtandi another shot. The trick will be continuing to work when the cognitive problems return. No work , no health insurance..... damned if I do, damned if I dont
My situation may provide a bit of a case study for adjusting Xtandi dosage. Dr Myers, towards the end of his career developed an ‘out of the box’ approach at that time. In Feb 2016, I started Xtandi at full dose. My PSA dropped to undetectable immediately. Monthly PSA tests continued to show undetectable. Dr Myers lowered my dose by 1 pill approximately every 6 months roughly, as long as PSA stayed undetectable. I finally dropped to 3 pills per week and still the PSA stayed undetectable, that is, until 5/31/22, when it popped up to .014.
All along, I had been asking about, what I call treatment pressure level versus time. My hypothesis was that Resistance was a function of Treatment Pressure and Treatment Duration. Perhaps it is ‘the area under the curve’ , if you plot TP vs TD, that determines when the Pca cells mutate to a treatment resistance form.
As soon as the adverse 5/31/22 test occurred, I went back to 4 pills per day. Seems the idea was that the PSA was no longer ‘sensitive’ to such a low level. A new PSA will be done shortly.
I have asked for a CTC ARV7 test as well as a blood draw dna mutation test. Xtandi has a number of mutations that cause resistance, including AR V7 mutation.
So, if the new test shows a higher PSA despite the full dose Xtandi, what is the best next step? Should Zytiga be tried, even though it’s highly cross resistant with Xtandi resistance. Or will this option just continue to apply more of a similar TP for a longer TP, triggering further mutations to AR driven therapies?
Perhaps the next step should be Chemo, either taxotere or jevtana [if it can be obtained]?
Should additional unique supplements be introduced, such as PectaSol-C Modified Citrus Pectin or say, doxycycline therapy.
Resistant populations that emerge during androgen axis targeting therapies are all likely to have cross resistance potentials. Though it is a black box. We see acceleration of sequential AR therapies at the time of failure.So in my view, from the perspective of evolutionary dynamics, it may be better to hit it with an unrelated therapy where their resistance related mutations no longer give an advantage.
So from this perspective alternating with a course of chemotherapy would make some sense before going on to another AR drug. Other options under the same logic are BAT (or modified BAT) and systemic molecular targeting with Lu-PSMA.
Unless you identify specific targetable mutations favoring immunotherapies.
I note Tall Allen has favored alternating AAR drugs with chemo. Could be a reset, Paul
Yes exactly. The trade off are the well known dangers of chemo. I know it’s almost impossible to get insurance approval for. Jevtana before taxotere ; but if can get approval, should one go for the jevtana?
Indeed it is true that “Chemo sucks!” But it is moderately short term and we recover, some faster than others. So the possible benefit of a short course must be weighed in the context of one’s life.I had docetaxel very early and it took me two years to feel 100% normal again. And did not even have the potential benefit of resetting androgen resistance to some degree.
I personally would favor Jevtana, lower risk of severe peripheral neuropathy which is the worst adverse effect, and often permanent. I believe if there is any PN, even to a slight degree, it should not be continued and switch to Jevtana. Similar to being “allergic” to a medicine, they can never go back to it.
I am not above gaming the system in such manner for my benefit. Do you perhaps some mild degree of idiopathic peripheral neuropathy to feet (soles) and hands? If someone can describe the symptoms properly none can refute it.
I started Enzalutamide/Xtandi at 160mg in August 2021. It was very effective knocking down the PSA. (.16). Got my Eligard shot in March, and with it the PSA was still low. I decided on my own to drop to 120mg to see if there was any change- there was not and PSA remained low. I just started 80mg to see what happens. It's only for 90 days until my next ADT shot, PSA check and Dr. visit so it shouldn't get too far out of whack if I need to stay at 120mg. I think I needed a big hammer to start the process, but can reduce it to maintain. We'll see.
Interesting comments from everyone. Most of the advice I have read on HU is to go as aggressive as possible but like everything I'm looking at all the data. I went from 930 (DX May 21) to 1 (currently) and been on 160 MG Enzalutamide. I am doing pretty good on side effects but am going to get Echo-cardiogram next week to check heart. I will definitely discuss this with MO next visit.
Interesting. I have been doing a deep dive for a couple of days. Long convoluted history, but recently we attempted a modified BAT. Problem was that T level was sustained too long, Never truly bi-polar and PSA never hit that drop point which usually hits at about 100 days. Have been very interested in Friedman's work and believe he is on track and his E2 theory fits well with what I've been reading about BAT. More specifically, Friedman differentiates between actions of typical AR (androgen receptors) and those receptor which are on the membrane surface (mAR). The deep dive was into the action of the mAR called ZIP9 which doubles as a zinc transport receptor and an androgen (T) receptor. This is the mAR which signals the coveted apoptosis (cancer cell death) which BAT is supposed to trigger. From what I understand from Friedman's scattered writings, he believes that a lutamide (mostly he speaks of Casodex) will only bind to the traditional internal AR, leaving the mAR to do their apoptosis work. I am not 100% sure this is true since Casodex (on their bicalutamide Wiki page) claims that it does antagonize this ZIP9 mAR. But evidently there are weaker and stronger bonds with ZIP9, Testosterone being a stronger one. (Hope I got that right...) Friedman believes that with Testosterone being administered to hit the mAR and a lutamide (Casodex) to block the internal AR, a double whammy can take out a lot of PCa at the same time. All that to say this. We are now back on ADT and coincidentally are just today starting a quarter dose of Xtandi and will likely jump back on the BAT bandwagon within a few weeks. Cheers to everyone in their battle. We started the recent chapter with a 1300+ PSA, ADT and Xtandi (full dose) took us down to .4 PSA and clear scans. Took an unintended vacation from both and tried BAT. Even with extensive mets earlier BAT wasn't terrible. Just 400 was too high and the bipolar didn't work. Don't be afraid to try it if you can talk your docs into it. The research on mAR does support the idea of protection from T if you can keep it talking to the ZIP9 receptor and not the other ARs.
Actually, the latest studies show that bicalutamide does in fact block zip9. Therefore, I can only recommend the combination of high dose T plus flutamide. If researchers test enzalutamide and determine that it does not block zip9, then I would change my recommendation to high dose T plus enzalutamide. It is important to be aware that zip9 will help PCa grow unless it is exposed to high dose T with the iAR being blocked.
So would you recommend adding the flutamide to the BAT protocol (flutamide concurrent with the ADT with 28 day 400 T shots?)
I know of at least one person who cycles enza in and out to allow T to do its work during its highest phase and reintroduces the blockade later in the cycle. That way the enza doesn't block the mAR during its height and yet does in the waning days.
I am unfamiliar with flutamide so will do some more reading. Thanks for chiming in.
Actually, there is a paper showing that DHT plus enzalutamide works better than enzalutamide itself. See Figure 3B of: biorxiv.org/content/10.1101...
The only way I can explain this finding is if enzalutamide does not block mAR (ZIP9). Since both T and DHT bind with the same strength to mAR, it is not necessary to use DHT. Therefore, in theory, high T (traditional BAT gets T over 3000) plus enzalutamide should be quite effective at killing PCa, more so than high T plus flutamide.
Info about zip9 seems to be newish and poorly understood. I don't believe our onco even knows there are both mAR and iAR and convincing him about a BAT protocol was difficult. He would definitely be more on board with enza and BAT than flutamide and BAT. He even balked at bic since it was older and "weaker." We're all learning together with no time to waste. Cheers!
Ideally, you don't want to use the T plus enza combo in place of just T until the BAT cycles are no longer holding the PSA in check. That could be an indication that there is lots of zip9 present, in which case high T plus enza should be more effective than when there is only a smaller amount of zip9 present.
Very encouraging information regarding half dose enzalutamide being non inferior to full dose. Presume these subjects were likely all CR to ADT alone? The low dose patients had much less prior chemo or abiraterone, so perhaps not as advanced. Though they were less healthy and functioning otherwise. (Perhaps why they were put on the lower dose. Yet still did as well or better.) Thanks for finding and posting this, as always!
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