Results of the EMBARK study was published this week (10/19/23) in NEJM. It compared high risk BCR PCa treated in 3 groups: Lupron ADT alone. Enzalutamide plus ADT. And Enzalutamide monotherapy. 5 year follow up for metastasis free survival. Results below. Interesting that Enza monotherapy (No ADT) was superior to ADT and nearly as good as the combined treatment.
Details are worth looking at in the full text. Castrate resistance was much lower with combination over ADT as was PSA progression and distant metastasis rates. Enza monotherapy has significant fatigue for many, and significant side effect of gynecomastia as expected with this. (Can be managed by breast radiation or tamoxifen). I don't see where they reported castrate resistance in the monotherapy arm??
This pretty much is the end of ADT monotherapy for the SOC in high risk BCR (or beyond). Those who cannot tolerate enza should pursue the darolutamide as the preferred ARSI in my opinion. Paul/MB
Patients with prostate cancer who have high-risk biochemical recurrence have an increased risk of progression. The efficacy and safety of enzalutamide plus an- drogen-deprivation therapy and enzalutamide monotherapy, as compared with androgen-deprivation therapy alone, are unknown.
METHODS
In this phase 3 trial, we enrolled patients with prostate cancer who had high-risk biochemical recurrence with a prostate-specific antigen doubling time of 9 months or less. Patients were randomly assigned, in a 1:1:1 ratio, to receive enzalutamide (160 mg) daily plus leuprolide every 12 weeks (combination group), placebo plus leuprolide (leuprolide-alone group), or enzalutamide monotherapy (monotherapy group). The primary end point was metastasis-free survival, as assessed by blinded independent central review, in the combination group as compared with the leu- prolide-alone group. A key secondary end point was metastasis-free survival in the monotherapy group as compared with the leuprolide-alone group. Other secondary end points were patient-reported outcomes and safety.
RESULTS
A total of 1068 patients underwent randomization: 355 were assigned to the com- bination group, 358 to the leuprolide-alone group, and 355 to the monotherapy group. The patients were followed for a median of 60.7 months. At 5 years, metas- tasis-free survival was 87.3% (95% confidence interval [CI], 83.0 to 90.6) in the combination group, 71.4% (95% CI, 65.7 to 76.3) in the leuprolide-alone group, and 80.0% (95% CI, 75.0 to 84.1) in the monotherapy group. With respect to metas- tasis-free survival, enzalutamide plus leuprolide was superior to leuprolide alone (hazard ratio for metastasis or death, 0.42; 95% CI, 0.30 to 0.61; P<0.001); enzaluta- mide monotherapy was also superior to leuprolide alone (hazard ratio for metastasis or death, 0.63; 95% CI, 0.46 to 0.87; P=0.005). No new safety signals were observed, with no substantial between-group differences in quality-of-life measures.
CONCLUSIONS
In patients with prostate cancer with high-risk biochemical recurrence, enzalu- tamide plus leuprolide was superior to leuprolide alone with respect to metastasis- free survival; enzalutamide monotherapy was also superior to leuprolide alone. The safety profile of enzalutamide was consistent with that shown in previous clinical studies, with no apparent detrimental effect on quality of life. (Funded by Pfizer and Astellas Pharma; EMBARK ClinicalTrials.gov number, NCT02319837.)
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MateoBeach
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I put out a post a while back on how the medical community is failing us.. From 2015-2021, it was 32% of MO's were using doublet therapy, and only 12% of Urologists...The PCF, AUA, and other organizations should be all over this issue...How do we get to a greater than 50% survival rate for 5 years in advanced prostate cancer??
My opinion for many of society's ills is education. If the old school doctors were forced to not only register for continuing education but be tested on their knowledge this problem should become less severe.
The latest therapies are a moving target so continuing education is paramount.
Agree. And urologists should be referring all patients with Pca to oncologists who specialize in Pca before treatment. Seems so many men just continue with urologists and don't see an oncologist.
Most medical specialty boards now require taking a comprehensive (hard!) recertification test periodically, typically every 7 to 10 years to maintain "Board Certification". However many practice institutions do not require this, so it just gets dropped. We can always ask our doctors "When was the last time you tested and were re-certified in your specialty board?"
Urologists do a lot of things, and may not have the bandwidth to keep up with the fast moving field of PCa treatments.For any other type of cancer, full-time board certified oncologists advise on treatments. Men may get a urologist.
Urologists have no excuse... I am on my walk, but I belive Stampede results came out in 2017, which showed the superiority of abiraterone plus ADT to ADT alone...I did a post on the medical community failing us and an update is due... along with vaccine updates review...
Tolerate it... we should never tolerate it... The Dog of Terror and I ALWAYS tell newbies, "Get thee to a Center of Excellence !!!" ... stay with your local urologist and you may have signed your own death warrant...
The observation that enzalutamide (ENZA) monotherapy might lead to more severe fatigue compared to enzalutamide combined with androgen deprivation therapy (ADT) can seem counterintuitive but is supported by emerging clinical evidence. Several possible explanations have been proposed:
1. Testosterone Levels and Androgen Receptor Activity
ENZA Monotherapy: Enzalutamide alone blocks androgen receptor (AR) signaling but does not suppress testosterone production. Elevated testosterone levels can lead to partial stimulation of the AR, causing a "compensatory" AR hyperactivation, which might contribute to fatigue.
ENZA + ADT: When combined with ADT, testosterone levels are suppressed, potentially leading to a more complete AR blockade, reducing AR activity and potentially mitigating fatigue.
2. Hormonal Imbalance
In ENZA monotherapy, higher testosterone levels could disrupt hormonal homeostasis and cause systemic symptoms like fatigue.
ADT suppresses testosterone more effectively, which might create a more stable hormonal environment when combined with ENZA, reducing symptoms of fatigue.
3. Differential Metabolic Effects
Testosterone plays a role in maintaining energy levels, muscle strength, and metabolism. ENZA monotherapy with elevated testosterone might disrupt these pathways more acutely, leading to higher fatigue.
In ENZA + ADT, the body's adaptation to low testosterone (as induced by ADT) may buffer the metabolic disruptions caused by enzalutamide.
4. Study and Patient-Reported Outcomes
Fatigue is often self-reported and subject to variability. Differences in study populations, timing, or severity of fatigue reporting in ENZA monotherapy and combination trials might contribute to the observed results.
5. Possible Neurostimulatory Effects of Enzalutamide
Enzalutamide has been shown to penetrate the blood-brain barrier and influence the central nervous system (CNS), potentially affecting energy levels and causing fatigue. This CNS effect could be amplified when testosterone is still present, as in monotherapy, due to residual androgen activity.
Supporting Evidence
The EMBARK study and similar trials found that combination therapy often results in better symptom control, including fatigue. This suggests that testosterone suppression by ADT might offset some of the side effects associated with enzalutamide monotherapy.
If you'd like a deeper dive into specific data or studies, let me know!
Yes Patrick. If they had an undetectable PSA at week 36 then they could go onto suspended treatment ("vacation"). 91% in the ADT + Enza group suspended for a mean of 20.2 months and were "on" the treatment or 32.4 mo. 44% did not receive Tx for 24 months.
For ADT mono only 68% qualified for suspension which averaged 16.8 months (On treatment 35.4 mo. 32% did not receive Tx for 24 months.
Eza mono was again intermediate: 86% qualified for treatment suspension which averaged 11.1 months. 20.4% did not receive treatment for 24 months. So they had the longest time-on-treatment of 45.9 mo average.
But the other question is how did these hormonal treatments affect emergence of castrate resistance? They formally report this as 3.9% (14/355) for ADT+ E vs 34% for ADT mono. (!) They cannot report it for Enza mono as they could always add Lupron, and these had supra-physiologic Testosterone levels, so do not meet criteria for CR. It is an additional unmeasured possible advantage of ARSI monotherapy as it could be followed with ADT when monotherapy fails.
Another measure is PSA progression which is available for all groups as a proxy for regimen failure: This is 2.3% (8/355) for ADT+E combo; 26% (93/358) for ADT mono; and 10% (37/355) for Enzalutamide monotherapy.
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