With all the limits of a retrospective study (otherwise I might almost become depressed...)
A real-world study of 41,379 prostate cancer patients found that GnRH antagonists lead to faster castration resistance than LHRH agonists, with a median time to CRPC of 10.9 vs. 17.3 months (HR 1.40, p=0.02).
Patients with metastatic disease at baseline had a 120% higher risk of early CRPC (HR 2.20).
Interestingly, patients on statins or with diabetes developed CRPC more slowly, suggesting a possible protective effect.
Im thinking exactly the same thing… I initially requested to remain on Firmagon because I’d read it conferred greater overall survival benefit… it seems that isn’t the case now.
I wonder if they separate out Firmagon from Regulolix how they stack up and if Regulolox is skewing those figures against antagonists.
Sorry for being ignorant to these things, but I don’t really understand what that means… is that an inferior way of measuring performance? I would have thought that comparing 40,000 patients over 10 years was a good way of measuring what works. But, I’m probably missing something?
Orgovyx was approved in late 2020. The data was between 1991(!) and 2020 there are probably zero people on Orgovyx.
Maybe antagonists were given preferentially to people with bone Mets to avoid flare. Maybe oncologists were more likely to prescribe antagonists than urologists.
They are certainly used much less than agonists so there is probably some selection bias going on.
When oncology vs urology is the top variable it makes me realize this is a BS study just to fill some conference time.
Or better, find the complete paper! The difference is too big, I think there would be a lot of noise about this if that was the real difference in performance.
in New Zealand we get goserelin as first line ADT which looks good in light of this study. I also started statins and metformin early on even though not a diabetic. Maybe we’re good choices as have just started abiraterone after 3.5 years as psa climbing. I was initially diagnosed advanced stage 4 in June 2021. Maybe some of the older drugs are better? We don’t get access to any of the new ones as not funded.
Sorry for not responding thoroughly earlier, but yesterday was a busy day. I also apologize if what I posted—mainly for the sake of reporting—upset you. As soon as the full data becomes available, I will check how this study was conducted, whether factors like comorbidities, the average age of the two arms, the presence or absence of metastases, etc., were balanced.
To be honest, I previously saw a study comparing GnRH agonists and antagonists, where one had a 1-2% advantage in long-term PSA suppression, which was not considered statistically significant. This is the first time I’ve seen them compared in relation to castration resistance, but looking at the numbers, I can instinctively say that if GnRH agonists truly provided a +70% time to castration resistance benefit, no doctor would prescribe antagonists anymore within a week. So, let’s stay calm and not jump to conclusions.
As already mentioned, this could very well be an article influenced by a pharmaceutical company (mentioned in the original abstract) or simply something thrown into the discussion to fill a gap. But I’ll keep an eye on it!
Antagonists induce abrupt, deep testosterone suppression, creating intense selective pressure on cancer cells to adapt via mechanisms like androgen receptor (AR) amplification, mutations, or alternative signaling pathways (e.g., glucocorticoid receptor activation). Agonists, with slower suppression (including an initial flare), may allow a more gradual adaptation, delaying resistance.
The transient testosterone surge with agonists might induce apoptosis in some androgen-dependent cells, potentially reducing early tumor heterogeneity. Antagonists avoid this flare, possibly preserving aggressive clones that thrive in low-testosterone environments.
However, clinical outcomes vary, and combination therapies (e.g., adding anti-androgens) complicate direct comparisons. Further research is needed to clarify these dynamics.
Thanks for this and the caveats about selection in this retro analysis. As Medline pointed out the androgen flare, and later mini-flares fromLHRH agonists might be significant. It appears to be so when they are used as adjuvant to RT. See:
Androgen Flare after LHRH Initiation Is the Side Effect That Makes Most of the Beneficial Effect When It Coincides with Radiation Therapy for Prostate Cancer
thank you for this. Was anyone else reflective of this finding?:
Patients with metastatic disease at baseline had a 120% higher risk of early CRPC (HR 2.20).
My dad was metastatic at “baseline”—some spread to bone and local lymph nodes… but he also hadn’t gone to the physician to get his PSA checked in a couple years due to COVID. Does this necessarily mean he is more likely to be resistant? I just would like more info about this finding. It worries me.
Hi! This isn’t really a new finding. Metastatic cancer tends to have greater genetic heterogeneity, which naturally increases the risk of progression. However, these numbers shouldn't be interpreted as if they come from an interventional clinical trial—they’re based on retrospective observational data, collected outside a controlled study setting. It’s better to view them as trends rather than precise predictions. (Honestly, I kind of regret having published this from ASCO GU 2025, it generated too much worry)
For example, the reported 10.9-month average time to castration resistance is much shorter than what has been demonstrated in modern clinical trials. In the ARANOTE trial, the combination of darolutamide and androgen deprivation therapy (ADT) significantly delayed progression to castration-resistant prostate cancer (CRPC) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). The median time to CRPC was not reached in the darolutamide plus ADT group after a median follow-up of 25.3 months, indicating a substantial delay in disease progression. In contrast, the placebo plus ADT group had a median time to CRPC of 19.2 months.
So, men under ADT only had anyway a median of 19.2 months to castration resistance, and this trial was controlled.
When researching agonist vs antagonist many years ago, the curves for OS and PFS showed an advantage for antagonists during the first year or so, after which the curves were roughly identical. So I went with degarelix for a couple of years, then switched to Lupron to avoid the injection pain whenever the nurse made a small procedural error.
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SBRT Added to Standard Tx Boosts Outcomes in Oligometastatic PCa - ARTO II~ Improved response & PFS compared to SOC, MedPage Today, 09/27/23
Efficacy and safety of BAT in CRPC following Abi or Enza resistance: A systematic review
