A hypothetical question regarding going castrate resistant.

[SViking]

I was having a debate with a friend who believes that once you go castrate resistant while on Orgovyx, you will never reverse that without second generation meds, or any further treatment like radiation, chemo, or Pluvicto. This is assuming the prostrate had been surgically removed. The basic question is, can you go from castrate sensitive to castrate resistant and then back to castrate sensitive?

[Tall_Allen]

No. There's never been a treatment that reliably does that. Castration-resistance reflects the evolution of the genomics of the androgen receptors. In some men, BAT was able to temporarily reverse PSA increases, but it is unclear if that was a true reversal (reflected on PET scans) or just a PSA phenomenon, and there is no reliable way of pre-determining who will respond and who will get worse.

[exeinoo in reply to Tall_Allen]

Are you referring to TRANSFORMER or RESTORE? Have you heard of STEP-UP?

[Tall_Allen in reply to exeinoo]

The small trial that found PSMA PET scans may be a better indicator of progression than PSA is this one:

jnm.snmjournals.org/content...

Biomarkers are elusive.

Here is a full description of trials published so far:

prostatecancer.news/2016/09...

STEP-UP is an ongoing trial:

clinicaltrials.gov/ct2/show...

[GP24]

Sometimes the number of resistant cells can be reduced, causing ADT and ARSIs to work again. This has been reported for chemo: prostatecancer.news/2022/10... but also for SBRT radiation to mets and lymph node dissections.

[GP24 in reply to GP24]

Let me add the studies I was refering to.

SBRT: ascopubs.org/doi/abs/10.120... "They [the patients] were reverted into an earlier stage of their disease again. "

ePLND: pubmed.ncbi.nlm.nih.gov/276... "Patients with CRPC responded again to ADT after ePLND."

[EdBacon]

Unfortunately not, it's like trying the to put the toothpaste back in the tube. There are things you can do to get a PSA response, but it's temporary and so not going back to castrate sensitive.

When men were first castrated in the 1940s, researchers thought they had found a cure for advanced prostate cancer. We all know what happened after that.

[Ahk1]

I have heard on this site that BAT can make some second generation ADT work again. There are trials for that I think. I might be wrong though.

[EdBacon in reply to Ahk1]

I think in one trial, it extended the effectiveness of Xtandi. I believe it was 5 months, but someone else might know for sure. By the way, it's also been shown that chemotherapy can extend Xtandi for around the same amount of time.

As far as I know, BAT is risky and you can end up speeding the progression.

[Seasid in reply to EdBacon]

I should not experiment with BAT. I have a bone met in my neck just under my skull. Very dangerous.

[Seasid in reply to Seasid]

The best would be to SBRT that met.

[exeinoo in reply to Ahk1]

You aren't wrong. Restore and transformer are completed. Step- up is verifying. Radiographic progression as well as PSA are monitored.

If run first BAT dramatically increases Zytiga and Xtandi effectiveness and duration.

[Tall_Allen in reply to exeinoo]

Xtandi, not Zytiga. But survival is not increased.

[exeinoo in reply to Tall_Allen]

In one arm of the RESTORE clinical trial, men with CRPC who had never received Zytiga or Xtandi were treated with BAT. The PSA response to BAT was low in this group at about 15%. However, some patients in this study went on to receive Xtandi or Zytiga after BAT. In these patients, 95% of the men had more than a 50% decrease in PSA, 85% of the patients had more than a 90% decrease in PSA, and 50% had PSA levels that became undetectable. The duration of response to Xtandi or Zytiga after BAT in this study was over 2 years. As a comparison, in the studies that led to the FDA approval of Xtandi or Zytiga as first‐line therapy for men with castration‐resistant prostate cancer, the PSA response was 78% and 62%, respectively and the duration of PSA response in both studies was 11 months.

[Tall_Allen in reply to exeinoo]

But those medicines increased survival, which is why the FDA approved them, whereas BAT did not.

[Tall_Allen in reply to Tall_Allen]

Also, some men seemed to have an accelerated PSA increase on BAT. Until they come up with an easy test for distinguishing those who benefit from those who progress, many more clinical trials will be needed.

[exeinoo in reply to Tall_Allen]

Many more clinicals are needed. Optimum time frames, dose, cancer state.Some men have increased PSA during Zytiga therapy. Or RT. Or chemo. More trials are needed for all of them and more are being conducted. More trials are needed for BAT too.

[exeinoo in reply to Tall_Allen]

Yes and using BAT prior increased the effectiveness of Zytiga and Xtandi. This needs to be explored and verified.

[SViking]

Thanks guys. What would account for this significant rise and then sudden decline?

graph

[Stevecavill in reply to SViking]

I would say the 2nd last dot is an aberration. The upward trend is pretty clear

[EdBacon]

I don't know if that last data point is significant. I'd wait and look at the next one or two and see if the overall trend continues.

[Cmdrdata]

The subject of castrate resistance was studied by Dr. Karim Fizazi at Gustave Roussy in France. He has many fairly new study/trial reports that indicate the reason why castrate resistant (with regard to PSA continuing to rise despite first & second generation testosterone/androgen receptor suppression. I am just at the resistant point where PSA has been rising from undetectable to 1.1 in the past 1.5 years despite being at castrate level. Fizazi is one of the principal investigator of ODM-208 trial, that attempts to treat CRPC when resistant to abiraterone or enzalutamide occurred. Look up his reports.

[SViking in reply to Cmdrdata]

Thanks. Do you have a link?

[Seasid in reply to Cmdrdata]

What is your ADT now?

[Cmdrdata in reply to Seasid]

Still On 1000mg of Abiraterone and prednisone. Have an appointment with a new Oncologist to discuss options.

[Seasid in reply to Cmdrdata]

Why don't you try Firmagon (Degarelix) injections?

[Cmdrdata in reply to Seasid]

Lupron, degarelix, and the new Orgovyx suppress testosterone production. Since I am already at castrate level and PSA is still rising, that means that taking those medicines will not do anything as I have already become “castrate resistant”. My goal is to help the researcher “find” a drug through trial that will help them find a “cure” for this disease, not just to prolong my life a fraction here nd fraction there.

[Seasid in reply to Cmdrdata]

Sorry, but how that (finding a cure) is related to not using Degarelix? Please explain.

[Cmdrdata]

ascopost.com/videos/2022-as...

And:

grandroundsinurology.com/up...

[Prostateless2020]

Would it not stand to reason that intermittent use of the Orgovyx would prolong the inevitable resistance? I am on Orgovyx and a 39 treatment radiation schedule now with an undetectable PSA. I plan on stopping the Orgovyx after 6 months and keep a close eye on my PSA. Doctors at Mayo strongly advised against the addition of Nubeca to my regimen. Excerpt: "Furthermore, I did recommend patient undergo androgen deprivation therapy with Lupron. Patient clearly prefers Orgovyx; I have no objection. However, I did caution patient using 2nd generation androgen deprivation therapy agents such as abiraterone or darolutamide, as there is propensity for neuroendocrine differentiation after being exposed to such agents. Given his significant low volume metastatic disease, I did recommend against 2nd generation androgen deprivation therapy."

And just to reiterate, I have had zero side effects with the Orgovyx, other than mild hot flush at night in bed. And my PSA dropped from 0.42 to undetectable within 4 weeks. The radiation treatments, however, hit me pretty hard. Within the first week of daily dosing, I experienced nausea, lightheadedness, dizzy and extreme fatigue. I will request a three day a week schedule now.