Adding Advanced AR drugs to ADT in non-Metastatic CRPCa Extends Overall Survival

[MateoBeach]

Three related studies presented at the May 2020 ASCO showed an overall survival (OS) advantage in non-metastatic castrate-resistant PC by adding:

1) enzalutamide to ADT (vs placebo) in the PROSPER phase III study

meetinglibrary.asco.org/rec...

2) apalutamide to ADT (vs placebo) in SPARTAN Phase III

meetinglibrary.asco.org/rec...

3) darolutamide to ADT (vs placebo) in ARAMIS Phase III

meetinglibrary.asco.org/rec...

These are wonderful and actionable results. But I am left with a few questions (Isn't it always the case?!) We don't know for sure which one to choose since the cohorts were different and may not be comparable. So we can go on which had the greatest effect on OS (perhaps apalutamide?), lower serious SEs (perhaps darolutamide?), or cost and better insurance coverage (perhaps enzalutamide?).

I am unclear on just how non-metastatic CRPCa actually kills? Is it truly non-metastatic or rather micro metastatic (not yet showing up on conventional scans)? So how different is it?

And I am also curious about why DHT (5-a-reductase) inhibition via adding dutasteride or finasteride to anti-androgen regimens seem to be absent. Has this matter been definitively addressed?

[teetertotter]

Excellent questions!

[pjoshea13]

In the CRPC setting, Dutasteride is likely to be beneficial when treatment resistance is due to alternative DHT production.

[1] (2018) Effect of dutasteride on castration-resistant prostate cancer

"The ... study showed that 41% of patients with progressive CRPC showed a decrease in their PSA level, with 17% showing a decrease greater than 50%. The median duration of the PSA response was four months."

"Notably, 8 (47%) of 17 patients exhibiting any response showed an initial increase followed by a decrease in their serum PSA level. The reason for the initial increase in PSA level is unclear. One possibility is that dutasteride required several months to produce its effects, a possibility made more likely by the fact that the drug requires about six months to shrink benign prostate hyperplasia. Another possibility is that dutasteride treatment caused a surge in PSA like that seen in chemotherapy. These results suggest that dutasteride should be continued for at least three months, even when the serum PSA level increases."

[2] (2017) A phase II trial of abiraterone combined with dutasteride for men with metastatic castration-resistant prostate cancer

"Dutasteride was added at the beginning of cycle 3 in order to further suppress residual DHT synthesis. ... Interestingly, the addition of dutasteride resulted in a 2-fold increase in serum abiraterone, which may reflect decreased abiraterone metabolism by 5α-reductases. This would be consistent with recent data indicating that an abiraterone metabolite, Δ4-abiraterone (D4A), is metabolized by 5α-reductases"

Small study: "Our study did not directly compare the efficacy of abiraterone and dutasteride versus abiraterone alone ..."

-Patrick

[1] ncbi.nlm.nih.gov/pmc/articl...

[2] ncbi.nlm.nih.gov/pmc/articl...

[MateoBeach in reply to pjoshea13]

Thank you Patrick. More pieces of the puzzle. Now where to put them?

[j-o-h-n in reply to MateoBeach]

Back in the box..... of course.......

Good Luck, Good Health and Good Humor.

j-o-h-n Monday 06/01/2020 11:01 PM DST