Why we add an AART drug to ADT?

[MateoBeach]

In response to a post asking if adding enzalutamide to ADT is beneficial:

Xtandi would increase T levels if not simultaneously using an LHRH ADT. It blocks AR in hypothalamus leading to perception of deficit and increased LH and testicular testosterone. So enzalutamide or apalutamide used without ADT will increase circulating T while simultaneously blocking it at the AR receptors. This may not apply to darolutamide which does not cross into the brain to reach the hypothalamus.

Bicalutamide as well as enzalutamide can control the cancer for some time (even years) without ADT for many. It did for me for 4+ years. However, one of the mechanisms of resistance is antagonist-to-agonist switching and it feeds the cancer and must be discontinued. This comes from point mutations in AR genes.

Other mechanisms for the eventual development of resistance to ARSI/AART drugs include AR amplification, AR clonal expansion, AR splice variants, and AR bypass to using glucocorticoid receptor GR to stimulate growth. Also increase rate of NEPC progression. So eventually they stop working, resistant to continued use.

On the plus side: AARTs block the ARs, prevent their nuclear translocation, enhances T-cell immune mediated killing (CT2), down regulate NAIP apoptosis inhibitor and blocks AR mediated transcription. Because they effectively slow PC replication, this then slows the rate of mutations accumulation and slows progression to castrate resistance. Even though this will eventually fail if continued without interruption for long enough. (Why some of us are betting on BAT.)

The ARAMIS trial in nmCRPC showed increased metastasis free survival of 40.4 vs 18.4 months. And PSA progression (resistance) was 33 months vs 7.3 months.

Darolutamide appears to be the best of the AART in that: It is not as susceptible to the Point mutations causing antagonist-to-agonist switching as enzalutamide or apalutamide, is the most potent AR inhibitor and shows increased anti-tumor activity. Also does not cross the blood-brain barrier so has better side effect profile.

So in answer to your original question: if you are going to be on continuous ADT, then it appears to be of benefit to be also on an AART drug, or abiraterone.

I will also post this summary for my friends on FPC. Paul/MB

[FlyJ]

Great summary, thank you!

[swwags]

ARSI = androgen receptor signaling inhibitor. What is AART? Sorry trying to wrap my head around this summary as it is tough to navigate (for me).

[MateoBeach in reply to swwags]

yes the terminology is confusing and abreviations make it worse! AART is used in some papers for Advanced Androgen Receptor Targeting drugs. Basically the same group but leaves out abiraterone as that blocks androgen synthesis rather that the AR as the others do.

[Scout4answers in reply to MateoBeach]

What are your thoughts on using just an AART drug alone, such as Daraludimide without Lupron?

[MateoBeach in reply to Scout4answers]

Many, including myself, used bicalutamide without Lupron (+/- dutasteride) as an alternative to ADT while still HSPC. Worked for me for nearly 5 years before antagonist to agonist mutation ended it. Darolutamide monotherapy should theoretically be an even better choice for the reasons discussed in this post. Would still have to deal with some gynecomastia by breast RT or Tamoxifen.

[MateoBeach in reply to swwags]

Different acronyms for basically the same group of drugs, the advanced “-lutamides”, and may include abiraterone even though its mechanism is entirely different. Confusing, so have to look at what is specific for any paper or study.

[Brysonal]

really useful summary. Thank you

[Ramp7]

Saved, Thanks!

[Ramp7]

Thinking about this post. I was on Hormone therapy for three years. I lost my desire to exercise and that contributed to the poor side effects. Exercise can really mitigate some of the negative stuff.