Enzalutamide Resistance & Treatment-Emergent AR Changes

[pjoshea13]

New Enzalutamide study, below [1]

Of particular interest to those who have been tested for germline (inherent) BRCA2 mutations:

"Progression biopsies revealed increased ... BRCA2 alterations (64.7% at progression versus 38.5% at baseline)."

It should be noted however, that a third of the 65 patients had already received Abiraterone, which would perhaps have affected baseline numbers.

"Genomic analysis of baseline and progression CTC samples demonstrated increased AR splice variants, AR regulated-genes, and neuroendocrine markers at progression."

A negative germline BRCA2 test does not preclude treatment-emergent (somatic) BRCA2 mutations at treatment failure. A PARP inhibitor (Olaparib [Lynparza] or Rucaparib [Rubraca]) might benefit more men than once assumed.

-Patrick

pubmed.ncbi.nlm.nih.gov/338...

Clin Cancer Res

. 2021 Apr 13;clincanres.4616.2020. doi: 10.1158/1078-0432.CCR-20-4616. Online ahead of print.

Phase 2 multicenter study of enzalutamide in metastatic castration resistant prostate cancer to identify mechanisms driving resistance

Rana R McKay 1 , Lucia Kwak 2 , Jett Crowdis 2 , Jamie M Sperger 3 , Shuang G Zhao 4 , Wanling Xie 5 , Lillian Werner 2 , Rosina T Lis 6 , Zhenwei Zhang 2 , Xiao X Wei 7 , Joshua M Lang 8 , Eliezer M Van Allen 6 , Rupal S Bhatt 9 , Evan Y Yu 10 , Peter S Nelson 11 , Glenn J Bubley 12 , Bruce Montgomery 13 , Mary-Ellen Taplin 14

Affiliations collapse

Affiliations

1 Medicine, University of California, San Diego.

2 Dana-Farber Cancer Institute.

3 Department of Medicine, University of Wisconsin–Madison.

4 Department of Human Oncology, University of Wisconsin–Madison.

5 Biostatistics and Computational Biology, Dana-Farber Cancer Institute.

6 Department of Medical Oncology, Dana-Farber Cancer Institute.

7 Medical Oncology, Dana-Farber Cancer Institute.

8 Carbone Cancer Center and Department of Medicine, University of Wisconsin–Madison.

9 Division of Hematology-Oncology, Beth Israel Deaconess Medical Center.

10 Medicine (Oncology), University of Washington and Fred Hutchinson Cancer Research Center.

11 Division of Clinical Research, Fred Hutchinson Cancer Research Center.

12 Division of Hematology and Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School.

13 Medicine, University of Washington.

14 GU Oncology, Dana-Farber Cancer Institute [e-mail].

PMID: 33849963 DOI: 10.1158/1078-0432.CCR-20-4616

Abstract

Purpose: Enzalutamide is a second-generation androgen receptor (AR) inhibitor which has improved overall survival (OS) in metastatic castration resistant prostate cancer (CRPC). However, nearly all patients develop resistance. We designed a phase 2 multicenter study of enzalutamide in metastatic CRPC incorporating tissue and blood biomarkers to dissect mechanisms driving resistance.

Experimental design: Eligible patients with metastatic CRPC underwent a baseline metastasis biopsy and then initiated enzalutamide 160 mg daily. A repeat metastasis biopsy was obtained at radiographic progression from the same site when possible. Blood for circulating tumor cell (CTC) analysis was collected at baseline and progression. The primary objective was to analyze mechanisms of resistance in serial biopsies. Whole exome sequencing was performed on tissue biopsies. CTC samples underwent RNA sequencing.

Results: 65 patients initiated treatment, of whom 22 (33.8%) had received prior abiraterone. Baseline biopsies were enriched for alterations in AR (mutations, amplifications) and tumor suppression genes (PTEN, RB1, and TP53) which were observed in 73.1% and 92.3% of baseline biopsies, respectively. Progression biopsies revealed increased AR amplifications (64.7% at progression versus 53.9% at baseline) and BRCA2 alterations (64.7% at progression versus 38.5% at baseline). Genomic analysis of baseline and progression CTC samples demonstrated increased AR splice variants, AR regulated-genes, and neuroendocrine markers at progression.

Conclusions: Our results demonstrate that a large proportion of enzalutamide-treated patients have baseline and progression alterations in the AR pathway and tumor suppressor genes. We demonstrate an increased number of BRCA2 alterations post-enzalutamide highlighting importance of serial tumor sampling in CRPC.

Copyright ©2021, American Association for Cancer Research.

[kaptank]

I think this has special relevance to the results of the Transformer trial and in particular the use of BAT prior to starting enza. We know that supra T "switches off" the expression of variant ARs (eg ARV7 among others.) But that is only one of a number of ways that T seems to sensitize the cancer to enza.

I am BRCA2 and I have used BAT along with the first generation anti androgen Bicalutamide. I am currently on a trial of abiraterone and niraparib but I do see enza in my future and when it happens it is a no-brainer to do at least 3 months of BAT first and possibly doing BAT part of the time, enza part of the time to extend its useful life.

[kaptank]

I see no reason to take it off the table. BRCA2 means that you would probably want to use a PARP inhibitor first, perhaps in combination with abi or enza.

[kaptank]

I don't doubt it!

However I have 2 problems with the Morgenthaler approach. The first is that 200mg every second week would likely not take you to true supra T levels. It is certainly high T but I think not enough to do all the things supra can do. The second thing is that enza has a half life of about 6 days, with a range of 3-10. You need to take a month off between enza and the next lot of high T to get it out of your system. There is no point to exogenous T when even small amounts of very powerful androgen blocker are present.

[kaptank]

400 would get you there. Not debating just informing discussion. When I did about 6 weeks of continuous supra T (with ADT) I did 200mg about every 4 days. That took me to supra and beyond. This question of running down the anti androgen when cycling needs more discussion. There is no mention I know of in the literature. There may be a simple explanation but I have not seen it.

[MateoBeach in reply to kaptank]

Very interesting. Could stop the enzalutamide two half-lives early and use regulovix to “coast into the next Supra T cycle. Just thinking. I am intrigued by this whole approach. “To Supra and Beyond,” ⚡️🚀

[kaptank]

Very interesting that BRCA2 is popping up in the somatic line after a time. Also interesting that much stronger PARP inhibitors (eg talazoparib and niraparib) are under development and trial.

[Balsam01]

This is very informative. Thank you for posting it!

[HopingForTheBest1]

Being BRCA2+ I benefited from having used Olaparib for 2 years, 1 year and 9 months with undetectable PSA until it started rising back up. Now on to ARV-110 trial, 4 weeks so far.

[MateoBeach]

What would be your “what if” choice if it were today as your 2nd line ADT choice?

[farm15]

Does this mean that if you carry the gene I do to stay away from Enza ?

[pjoshea13 in reply to farm15]

The message is that men who do not have the germline gene variant, might develop it during Enza resistance. And that the PARP inhibitors may be useful for more men than one would expect.

-Patrick

[farm15 in reply to pjoshea13]

Thank you!

[pjoshea13]

Hi Nala,

Well, my thinking, with new treatments that do not cure and where resistance can occur quickly, is that aggressive treatment leads to aggessive variants. So, for men who are gung ho about treatment, I'd say take it slowly. Don't rush into something that will leave you in a far worse state six to twelve months from now. Understand that second line androgen receptor axis drugs are palliative. To be used when needed & not before IMO.

Enza is a great drug, but I would be looking for a partner drug that is not AR-axis based. & perhaps a third too. The intent being to get ten years or more out of the therapy.

Remember when being HIV-positive was a death sentence? Those guys now have a cocktail of drugs that have turned HIV into a manageable condition.

With metastatic PCa, the history has been: first we try this; then we try that; & maybe something else; & then you die. A sequential approach that is largely ineffective for mPCa in men who otherwise would have a decade or two or more remaining.

Best, -Patrick

[farm15]

Thank you!

[MateoBeach]

A quick search shows the half life of apalutamide to be around 2-3 days, and that of darolutamide to be 20-23 hours. So these would be much better choices, from this standpoint, to pair with the 8+ week cycles of SPT in Dr. Mortengaler’s approach for advanced disease T cycling in advanced disease.

[HopingForTheBest1]

Unfortunately, I'm sure it's true for most MOs. They just can't keep up.

[MateoBeach]

Well no sh*t. Enzalutamide resistance arises from enzalutamide treatment. Bummer.