New paper below. Note that the link is to the full text & some will want to read that.
Resistance to Enzalutamide (Xtandi) and Abiraterone (Zytiga) is often associated with the emergence of, & selection for, the androgen receptor splice variant AR-V7. This is a functional receptor that has no need of an androgen ligand.
"The clinical importance of AR-V7 in the setting of treatment with AR-directed agents was demonstrated in a recent pilot study of patients with mCRPC treated with abiraterone or enzalutamide. In this prospective study, AR-V7 status was determined ... in 62 patients and was associated with clinical outcomes for abiraterone (n=31) or enzalutamide (n=31). In both cohorts, the rate of PSA decline ≥50% (PSA50) was high in the AR-V7 negative patients (52.6% and 68% for enzalutamide and abiraterone, respectively), but no AR-V7-positive patients achieved a PSA50 response."
"Moreover, in both cohorts, the AR-V7-negative group demonstrated a significantly higher disease-free survival and" overall survival.
Galeterone may be the answer. (Although, like the next Microsoft security fix, the next drug is never the complete answer. IMO. "Despite the many advances achieved thus far in the understanding of the biology of mCRPC, it is clear that with more active AR-directed drugs the complexity of the mechanisms of resistance and progression is increasing, and novel approaches are needed to improve patient outcomes.") But it's an important drug.
"In order to evaluate galeterone’s efficacy for AR-V7 positive patients, the first biomarker-driven Phase III randomized trial in mCRPC (Figure 2; ARMOR3-SV, NCT02438007) has been launched and will compare the efficacy of galeterone against enzalutamide in mCRPC patients harboring AR-V7, and hopefully will demonstrate activity in this refractory patient population. Meanwhile, additional Phase II trials are being planned using galeterone in the post-abiraterone and post-enzalutamide populations. Finally, if galeterone is truly capable of targeting and degrading AR-V7 and other splice variants, it remains possible that this agent may theoretically sensitize (or even re-sensitize) CRPC patients to treatment with abiraterone and enzalutamide, although this hypothesis remains to be tested."
Drug Des Devel Ther. 2016 Jul 15;10:2289-97. doi: 10.2147/DDDT.S93941. eCollection 2016.
Galeterone for the treatment of advanced prostate cancer: the evidence to date.
Bastos DA1, Antonarakis ES2.
Author information
Abstract
Major advances have been achieved recently in the treatment of metastatic castration-resistant prostate cancer, resulting in significant improvements in quality of life and survival with the use of several new agents, including the next-generation androgen receptor (AR)-targeted drugs abiraterone and enzalutamide. However, virtually all patients will eventually progress on these therapies and most will ultimately die of treatment-refractory metastatic disease. Recently, several mechanisms of resistance to AR-directed therapies have been uncovered, including the AR splice variant 7 (AR-V7), which is a ligand-independent constitutionally-active form of the AR that has been associated with poor outcomes to abiraterone and enzalutamide. Galeterone, a potent anti-androgen with three modes of action (CYP17 lyase inhibition, AR antagonism, and AR degradation), is a novel agent under clinical development that could potentially target both full-length AR and aberrant AR, including AR-V7. In this manuscript, we will first discuss the biological mechanisms of action of galeterone and then review the safety and efficacy data from Phase I and II clinical studies of galeterone in patients with metastatic castration-resistant prostate cancer. A Phase III study of galeterone (compared against enzalutamide) in AR-V7-positive patients is currently underway, and represents the first pivotal trial using a biomarker-selection design in this disease.
KEYWORDS:
AR splice variants; AR-V7; castration-resistant prostate cancer; galeterone
PMID: 27486306 DOI: 10.2147/DDDT.S93941
[PubMed - in process] Free full text
Written by
pjoshea13
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Patrick, unfortunately this is not the evidence to date. The Armor3-SV phase 3 trial has already been halted do to lack of evidence for the efficacy of galeterone in ARV7 patients compared with enzalutamide. This was a big disappointment.
Tokai Pharmaceuticals Inc. (NASDAQ:TKAI), a biopharmaceutical company focused on developing and commercializing innovative therapies for prostate cancer and other hormonally driven diseases, today announced that it plans to discontinue the ARMOR3-SV clinical trial, the company’s pivotal Phase 3 study comparing galeterone to enzalutamide in treatment-naïve metastatic castration-resistant prostate cancer (mCRPC) patients whose prostate tumors express AR-V7, following the recommendation made yesterday by the trial’s independent Data Monitoring Committee (DMC).
Based on a review of all safety and efficacy data, the DMC determined that the ARMOR3-SV trial will likely not succeed in meeting its primary endpoint of demonstrating an improvement in radiographic progression-free survival (rPFS) for galeterone versus enzalutamide in AR-V7 positive mCRPC.
In making its recommendation, the DMC did not cite any safety concerns with galeterone in the trial.
ARMOR3-SV is the first pivotal clinical trial in mCRPC to prospectively select AR-V7 positive patients, a population with an unmet medical need and aggressive disease course. The company plans to present data from the trial in a scientific forum once fully available and analyzed.
“We are very disappointed by this outcome. An immediate priority is to analyze the unblinded study data in detail as we evaluate potential paths forward for galeterone and our pipeline,” said Jodie Morrison, President and Chief Executive Officer of Tokai. “We are deeply grateful for the support and commitment from the patients participating in the study,
their caregivers, and the study investigators and their staff.”
The company intends to evaluate its ongoing ARMOR2 expansion in mCRPC patients with acquired resistance to enzalutamide, and the planned study in patients who rapidly progress on either enzalutamide or abiraterone acetate.
Tokai plans to allow all patients currently enrolled in the ARMOR2 and ARMOR3-SV trials to continue on therapy following consultation with their physicians and study investigators. The appropriate health authorities and clinical study investigators are being notified that ARMOR3-SV is being discontinued.
Thanks to Len & Paul who were aware that Tokai had pulled the plug on Armor3-SV on the 26th. The paper I posted was new but already out of date.
ARMOR3-SV compared "the efficacy of galeterone against enzalutamide in mCRPC patients harboring AR-V7".
I was a bit puzzled by this. With Xtandi, men with AR-V7 would presumably, ultimately experience treatment failure, attributable to selection for AR-V7. It seems that, quite early in the trial, Galeterone was not going to do better than Xtandi, so the trial was aborted. But does this mean that Galeterone has no benefit? e.g. in those who have failed Xtandi or Zytiga due to AR-V7.
From clinicaltrials.gov for ARMOR3-SV [1]:
Inclusion Criteria:
- Progressive metastatic (M1) disease on androgen deprivation therapy
AR-V7 may exist at any time, from diagnosis onward. At early stages, if present, it is likely to be in an insignificant number of cells. Testing positive for AR-V7 in CTCs says nothing about its relative presence. Having AR-V7 doesn't mean that Xtandi or Zytiga wouldn't work for a while. Depends on how many non-AR-V7 cells are present.
A drug that was good at killing PCa cells containing normal AR (androgen receptor) would give AR-V7 cells a significant survival advantage. But AR-V7 isn't the only AR splice variant, & splice variants aren't the only reason why PCa becomes drug-resistant. No reason to expect Galeterone to be immune to drug resistance.
The ARMOR3-SV trial seems to have been a gamble that, AR-V7 aside, Galeterone was a better drug than Xtandi, or at least equal. Seems that it wasn't.
The stock market has reacted as though the drug is useless. Might that be an over-reaction?
Based on a review of all safety and efficacy data, the Data Monitoring Committee (DMC) determined that the ARMOR3-SV trial will likely not succeed in meeting its primary endpoint of demonstrating an improvement in radiographic progression-free survival (rPFS) for galeterone versus enzalutamide in AR-V7 positive mCRPC. In making its recommendation, the DMC did not cite any safety concerns with galeterone in the trial.
Tokai plans to allow all patients currently enrolled in the ARMOR2 and ARMOR3-SV trials to continue on therapy following consultation with their physicians and study investigators.
"In August 2017, Tokai Pharmaceuticals discontinued the development of galeterone. On December 17 2018, it was announced that Educational & Scientific, LLC (ESL), in conjunction with University of Maryland ventures, would develop the drug." [1]
PMID: 29861848 was a Newcastle University [UK] study, & Daniel T. Dransfield was working for Tokai at the start (presumably well before 2017) - he is with Siamab Therapeutics now.
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Masofaniten +Enzalutamide This could be a game changer...Science is coming to our aid
