Dual ARi in mCRPCa - Antonarakis = 'Combo of 2 AR-directed agents should not be utilized in clinical practice at this time', MedPage 7/20/23

[cujoe]

Posted without comment for the SOC crowd.

Emmanuel Antonarakis, MD, on Dual Androgen Receptor Inhibition in Metastatic Castration-Resistant Prostate Cancer– 'Combination of two androgen-directed agents should not be utilized in clinical practice at this time', MedPage Today, ASCO > Prostate Cancer, by Jeff Minerd , Contributing Writer, July 20, 2023.

A phase III trial found no survival benefit for the combination of enzalutamide and abiraterone in men with metastatic castration-resistant prostate cancer, but it did find something else noteworthy.

A pharmacokinetic analysis found that the clearance rate of abiraterone was two to three times higher when administered with enzalutamide, Michael Morris, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues reported in the Journal of Clinical Oncology.

They said that although that pharmacokinetic effect might have blunted the clinical impact of the combination on survival, it did not prevent the combination from having more side effects than use of enzalutamide alone.

The two drugs use different mechanisms to target androgen receptor signaling, and the researchers had hoped the combination would overcome drug resistance. Abiraterone targets extra-gonadal androgen synthesis, while enzalutamide directly targets the androgen receptor.

In the following interview, co-author Emmanuel Antonarakis, MD, endowed professor and associate director of Translational Research at the Masonic Cancer Center of the University of Minnesota in Minneapolis, elaborated on the findings.

What possible mechanism or mechanisms might underlie the increased clearance rate of abiraterone when given with enzalutamide?

Antonarakis: Although the exact mechanism is incompletely understood, it is known that enzalutamide is a strong inducer of the CYP3A4 enzyme that can affect the circulating concentrations of other drugs that are metabolized by it. Since abiraterone is a substrate of CYP3A4, induction of this enzyme by enzalutamide leads to more rapid breakdown of abiraterone in this context.

Might a different combination of drugs that target androgen receptor signaling work better?

Antonarakis: I don't think so. I believe the main lesson from this study is that dual androgen receptor inhibition is not superior to monotherapy. In my opinion, it is unlikely that the drug-drug interaction was the primary reason that a survival benefit with combination therapy was not observed.

Radiographic progression-free survival was 3 months longer in patients treated with the combination, and the result was statistically significant. What is the clinical significance of this finding?

Antonarakis: Unfortunately, in the absence of a survival benefit, a slight prolongation of radiographic progression-free survival is not clinically meaningful, especially because the enzalutamide-abiraterone combination produced greater toxicity (fatigue, hypertension, liver dysfunction, arrhythmias).

A secondary objective of the trial was to assess the relationship between radiographic progression-free survival and overall survival. Why did you do this and what did the study find?

Antonarakis: This analysis was conducted in order to determine whether radiographic progression-free survival could potentially serve as an intermediate regulatory endpoint for future phase III trials in metastatic castration-resistant prostate cancer. This study, as well as others conducted by the Prostate Cancer Clinical Trials Working Group, have shown strong and consistent associations between progression-free and overall survival in the context of androgen receptor-targeting therapies. Thus, radiographic progression-free survival might be a reasonable primary endpoint in this setting moving forward.

Is there anything else you would like to make sure oncologists understand about this study or this topic?

Antonarakis: This has been the second study of combination androgen receptor-targeting therapy that has failed to show a survival benefit. A prior phase III study of abiraterone plus apalutamide versus abiraterone alone also showed a significant progression-free survival benefit without a corresponding survival benefit.

As a result of these two negative trials, enthusiasm has diminished for conducting additional studies combining androgen synthesis inhibitors with androgen receptor antagonists. The combination of two androgen-directed agents should not be utilized in clinical practice at this time. (emphasis added.)

MedPage article is here (It provides a link to a PDF download of the full paper):

Emmanuel Antonarakis, MD, on Dual Androgen Receptor Inhibition in Metastatic Castration-Resistant Prostate Cancer– 'Combination of two androgen-directed agents should not be utilized in clinical practice at this time', MedPage Today, ASCO > Prostate Cancer, by Jeff Minerd , Contributing Writer, July 20, 2023.

medpagetoday.com/reading-ro...

Seems to be one of those rare occasions when docs are saying less is more!

Stay S&W, Ciao - K9

[MateoBeach]

Importand info K-9. Thanks for posting it. Paul

[cujoe in reply to MateoBeach]

✌️

[Justfor_]

Shall an observation like this make some kitchen sink evangelists reconsider? I highly doubt it.

[KocoPr]

So since darolutamide is metabolized in the liver by CYP3A4 also it is probably not necessary to coadminister with Orgovyx.

Although during BAT cycles during the darolutamide washout cycle wouldn’t it be beneficial to keep T and thus DHT down? Maybe this is where one could use finistrride (DHT inhibitor) during these daro washout cycles since it’s half life is from 5-16 hours.

“Finasteride undergoes extensive metabolism in the liver (hepatic metabolism) via the cytochrome P450 enzyme system, specifically CYP3A4, into two active metabolites with less than 20% of the activity of finasteride. Finasteride has a half-life of elimination from the serum of 5 to 6 hours, ranging from 3 to 16 hours. In elderly patients (greater than 70 years of age), the half-life can be prolonged to 8 hours. In comparison to dutasteride, the half-life of finasteride is markedly shorter. Dutasteride has a half-life of 4 to 5 weeks. “

ncbi.nlm.nih.gov/books/NBK5...

What say you all?

[NPfisherman]

Devil Dog,

Attacking the same point (AR) with various agents is not the answer. Resistance develops.

We need new agents that can attack other weak points, slowing the development of resistance, and enhancing disease suppression. Not more of the same old ..same old ...

My 2 cents fwiw...

DD

[cujoe in reply to NPfisherman]

Dangerous Dave - Fully agree with your 2 cents. This passage from a paper I will post on later today (hopefully) sums it up pretty well:

"Second-generation AR antagonists such as enzalutamide [72] and apalutamide [73] can impair ligand-dependent AR-mediated transcription and helped improve survival of mCRPC patients [74,75]; ultimately, however, patients will progress to lethal disease. Neuroendocrine prostate cancer (NEPC) is mainly characterized by the lack of expression of both AR and AR downstream targets, and by the expression of neuroendocrine differentiation markers. It can develop de novo or, more prevalently, can be induced by AR-mediated therapy as treatment-emergent NEPC (t-NEPC) [76,77]. Molecularly, these types of PCa are marked by TP53 and RB1 loss, and by AURKA and MYCN amplification [78]. The emergence of tumors that lack both AR and neuroendocrine markers, known as double-negative PCa (DNPC) [11], is also related to anti-AR therapies. Regardless of the mechanism by which cells can achieve androgen independence, they represent a therapeutic hurdle that requires alternative strategies to improve patient survival."

The search for those strategies and resulting agents goes in saecula saeculorum. May we all be around to see them reach the clinic.

As we wait. let's do what we can with what we know now to Keep Staying S&W,

Ciao - K9 terror

[Justfor_ in reply to cujoe]

This is what happens when a total AR shut-off is enforced. Drill some tiny holes into the dividing wall, so that a little bit can trickle through to slow down the deadly cells invasion.

[cujoe in reply to Justfor_]

Justfor_ You'd think by now the MO community would have figured that out and modified SOC treatment stategies. BTW, your return to the discourse indicates you are back in "good" health. Welcome back . . . now keep it S&W, Ciao - Kaptin K9

[Justfor_ in reply to cujoe]

Thank you very much cujoe. My long COVID is almost over. Last scene the cardiologist prescribed some Beta blocker to lower my pulse rate as he said: "COVID does this", i.e. Tachycardia. As to my opinion regarding the pace at which the MO community figures things out, I will quote a well-known Greek traditional saying: "Ουδείς μωροτερος των διδασκάλων πλην ιατρών". Freely tanslated as: "No-one more silly than teachers with the exclusion of (medical) doctors".

[cujoe in reply to Justfor_]

Your Greek heritage connects you with one of the past civilizations that was founded on wisdom. I wish I could say that about mine.

BTW, for what it's worth, I've been trying to convince my sister that the tachycardia she has experienced since mid-2020 is likely related to the COVID vaxxs, an asymptomatic infection, or both. She's drinking the mainstream cool-aid and keeps getting boosters, so I've stopped even mentioning it now - even though she continues to have racing heartrate issues. I have a feeling we will eventually come to understand the large degree of disinformation we were fed about COVID. I believe Sweden got it right - protect those at risk (that were 95+% of the deaths) and let the rest of the population get on with their lives.

I hope your long COVID is not much longer than now. Keep it S&W.

Ciao - K9