Two new advanced hormonal agents (apalutamide and enzalutamide) increase survival in metastatic hormone sensitive prostate cancer (mHSPC)

[Tall_Allen]

New indications for 2 previously approved drugs - Erleada and Xtandi. I don't have all the details yet on Xtandi, but it is clearly successful for mHSPC. I'll update after the ASCO meeting. Here's what I know so far:

pcnrv.blogspot.com/2019/05/...

[tallguy2]

This is big news! Thanks for posting these results.

[Longterm101]

Thx for the info

Any thoughts on why one would take Zytiga vs apalutamide?

[Tall_Allen in reply to Longterm101]

Good question. There was no direct comparison, so it's impossible to say. There will be a comparative STAMPEDE trial of Zytiga vs Xtandi - results probably a few years away. Zytiga is cheaper and has a longer track record. I haven't seen the full list of adverse events for Erleada when taken for this indication.

[ellie2211 in reply to Tall_Allen]

Thank you, Are there any updates to this?

[Tall_Allen in reply to ellie2211]

I'd expect approval by the end of the year.

[tkalaf in reply to Longterm101]

Don't know the exact details, but was told by my MO (the one running the clinical-trial I'm in) that each of these approached the disease from a 'different' perspective. He explained how they worked ... but not being in the medical profession most went over my head. ):

I consumed full dosages of both of these medicines (along with other medicines) daily. In addition to this massive pill intake, I was given monthly stomach injections of degarelix (Firmagon). Immediately after this 3 month course of treatment, I had my RP surgery.

Cancer research centers ended up with all the extracted bio-matter from my surgery. This clinical-trial recruited only 22 participants, as the trials' objective was a drug interaction study. Because of the quantity of medicines involved in this trial was significant, I had to take blood tests to check kidney & liver health, get an EKG to check my hearth health, etc.

So after all this, I guess I'm saying that its' not a question of 'which' is better. It's more of a question of what is needed. That is to say ... it may be one or the other is best ... or it could be both combined is best for someone. It's over my head. I was happy though, that I got through this treatment, am doing well, and have helped PCa research along the way.

[Wings-of-Eagles in reply to Longterm101]

I was DX with St 4 with 4+3=7 Gleason scores and 71 PSA in Oct 2012. By Oct 2014 it came down on Lupron, but rose again to 5.5. Put on Zytiga, and it almost immediately brought my PSA down from to undetectable -for the past 54 months. Thats a pretty good reason! I know it does not work for everyone, but I have heard many more success stories with it as opposed to Xtandi,t hough I know like TA says no direct comparison studies either way.

[Tall_Allen in reply to Longterm101]

Here's a new study indirectly comparing apalutamide and enzalutamide for non-mCRPC. They report:

"In summary, we found no significant difference in metastasis-free survival, time to PSA progression, overall survival, or adverse events among patients treated with apalutamide or enzalutamide with ADT for nmCRPC. Therefore, treatment choice will probably depend on physician familiarity, pharmaceutical coverage, and other health economic considerations."

sciencedirect.com/science/a...

[Wings-of-Eagles in reply to Tall_Allen]

Thanks Allen, your the man.!

[TNCanuck]

Thank you, Allen!

[Schwah]

I’m a big proponent of combining drugs that approach PC in different directions. That’s what w learned when we found chemo and adt and Zytega and adt and now these drugs and adt all work better than either alone. And that’s why I used all three. As I understand it Xtandi is similar to the approach of Zytega which is why only 20% of men who fail Zytega have a good response to Xtandi. So seems unlikely that Xtandi and Zytega together would be helpful. But how about Erleada? Does it use a different approach that could indicate combining it with Zytega and adt could be a benefit ?

Schwah

[pjoshea13 in reply to Schwah]

When news came out that those who failed Zytiga were often resistant to Xtandi, & vice versa, experts said that they were not surprised, because the drugs used a similar approach. This was misleading. Zytiga (Abiraterone) is a CYP17A1 inhibitor & targets the conversion of pregnenolone and progesterone to DHEA and androstenedione. Xtandi (Enzalutamide) is an antagonist of the androgen receptor (AR). Very different approaches.

But they are both designed to interfere with the AR axis. In that sense, they are similar in approach to Lupron, DES, Casodex, etc, etc. And to Erleada (Apalutamide), which, like Xtandi, is an antagonist of the AR.

What would be different is a drug that does not target the AR axis, coupled with one that does.

You say "seems unlikely that Xtandi and Zytega together would be helpful". I disagree. While the target remains the AR axis, it makes sense to combine the two - just as doctors combined Lupron (hormone inhibitor) with Casodex (AR antagonist). Zytiga (hormone inhibitor) with Erleada (AR antagonist) makes sense too.

A major problem is cost. Good luck getting approval.

& side effects might be too onerous for some.

-Patrick

[Tall_Allen in reply to pjoshea13]

Zytiga does not target the AR. It prevents the body and the tumor from manufacturing androgens.

[pjoshea13 in reply to Tall_Allen]

I never said that it does.

I wrote that it:

"targets the conversion of pregnenolone and progesterone to DHEA and androstenedione"

& that it was:

"designed to interfere with the AR axis"

The term is not my own. e.g.:

"Despite distinct mechanisms of action, abiraterone and enzalutamide both target AR-axis signaling and share mechanisms associated with treatment resistance; therefore, there is potential for cross resistance." [1]

"agents such as abiraterone or enzalutamide targeting the androgen receptor (AR) axis are highly effective" [2]

"AR axis-targeted therapy such as abiraterone that interferes with androgenic stimulation of prostate cancer growth is considered as an essential standard of care for mCRPC." [3]

-Patrick

[1] academic.oup.com/annonc/art...

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

[3] cancertm.com/article.asp?is...

[Tall_Allen in reply to Schwah]

Erleada, like Xtandi or Casodex, is an anti-androgen - it acts on the androgen receptor (AR). The main advantages are:

• It prevents proliferation of the AR (proliferation of the AR makes it super-sensitive to even the smallest amount of androgen).

•Unlike Casodex, the never becomes "food" for the AR

• It binds 7-10 x more strongly to the AR vs Casodex, and is more specific for the AR (it doesn't compete for receptors for other steroids)

• It does not stimulate the translocation of the AR into the nucleus (where it would bind to DNA and cause cell replication)

• It works at a lower dose than Zytiga (higher therapeutic index)

• It penetrates the blood/brain barrier less than Zytiga (less apt to cause seizures)

Unlike Zytiga, it does not prevent adrenal and intra-tumoral synthesis of androgens.

It is unknown if cross-resistance occurs with Zytiga.

[Hidden]

Thank you for posting Allen. Sounds hopeful. My husband has not had great success with his treatments to date. Nothing has worked more than a year before seeing rise in PSA. He was just taken off of Xtandi after 10 months with increased PSA. He began Erleada April 1.

We shall see. Keep posting !!!!!!

[snoraste]

It'll be interesting in a year or two to see a side by side of this trial vs STAMPEDE and LATITUDE.

[Tall_Allen in reply to snoraste]

I hope STAMPEDE will randomly assign men to apalutamide or Zytiga/Xtandi/Taxotere.

[rust]

Yes, good news. I find it interesting that the study showed that class 3 and 4 events were experienced by 40% of participants at 2 years of study duration but only 8% discontinued because of side effects.

[Tall_Allen in reply to rust]

Adverse events were similar for apalutamide and placebo (I haven't seen the details). That may suggest that the adverse events experienced were due to the cancer, previous treatments or ADT and not the apalutamide.

[henukit]

The more the merrier As always, thank you for posting timely and useful updates.

Since it looks like I'm about to turn castration resistant I should ask if I can get Erleada approved by insurance already. Having mix of HS and CR types makes sense to hit them both.

[Abiathar]

Great job at reviewing the studies.

[Racer26]

Thank for helping to inform us all, this site has been a blessing for me. educating your self is truly a help when you talk to the MO