To state the obvious: early use of Zytiga or Xtandi extends survival in APC

[Tall_Allen]

I was chagrinned to read a post here the other day by a patient advocating less use of advanced hormonal therapies. He cited Rahul Aggarwal's study of treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC). Since I know and respect Dr. Aggarwal, I reached out to him and told him what that ill-informed patient was advocating. Here's what he replied:

"Although long term androgen deprivation therapy may be associated with the development of treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC) in a minority of patients, multiple studies have confirmed the long-term benefit of abiraterone and enzalutamide for prostate cancer patients in various disease settings. Use of these agents should not be limited by concern for the subsequent development of t-SCNC.”

• His study does not prove that those meds cause t-SCNC, but only shows an association in heavily pre-treated men with mCRPC. This is an important distinction. (It's like observing that many men with high PSA have prostate cancer (an association) and erroneously concluding that high PSA causes prostate cancer.)

• t-SCNC may simply be part of the natural course of advanced PC, and may occur whatever treatments are used. The hormone therapies may only be selecting for the resistant cancer that survives their use. The resistant cancer may always have been there.

• Zytiga and Xtandi have been proven to add years of life in the mHSPC setting in some men, and months in the mCRPC setting, so avoiding those medicines will reduce expected survival.

• A recent study at Johns Hopkins showed that the t-SCNC subtype is less virulent than de novo SCNC onlinelibrary.wiley.com/doi...

Remember, stuff on this forum (from me or anyone else) is not medical advice. Many patients post research that they do not really understand, and often misinterpret. They may be good topics for discussion with one's oncologist, but they should never be taken as sufficient reason to alter therapies. There is a lot of good information shared here too. I wish that I had more time to critique all the misinformation on this site, but there aren't enough hours in the day - I only manage to read what lands in my inbox and ignore much of the low-level research posted on this site.

[SPEEDYX]

With progress there are always shared risk!!!...We pray for the best outcome.

[StayingOptimistic]

Very good points, TA. Thanks for posting them.

[cesanon]

Tall_Allen

Thanks for doing such a good job of keeping this community so very very very well informed.

Your informational vigilance is likely saving lives, or at least materially improving the quality of life for many people.

Not just on this forum, but beyond and the information you post here and on your blog leaks out and spreads.

Thanks

[Jmr11820]

Thank you sir.

[pleinairpainter]

Much appreciate your vigilance to keep us informed and to correct or amend misleading information.

[treedown]

Thanks !

[Kaliber]

Amen brother. Thanks for all your great work here. 👍👍👍

[fluffyfur]

Thank you so much TA.

[kmack57]

Thanks TA I appreciate your input.

[Doggedness]

Thank you!

[ocman]

Thanks T_A, we always appreciate your input!

[MiRob]

Thank you T. Allen 🙏🏻

[Nicnatno]

TA, I'm on Xtandi now, so I hope to get a lot of years out of it.

Nick

[tallguy2]

Excellent post, thanks for sharing.

While I’m at it I encourage all of us to watch the Phase 2 trial at MD Anderson that involves two immunotherapy drugs. Very promising early results were reported during a webinar earlier this week. I don’t know if they recorded the session. Very technical but I came away feeling that when men fail the second-gen anti-androgens there is going to be a new option besides Jevtana.

[Tall_Allen in reply to tallguy2]

Which 2 immunotherapy drugs?

[tallguy2 in reply to Tall_Allen]

Nivolumab and Ipilimumab. Study is being led by Dr. Padmanee Sharma.

[tallguy2 in reply to tallguy2]

This study is being conducted at many other sites in the USA and world-wide. All I can say is the results presented in preliminary form are quite amazing. Nobel Laureate Jim Allison was on this webinar.

[Tall_Allen in reply to tallguy2]

Great to hear! I know it was reformulated from the first trial because side effects were too harsh, and it had minimal impact. I think they increased the nivo and decreased the ipi - sounds like they got it right this time.

[tallguy2 in reply to Tall_Allen]

I am looking for the recording and coming up blank. I came away with a lot of hope based on this webinar!

[Blueslover in reply to Tall_Allen]

How is effectiveness assessed for this new CT?

I've just had Provenge and have been told there is no way to assess it's effect

[Tall_Allen in reply to Blueslover]

They are looking for regression of tumors and fewer new tumors in those who take it vs those who don't. With immunotherapies, there may or may not be an effect on PSA. Effectiveness is assessed by randomized clinical trials, comparing groups of men who took it vs groups of men who took something else. It may or may not be obvious in any individual. For the individual, it may be impossible to predict what would have happened without the drugs.

[Blueslover in reply to Tall_Allen]

Thanks.

So does Provenge have so little expected effect that MO's know that PSA or scans will not change?

[Tall_Allen in reply to Blueslover]

It has a significant expected effect- those taking it live longer, whether PSA or scans change or not.

[Blueslover in reply to Tall_Allen]

Thank you

[Hidden]

Thanks for the additional information!

[Bodysculpture]

Thank you Allen

You have helped me so much

[Haniff]

As always my heartfelt gratitude for going the distance and updating all of us, thanks TA ❤️

Haniff

[kaptank]

A year ago I confronted an onco I was considering changing to with this proposition to see what he made of it. It was pretty much TA's explanation along with a gentle hint that concluding that SCNC was caused by prior exposure to the new antiandrogens was a classic example of the ancient fallacy of post hoc ergo procter hoc (after the fact therefore because of the fact. He got the job.

[leo2634]

Thank you TA. and Tall guy2 you have filled my day with hope.

[curious-mind1]

I agree totally. My dad was on Zytiga for over five years, continuously, at full dose. Dr. Myers started him on the drug the second scans showed appearance of mets outside of the prostate bed. Last four years he was at a PSA of <0.006, Zytiga cleared all mets on the spinal cord and around the kidneys. Ultimately, he died of a brain anneryism and not his aggressive cancer, which was diagnosed as a Gleason 7 in 2000. These drugs certainly add years of cancer control when used earlier in the course of the disease!

Arthur

[Hidden in reply to curious-mind1]

Did you dad have any radiation or chemo to augment that ADT?

[curious-mind1 in reply to Hidden]

No radiation or chemo. He did take Avodart and Lupron, per Myers' protocol at the time, as well as a low dose Estradiol patch to control side effects from the Lupron. Myers was prepared to augment the ADT with Xofigo or chemo, but Zytiga provided such good disease control, that it didn't become necessary.

My dad did have radiation therapy as his original treatment after diagnosis in 2000, along with a course of Lupron. He then went into a ten year remission from 2001 to 2011, before mets showed up in September 2014.

[depotdoug]

Hope.

[dorke]

Thank you TA for the time and dedication you put for this forum.

In general we were blessed in this forum to host several people like you that the word altruism is not strange for them.

[davebliz]

Thanks TA.

[Cateydid]

I'm so grateful for the shared experiences on this forum, especially those supported by viable data. Thank you all!

[tom67inMA]

My MO was recently commenting that he has a couple other neuroendocrine cases. I mentioned the possible connection to abiraterone, and his reply was along the lines of "oh... wait... I forgot to give them abiraterone!" He has a great sense of humor.

[dress2544]

Thanks T.A. for your valuable post

[Dd7757]

TA...is “ Simply The Best”.

[Jawbreaker]

Thank you for comments , much appreciated

[garyi]

This forum, and TA, never fail to inform and amaze me. Thank you for your caring devotion.

[Schwah]

I am so happy that you do not let the naysayers slow you down. Your work does not go unnoticed!

Schwah

[MateoBeach]

Thank you Tall_Allen. You are a valuable beacon for better treatment choices for all of us struggling with this terrifying disease on this and other sites. Please persist! Namo Namah

[Hidden]

"The hormone therapies may only be selecting for the resistant cancer that survives their use." Isn't this the risk? So if Zytiga early use, selection of resistant cancer cells from beginning?

What do you think about this study:

sci-hub.tw/10.1038/s41467-0...

[Tall_Allen in reply to Hidden]

That's just a pilot trial. When actually tested in full-scale RCTs (STAMPEDE and LATITUDE), CR does not come sooner with early use of Zytiga - in fact, the opposite is true - CR (failure-free survival) comes later when Zytiga is used earlier. The bottom line is patients live longer when Zytiga is used earlier.

[LearnAll in reply to Hidden]

The issue of early and excessive use of ADT and early castration resistance is not dead yet.

In next few years, more and more clarity will be there about this topic because more research will reveal that prolonged, heavyduty ADT in fact leads to treatment resistant mutant cancer cells. At present, we just have to wait and see. No conclusion yet.

[Tall_Allen in reply to LearnAll]

Throw away your crystal ball - it obviously is on the blink. It directly refutes what Aggarwal says - and I trust him a lot more than your intuitions.

[LearnAll in reply to Tall_Allen]

No need to be unnecessarily angry. I am raising a possibility based on some research articles. You do not have to defend SOC so forcefully. Truth will defend itself. In the mean time, I have not/am not asking anyone to change their treatment plan. Just raising a doubt should not invite your rage. Everyone can have an opinion.

[Tall_Allen in reply to LearnAll]

Everyone is entitled to their opinion, but there is only one version of the facts, which you persist in ignoring, sadly. Not angry. Mostly sad that you are in denial and trying to bring others into it.

[LearnAll in reply to Tall_Allen]

When I started the post about possibility of Neuro endocrine differentiation, my aim was to create awareness about NE cell differentiation so members who are on Heavy duty ADT can keep close watch on biomarkers and scan findings to catch NE cells as early as possible.

I never knew that my post will create so much chaos and contraversy. That was unintended consequence.

I myself check LDH, Chromogranin A, Neuron enolase and osteolyic lesions on bones on regular intervals to monitor if any neuroendocrine component is starting.

People on this forum are intelligent and not gullible to change treatment because of opinions expressed by individual members. They will take into consideration all opinions and work with their doctors to get best treatment. That's what I believe.

[Tall_Allen in reply to LearnAll]

Whatever you decide to do for yourself is your business. When you advocate it to others, pretending that facts back up your choices, that is a very destructive thing to do. STAMPEDE and LATITUDE results are not matters of opinion, they are facts. I could understand if you were ignorant of the facts, but I and others have repeatedly pointed them out to you, and yet you persist in presenting "alternative facts" (that's what Kellyanne Conway calls them - I call them out and out lies).

[LearnAll in reply to Tall_Allen]

Stop your bullying language...I am not prescribing anything to anyone...You need to stop fighting and behaving like a bully. I presented the post based on some research articles which raised possibility of neuro-endocrine differentiation. And I am stating again that we do not know for sure if this possibility is true. But one thing is sure that number of neuro-endocrine cases are dramatically going up...You do not have monopoly on opinions. Now stop and mind your own business.

[Tall_Allen in reply to LearnAll]

When you write posts that harm others, it is everyone's business. You heard from the horses mouth that you were misinterpreting his research - what more do you need? I think that everyone on here knows what your "opinions" are worth by now. You are free to express them, and I am free to point out that they are incorrect and misleading.

[LearnAll in reply to Tall_Allen]

Not even one person has been harmed in any manner by my pointing out possibility of NE differentiation with heavy,prolonged ADT, In fact, it helps people as they can now be more vigilant about any change in cancer cells early on and also keep their doctors to watch more closely when patients are well informed about a possible risk.

I will certainly avail my right to express my opinion based on scientific information. My goal is not to win arguments with you...you can consider yourself a winner. Refrain from falsely accusing me that my posts are harming anyone. I do not ask anyone to try any substance or complementary treatments...I only present facts.

I have full confidence in member,s ability to sort out information and opinions and make informed decisions about their care. They are not babies who can get mislead.

[Tall_Allen in reply to LearnAll]

How could you possibly know if any members here refrained from taking life-prolonging medications because of your misleading posts?

You went further than merely posting Aggarwal's study - you titled your post "WHEN CURE BECOMES WORSE THAN DISEASE..." and went on to say "to protect yourself from overzealous, unnecessary, very toxic treatments." You are harming patients. These are not facts- these are misleading statements. If you were merely ignorant - fine- now you know the truth directly from Aggarwal - just delete your thread, so no one else will be harmed.

[ctarleton in reply to LearnAll]

Seems to me that there already are some findings/conclusions that have been verified and published. For example, in the LATITUDE trial, the use of ADT plus early Zytiga/Abiraterone delayed median progression-free survival from 14.8 months to 33.0 months. See Figure 1, Chart B in this report of trial results in the NEJM.

nejm.org/doi/full/10.1056/n...

The treatment effect in the added early abiraterone group was consistent across all the prespecified subgroups, which are typically indicative of "castration resistant" prostate cancer. See the Supplementary Figure S3 on page 8 of the Supplementary Appendix, showing the details of consistently demonstrated benefits across the entire range of the usual clinical measures which are indicative of advancing castration resistant disease, along with their 95% statistical confidence intervals.

nejm.org/doi/suppl/10.1056/...

If and when any delayed or intermittent or otherwise lower than recommended doses or regimens of basic or enhanced combination ADT treatments might be put to ethical, well-designed clinical trials, and they are completed, we can see those trial results when they are published in the peer-reviewed journals and at the major prostate cancer conferences.

My hat is off to all who participate in well-designed clinical trials that may advance our knowledge while protecting the participants. Some tentative hypotheses and ideas are harder to test with scientific rigor than others.

[Hidden]

Another question: in the study LATITUDE you have a great advantage with early use of Zytiga, but they did not put in account the time of the use of Zytiga after ADT failure, did they?

That is: ADT + Zytiga vs ADT and ADT + Zytiga once ADT alone failed.

[ctarleton in reply to Hidden]

Details about the patients and treatments and results in the LATITUDE study are here, including Overall Survival when, by the unanimous recommendation by the independent data and safety monitoring committee, the trial was unblinded and crossover was allowed for patients in the placebo group to receive abiraterone.

nejm.org/doi/full/10.1056/n...