Optimal chemohormonal sequencing for metastatic castration-resistant prostate cancer MAY be Taxotere->Zytiga->Jevtana->Xtandi

[Tall_Allen]

Alternating chemos and hormonals like this seems to be optimal for metastatic castration-resistant prostate cancer (mCRPC). Other therapies may be able to be piggybacked so they can be tried sooner.

pcnrv.blogspot.com/2019/12/...

[cesces]

Hmmmm but taxotere can have such nasty side effects. That would seem like a reason to start first with something not so harsh.

[Tall_Allen in reply to cesces]

You got that backwards. Did you reead the article?

[cesanon in reply to Tall_Allen]

No but I will.

[Doggedness in reply to Tall_Allen]

I read the article and it was good to read it but the sampling was poor... so I wouldn’t put much credence in the results. Group A and Grouo B didn’t just differ in order of medications but degree of bone mets AND castrate resistance! I am surprised it was even published to be honest... still, I like that they are thinking about the order of medications and hopefully a fairer test will follow

[Tall_Allen in reply to Doggedness]

I agree -that's why I capitalized the word MAY in my title. The Mayo study was sub-par as it stands. Maybe when it gets published it will have propensity score matching. But even if they are just equal in oncological outcomes (as in the STAMPEDE RCT of mHSPC), I think there are good reasons to do docetaxel first.

[Escudilla in reply to cesces]

Taxotere does indeed suck. I'm not looking forward to going back there at some point.

[Escudilla]

Maybe I lucked out. That approach seemed logical to me at the time. Take the hit and go for the biggest cancer kill while I was fresh. I did 6 docetaxel after diagnosis immediately followed by 17 months of enzalutamide. I had a good response from an aggressive PC. What's next is indeed my question. Thanks Allen!

[Escudilla]

Hey TA. Is there any data on taxanes at reduced dose? Is it really necessary to almost kill us, to kill cancer?

[Tall_Allen]

Yes, it's been tried, but it's not as effective. As you see, the toxicity is equal to the toxicity of the advanced hormonals, although different in kind.

[dockam]

Thanks for this research. I'm at the stage where despite ADT (Lupron /Casodex) PSA has reached 9.1 after restarting ADT in 12/2018. I had 15 Taxotere chemo sessions in 2015. MO wants to try either Zytiga or Xtandi. Would it be appropriate to rechallenge the PCa with 6 Taxotere sessions, then do the above sequence

Mahalo

Randy

[Tall_Allen]

You already had a lot of Taxotere infusions. Why not move onto Zytiga? If you have bone mets, maybe Xofigo first?

[dockam in reply to Tall_Allen]

Thanks, that's what I thought. No bone Mets.

[Hidden]

From what I know, if Taxotere (Docetaxel) was used early, most doctors will first rechallenge Taxotere after a second-line such as Zytiga before going to Jevtana (Cabazitaxel). My guess is it's mainly cost.

[Tall_Allen in reply to Hidden]

I think the new cabazitaxel study changed that practice, or should

[Hidden in reply to Tall_Allen]

In the link you posted, I see a comparison between Jevtana and a different second-line hormone treatment. That makes complete sense. If the patient is fit enough, I think chemotherapy is generally the best choice after second-line ADT becomes ineffective, mainly due to cross-resistance between drugs..

However, I don't see Cabazitaxel being shown to be superior in the third position as compared to Docetaxel. We know from the FIRSTANA trial, that they are equally effective in the first-line setting. I see you linked that trial information.

I'll discuss this with my doctor at the next visit since I will most likely be in that situation down the road.

[Tall_Allen in reply to Hidden]

I agree completely. Yes, you are right that they didn't compare a rechallenge with docetaxel to de novo cabazitaxel as the third-line therapy. My feeling is that we know taxanes incur resistance eventually, and if you've had docetaxel once, especially like Dockham who had 15 infusions, there are probably some docetaxel-resistant cells, and since there doesn't seem to be any cross-resistance between docetaxel and cabazitaxel, why not move on to cabazitaxel? One can always try alternating them for as long as they both last.

I've gotta say that it is wonderful to have this "problem." I remember all too well when docetaxel was the only choice. It's so nice to have options, and more coming down the pipeline.

[Hidden in reply to Tall_Allen]

There are some doctors going straight to Cabazitaxel following second line ADT. One thing that concerns me is the accumulative nerve damage and developing neuropathy on the second go-around with Docetaxel. There's less risk of that with Cabazitaxel although it has a bigger myelosuppressive "footprint".

Like you said, we are lucky to even have a second-line chemotherapy available. Less than 10 years ago, all that was available with a survival benefit was ADT and then Docetaxel chemotherapy.

A bit off topic, but there is a trial going on in Australia comparing Cabazitaxel to LU-177 for patients who have been pretreated with Docetaxel and second-line ADT. I'm interested to see what that shows.

[tallguy2]

Thanks for posting this article. It is an excellent summary of where current medicine is and in what order.

I didn't find the side effects of taxotere to be intolerable, but not everyone is in the same shape. I had no nausea and maintained my swimming schedule except for days 2-4 after each treatment. My message to fellow Gleason 8, 9 or 10 men: don't let the word "chemo" scare you. Yes, you will experience fatigue. But the physicians know how to prevent nausea and with the Neulasta device they can keep you out of the hospital by pushing up white blood counts.

I am ready for abiraterone (plus perhaps a trial drug) early in 2020 and have already been pre-approved by my insurance for the next round of chemo per the results Tall_Allen has shared with us. (May have to skip Xtandi given that my father had a seizure on this drug).

Merry Christmas and Happy Holidays to all!

[Hidden in reply to tallguy2]

You said: "My message to fellow Gleason 8, 9 or 10 men: don't let the word "chemo" scare you"

Just want to second that. We need every effective treatment we have. We can't afford to throw out chemotherapy. The side effects are not that bad for most and usually for only 1 out of every 3 weeks. There are also medications to help with side effects.

[cesanon in reply to tallguy2]

"maintained my swimming schedule"

How can you go swimming with a tube taped into one of your major veins?

[tallguy2 in reply to cesanon]

I didn't have a port. My Taxotere chemo was done using an IV in a vein in the top of my hand. It was removed after each infusion. Of course I had to wait a day until the Neulasta device attached to my belly did its thing. Then I removed it and off to the pool I went!

[cesces in reply to tallguy2]

What is a "Neulasta device"?

[tallguy2 in reply to cesces]

Neulasta is an on-body injector that is attached to either your arm or your belly after each chemo round. It is set to inject Neulasta exactly 27 hours after it is taped to your body. Then you remove it. Neulasta helps the body build up white blood cell counts that are otherwise decreased because of chemotherapy. I am convinced that this gadget is worth the approximately $3,000 they charged my insurance company each time. Yes it is expensive but it kept me out of the hospital. Many men who don’t use Neulasta end up getting sick or infections.

Hope this helps!

[kaptank]

Many thanks TA for a timely update on sequencing. That is invaluable info to me.

[cesanon]

Tall_Allen

I read the your article and the the links it provide:

(a) pcnrv.blogspot.com/2019/12/...

(b) suo-abstracts.secure-platfo...

(c) europeanurology.com/article...

(d) thelancet.com/action/showPd...

(e) urotoday.com/conference-hig...

(f) urotoday.com/conference-hig...

1. Some Nice Work,

Thank you very much. It is a tour de force that everyone here should read... 3 times.

2. First Dumb Question.

You mention " researchers at the Mayo Clinic reported on 112 patients with metastatic castration-resistant prostate cancer"

And you refer to biraterone (Zytiga) and enzalutamide (Xtandi) as "second-line hormonal therapies"

So at least that study started with people who were using Lupron and Casodex first. Before escalating to Taxotere/Zytiga/Xtandi.

You are a bit unclear as to whether, in your current opinion, you think that Taxotere should be preceded with Lupron and Casodex.

What do you think for someone who has to make a decision today without waiting for more data? Lupron and Casodex first? Or just skip them? Or take them with Taxotere?

3. Second Dumb Question.

You sort of make light of Taxotere side effects. But a long term implant of a plastic tube into a major vein followed by "permanent nephropathy in both hands and feet" scares the bejeebies out of me.

See for example at least one person's side effects (and others hear have mentioned similar):

healthunlocked.com/advanced....

Am I overestimating the potential severity and permanency of the Taxotere side effects?

Or am I underestimating the potential severity and permanency of the Zytiga/Xtandi side effects?

Does anyone else with first hand experience in these side effects have any input on this question?

[Tall_Allen in reply to cesanon]

1. Thank you.

2. Taxotere or second-line hormonals should always be given along with Lupron (or similar). I was too lazy to type "+ADT" next to every mention of a chemo or second-line hormonal - assume it is there, please. I don't have a strong opinion on Casodex. If there are significant mets at diagnosis, it's probably a good idea to begin with Casodex before Lupron, or, begin with Firmagon and switch to Lupron for convenience.

3. I don't make light of the side effects. I just said they are similar in degree, although different in kind, to second-line hormonals- serious side effects were experienced by 39% in both groups. I also wrote that side effects are less onerous if chemo is used earlier. If you want to be scared off by rare side effects, you can equally well be scared off by the second-line hormonals. 11.3% of the hormonal users died from adverse events related to therapy vs 5.6% of the Jevtana users. Relatively common (>5%) adverse events that occurred more frequently among those taking hormonals were psychiatric disorders, musculoskeletal pain, renal disorder, cardiac disorder, joint pain, spinal cord/nerve-root disorders, hypertension and bone fracture.

Anecdotes are not a good way to predict what your experience will be.

[cesanon in reply to Tall_Allen]

TA

What is the advantage to "begin with Firmagon and switch to Lupron for convenience"? How is that superior to just starting with Lupron?

[Tall_Allen in reply to cesanon]

If there are significant mets at diagnosis, and especially when there is pain, Lupron can make symptoms worse before it makes things better. It's a GnRH agonist, meaning that it causes a surge of testosterone. It is the surge that causes the testicles to shut down any further T production. Firmagon is a GnRH antagonist, which directly shuts off T production. There will be no surge if Lupron immediately follows it.

[Sharksrule]

Yes I echo kaptank sentiments. THANKS SO MUCH! Happy holidays to all my brothers in arms. Battle on!

[Cheerr]

Thank you for the useful information. I know it’s meant for mCRPC. But I’m hoping we can follow the same while currently being mHSPC ?

[Tall_Allen]

Here's info on mHSPC:

pcnrv.blogspot.com/2017/06/...

Zytiga, Erleada, and Docetaxel are currently approved for mHSPC, Xtandi and Jevtana are not. If you progress while taking Zytiga, Erleada or Docetaxel (all with ADT), you are in the mCRPC category.

[Hidden]

As soon as my husband was diagnosed he was started on Zytiga. He was taking the full dose and had horrible side effects. Had echo, CT's. Everything normal. They took him off the Zytiga for three weeks to make sure it was the medication causing all his issues. It was. Two weeks ago, back to the oncologist and it was decided to try the Zytiga at half dose. He has been having no issues at all. My question should he have started on the chemo first and then moved on to other drugs? When the Zytiga stops working then do chemo? His PSA is still going down. Last month it was 0.09. Thanks.

[Tall_Allen]

Great response to the lower dose! The research is equivocal on which is better first, as you can read. "Shoulda" is a losing game - just accept the great results and move forward.

[keepinon]

Great post! It is information like this that keeps me coming back to this forum.

[j-o-h-n in reply to keepinon]

Then I guess my inept attempt at humorous posts don't mean kaka........... geez...thanks..I'm hurt...

Good Luck, Good Health and Good Humor.

j-o-h-n Sunday 12/08/2019 9:34 PM EST

[keepinon in reply to j-o-h-n]

I did not realize how fragile your ego is. Mea Culpà. You are actually a very funny guy and the best reason to come here day after day! You really know how to lighten things up. And I am 77% serious when I say this. 😁😍

[j-o-h-n in reply to keepinon]

Okay thanks but I'm still 23% hurt....BTW please forgive me about this question, but who's this guy Mea Culpa?

Good Luck, Good Health and Good Humor.

j-o-h-n Monday 12/09/2019 4:39 PM EST

[keepinon in reply to j-o-h-n]

Mea Culpa is my go to for an apology, because half the time people have no idea what I am talking about! heh,heh.

[j-o-h-n in reply to keepinon]

Make that 100% of the time............. 👀

And I thought Mea Culpa was a player from Nigeria who plays for the NY Rangers.....

Good Luck, Good Health and Good Humor.

j-o-h-n Monday 12/09/2019 4:59 PM EST

[keepinon in reply to j-o-h-n]

You are thinking of his cousin, Mia Culpa. 😬

[monte1111 in reply to keepinon]

Touche!

[j-o-h-n in reply to monte1111]

You're right.... Mia, Mea's cousin.... Well I guess there ain't no Moa.....

Good Luck, Good Health and Good Humor.

j-o-h-n Monday 12/09/2019 7:18 PM EST

[monte1111 in reply to j-o-h-n]

Sure there is. Moa's sister is Mooa.

[j-o-h-n in reply to monte1111]

You're confused... that's her cow.......

Good Luck, Good Health and Good Humor.

j-o-h-n Monday 12/09/2019 10:35 PM EST

[SeosamhM]

Great post TA. Now for the practical question on when this type of sequencing becomes de rigueur for MOs and the insurance companies that support their suggested treatment regimens. Thoughts from you or the group on this?

[Tall_Allen in reply to SeosamhM]

Well, all of them are already approved for mCRPC. I wouldn't think insurance would be an issue. MOs at the top centers already know all this. Patients may be able to play a role for MOs in community practice depends by making sure they have seen those studies.

[immunity1]

Always good to think through the issue of sequencing treatments for mCRPC. In general, I agree with your suggestion TA - based on hard evidence and first principles. One exception, for anyone with clearly PSMA-imaged oligomets, esp soft tissue, Lu177, therapy should take place as early as possible upon mCRPC progression and precede second generation ADT or chemo therapy. With the caveat, if you can afford it. =Rob

[Tall_Allen in reply to immunity1]

Did you read the article? I addressed radiopharmaceuticals there.

[immunity1]

Yes, I did read it and agree with the sentiments even if some of the conclusions of the study cited need support with prospective studies (this is often the case when we are looking into the future). My point is from my experience, that radiopharmaceuticals need to be used early in the course of mCRPC (or possibly even better, post primary treatment when mHSPC). I cannot prove this, with no refereed refs to support me at this time.

[Tall_Allen]

As I wrote, there is probably an optimum point of PSMA avidity. It undoubtedly varies with time - there is a "too early" and a "too late." I'm also not sure that it should precede chemo or second-gen ADT. There is a lot to be said for reducing the tumor burden universally (ie, get rid of as many PSA-non-avid cells as possible first so they do not take over when the PSMA therapy starts). There is also a temporary upregulation of PSMA in the first 3 months after enzalutamide for mCRPC, so that may be the optimal time. There is much to learn.

The only sequencing that lacks a prospective clinical trial is the first, as I wrote. All the others (abiraterone before enzalutamide, and cabazitaxel third) have prospective trials.

[GeorgeGlass]

what if I did not do chemo at the start of Lupron, then where would it fit in the sequence if used after castration resistance begins? Also, where would Nubeqa fit in?

[Tall_Allen]

Same sequence if chemo was used when newly diagnosed, imho. Nubeqa is not approved for metastatic prostate cancer.

[Bird8]

Great info, TA.