Choose Capivasertib or 177Lu-PSMA-617 clinical trial or stick with ADT + radiation?

[LongTimeRunning]

Hi Folks,

My PSA is up to 49 from 24 last summer. After bone scan, CT scan indicated 3 sites of mets (2 on pelvis, 1 on L5, overall “low volume”). Otherwise feeling great, working out most days. 58.

I was finally able to get in this month to see a Medical Oncologist. Starting on ADT next week. Meeting with a radiation oncologist next month for a discussion, but thinking about some clinical trials in Vancouver and am looking for some thoughts from folks.

One trial involves Capivasertib which my MO is running, a treatment which hasn’t been discussed a lot, and the other 77Lu-PSMA-617, which has been discussed a fair bit. Still digesting all the info and I was leaning towards the latter, but all the information and interesting discussion gives me pause. Both are randomized which adds another element of uncertainty. I see 3 options (and 5 possibilities of treatment):

(1) Just do ADT and then possibly radiation (maybe to bones with stereotactic treatment, will get more info after meeting with RO)

(2) The CAPItello-281 clinical trial: Enroll in the study, get screened for PTEN deficiency (3-4 week time frame; ~20% chance of having it) and if deficient get randomized (50% chance) into getting either Capivasertib + ADT or placebo + ADT.

(3) PSMAddition: Enroll in study, get screened for PSMA expression (PET/CT) and if so (which seems likely) be randomized (50%) into getting either 177Lu-PSMA-617 + ADT or into standard care control arm. In the control arm I would be allowed to undertake additional radiation treatment.

MO says both trials are good, but he's not pushing me in any direction. I’d like to contribute as a data point, but I do need to think of the best path forward. Any thoughts on whether or not these new treatments that much better (if I get them) then ADT + radiation alone given that I am just starting treatment of any sort?

[Tall_Allen]

I think some tests may help you decide:

(1) PSMA PET scan will tell you if your metastases are PSMA avid. If so, the PSMA addition trial may be a good first choice. Even if you are in the SOC group, you still get to do #1.

(2) If possible, a genomic test of one of your metastases. It will tell you if you have PTEN loss but will also tell you if your metastases are BRCA+. If PTEN loss, the CAPItello trial may be good. A recent trial of ipatasertib, a similar drug, had only modest results in more progressed men, but used earlier may have better results. There is also a trial of a PARP inhibitor+Xtandi in newly diagnosed men.

There is controversy about triplet therapy (docetaxel+darolutamide/abiraterone+ADT) in newly diagnosed oligometastatic men. A recent analysis (yesterday) showed that the triplet increased survival even in oligometastatic men:

ascopubs.org/doi/10.1200/JC...

The SBRT should be to your prostate (called debulking). SBRT to your metastases has no proven benefit, but why not? ADT alone is not enough. Even if you decide against triplet therapy, SOC is to have a second line hormonal in addition to ADT.

[LongTimeRunning in reply to Tall_Allen]

They did take a sample to test for BRCA+, but I need to enroll in the clinical trial to do a specific test to see if PTEN loss is present (my understanding is that they are separate tests, but I could be wrong and need to clarify with MO). I could enroll in CAPItello , but if not PTEN-deficient I would have a short window for getting in the PSMAddition trial once that formally starts. PSMAddition intake requires one to be on ADT for no more than 45 days. Given that PTEN-loss analysis takes up to 4 weeks so I might have a 1-2 week leeway to enrol in PSMAddition to get PSMA Pet etc.

Of interest is "In 100 people receiving capivasertib, more than 10 and up to 100 may have side effects" (hypergycaemia, nausea, etc.). I wonder if the placebo in CAPItello (or any other trial) is engineered to have side effects only. How would that affect any "placebo effect"?

I was told that the radiation would be +/- to the bones. So, I agree why not if they can target it effectively. But if Lu177 can do the same thing maybe better then the PSMAddition trial might be worth aiming for. I've got to make decisions pretty soon on this.

Standard treatment that I am starting on is Abiraterone + prednisone/prednisolone.

[Tall_Allen in reply to LongTimeRunning]

I've never heard of a genomic test on tumor tissue that did not test for PTEN loss as well as BRCA.

Here's the evidence for debulking the primary (the prostate) in oligometastatic men:

prostatecancer.news/2018/09...

They would never give a placebo that has side effects.

[LongTimeRunning in reply to Tall_Allen]

Thanks for the link.

With up to 100% of men getting side effects on capivasertib I would wonder if you might start to suspect you are/are not on the drug and if that impacts analysis. You could have some of the side effects associated with capivasertib and not be on it and think you are and vice versa. Perhaps that statistically balances out.

[Tall_Allen in reply to LongTimeRunning]

💯 The only way to know is from the randomized clinical trial where they compare the SEs of the drug to the standard of care. That said, I think one has to expect SEs from every therapy. Triplet, which is the current SOC, has SEs mainly from docetaxel - the second-line hormonal added little to the SE profile.

[LongTimeRunning in reply to Tall_Allen]

MO told me that BRCA was not part of the PTEN test, but is being done separately as part of SOC and biobank testing.

[RyderLake2]

Hello,

I too am a Canadian and like you I also live in British Columbia. I have been fighting PCa for a very long time. At the end of May it will be ten years. I have been on Zoladex (goserelin) for nine of the ten. For one year I was on Firmagon (degarelix). After four and a half years my PSA started climbing slowly so my Medical Oncologist added Xtandi (enzalutamide). I stayed on that drug for five years. By September of last year it was becoming obvious that Xtandi was no longer working. I was told in B.C. it was not possible to switch to Zytiga (abiraterone). Since I was not quite ready for chemotherapy my options were becoming somewhat limited. Fortunately with the support and recommendation of my medical oncologist I applied to the Point Biopharma SPLASH trial being run by the B.C. Cancer Agency (BCCA). This trial is investigating the use of Pluvicto (Lutetium-177) before chemotherapy. Only 400 men worldwide and only ten from B.C. I was the tenth and last one chosen! I consider myself to be very, very lucky. Although I am not on the Lutetium arm, I am on the Standard of Care (SOC) arm. The trial allows for a crossover to Lutetium if the SOC drugs fail to work. In my case, the SPLASH trial wanted me to quit Xtandi cold turkey and switch to Zytiga plus Prednisone. I am on Zytiga right now.

This brings me back to you. The Astra Zeneca CAPItello-28 clinical trial was not an option for me four months ago but it does sound promising. I have never heard of the PSMAddition trial. Where is it being offered? My recommendation (for what it is worth) is to try anything to do with Lutetium. The Germans, English, Australians and indeed most of the world has been using this radioligand therapy for many years. It was approved for North America only very recently. The acceptance of Lutetium-177 in Canada was based on the VISION trial and only after chemotherapy. If nothing else, by enrolling in a clinical trial you will be offered a PET scan and, as perhaps you know, the queue for this type of scan (if you are not in a clinical trial) is a mile long. B.C. only has four, two in Vancouver, one in Victoria and one in Kelowna. Good luck with your decision. Perhaps we should stay in touch. As mentioned, I have been battling this disease for a very long time, worked with some outstanding doctors, and had to make many decisions along the way. I might be able to help you with your questions.

[LongTimeRunning in reply to RyderLake2]

Hi RyderLake2

Thanks for filling me on your journey. Good to hear that you were able to be enrolled in SPLASH!The PSMAddition is not yet active. They are still going through administration approval and are not enrolling just quite yet (near future), but I appear to be a good candidate. It would be run out of Vancouver, but I'm not sure if they would have a few other localized trials under the same umbrella in other parts of the province. You are right - getting in to things like PET scans is quite the process by itself. I'm actually leaning towards this trial. I've read some info on potential toxicity of Lutetium-177 if the tumor load isn't high, but if this were still more effective in cleaning house than the debulking via radiation that Tall_Allen wrote up about, then I'm willing to risk it. Perhaps with lower tumor loads more micro-metastasis would be latched on to and destroyed (vs few or none via more conventional radiation)?

If PTEN/BRCA is not an issue then looking into the Lu-177 trial is easier (a lot of first day meeting the MO confusion and paperwork, but the sample could be back within a 1-2 wks if its been sent out for wherever they do the analysis). In any case I really appreciate the offer to stay in touch. I will definitely keep you mind!

[chrisrock]

Looking at your disease status, PSMAddition trial will be a better choice.

[LongTimeRunning in reply to chrisrock]

Yes - I went for that one and very recently was accepted into it after some admin-related delays. I've been assigned to the treatment arm and first injection is this week!

[chrisrock in reply to LongTimeRunning]

Great 😎