...as I reported, one of the patients on the trial (with ATM mutation) had a 100% remission...
ascopubs.org/doi/10.1200/JC...
and here is the report about the patient (I will try to track him down to ask how how he is now)...he has an ATM mutation
Second generation selective PARP inhi... - Advanced Prostate...
Second generation selective PARP inhibitor: PETRANHA: Phase 1/2 study of AZD5305 + novel hormonal agents in patients mPCa
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Maxone73
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45 Replies
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You are good!
Thanks for the info. I have a BRCA2 mutation so this is of interest to me.
Do you, or anyone here, know why oncologists wait until we become castration resistant before considering PARP inhibitors?
Why not tackle the BRCA1 or 2 mutations with PARP earlier on? Is it just a matter of costs or is it too dangerous to use this unless you are already at death's door and have nothing left to lose?
EdBar said that he is using parp inhibitors as a last resort drug because it will work 100 % (my interpretation) and until then you can experiment with whatever you want like SBRT of your Mets etc.
If you use it up you are losing the last resort drug which will work maybe for 18 months.
This is only my interpretation for more you can ask EdBar for more information.
Very good answer. I have BRCA2 + ATM, uses Ola in the BAT period, keeps PSA flat while I am resensitizing the cells to Daro after three cycles. Works perfect.
After two years on parp inhibitors your whole body is cleaned up from the BRCA mutation and that's why the effectiveness is limited to up to two years.
Hi Seasid,
I am not sure I understand this. If our bodies is cleaned up from BRCA mutation within two years, that sounds good to me as the absence of that mutation should then make the cancer much less aggressive. What is the downside part that I am not seeing? Unless you meant that after 2 years, the BRCA mutation will come back?
I believe that the downside is that you used up your last resort drug which works very well but for a limited time. I don't believe that his mutation came back. You could read hopingforthebest stories in hip posts. He reported what I just said.
Is your mutation only in your cancer or is it in your whole body?
I don't know the answer to that one. When they told me 3 years ago that I had the mutation, they told me that I probably inherited it from my mother who died from breast cancer when she was 45. I have outlived her by almost 11 years now.
You could find that out with the simple blood test.
Or I can ask my MO to look into my files to see if it is specifed in there.What would be the difference in knowing if the mutation is in my cancer or whole body? Does it impact the choice of treatment?
I really don't know. I have no idea if the clinical trials take care of that information.
I just know that until I run out of options I will not do genetic testing because the cancer mutates all the time.
If you have actionable mutation in your whole body it would be good to know and you could find that out without a tissue biopsy.
I believe that they usually do the analysis of the tissue biopsy and if they find an actionable mutation in the tissue than they do the blood sample analysis to see if only your cancer has a mutation or is it inherited from your mother.
I would not biopsy my tissue until I run out of options, but I would gladly find out if inherited the mutation and that could be accomplished from your blood sample anytime.
I am not a big fan of the tissue biopsy (you could spread the cancer that way plus if you biopsy your lungs your lungs could collapse and you would end up in a hospital for 14 days plus with reduced Lung volume.
Here is:
HopingForTheBest1
Profile:
healthunlocked.com/user/Hop...
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Bio
After having experienced accelerating PSA in a short period, I had an MRI fusion guided biopsy in June 2018 that showed 12 out of 16 cores positive and Gleason 9/10. Metastasis to pelvic bone.
Started on ADT therapies and joined SIMCAP clinical trial at CINJ. After 4 months on ADT and PSA dropping from 20 to 0.12, I had robotic laparoscopic prostatectomy on Nov 14 2018. On ADT (Zytiga, Prednisone, Eligard and Xgeva). Zytiga lost effectiveness after just 6 mos as PSA started to quickly rise to 0.55 after surgery.
In 12/18 I had genetic testing thru Color.com (from saliva sample), as well as from Foundation Medicine (from tissue sample) which both showed BRCA2+. This answers why I have aggressive PC. Also have MSS, low tumor burden, TMPRSS2 and PTEN loss.
Went on to PARP inhibitor Olaparib (2/19) which brought PSA down to <0.01 in <3 mos. Continued undetectable for 19 months until rising to 1.98 within the last 4 months.
Constantly searching for next viable systemic treatment options, with 2 small 2-3mm spots found on lung on recent (12/20) Axumin and PSMA scans. Pursuing clinical trial options in my future.
Was on ARV-110 trial at Weill Cornell. Wasn't working and was taken off the trial after just 8 weeks.
Went on to a new trial at Weill Cornell for 24 weeks using a triple therapy of Actinium225-J591 one initial injection + Xtandi pill daily + Keytruda infusion every 6 weeks. Unfortunately, it did not benefit me. On to Chemo combo of Cabazitaxel and Carboplatin every 3 weeks for up to 4-5 months. After first round PSA dropped 80%. Minimal side effects.
Reversion mutation - re-challenging with a PARP no longer an option2 years ago•7 Replies
After being on Olaparib PARP for 2 years, I recently had a Guardant liquid biopsy. It identified that my BRCA2 mutation has become a "reversion" mutation, which means that PARPs will no longer be an effective treatment for me. A reversion mutation restores the ability of the gene to produce a functional protein.
Here is the post. You can see it for yourself:
Replies•
Har036 profile imageHar036
2 years ago
I’m sorry to hear that for you. I was hopeful that you could restart it. My husband has been on Lynparza for the past 25 months and his PSA has been undetectable. He also had 6 Xofigo treatments last year. I believe that the combination of the two treatments was the key. Today is his lab appointment and we’re praying that all is well. You are also in our prayers. I hope that you’ll find the next responsive treatment soon.
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HopingForTheBest1 profile imageHopingForTheBest1Har036
2 years ago
I am currently on chemo combo of Jevtana & Carboplatin. Having my 11th treatment today. Latest blood work shows PSA down from 48 to 26 since #10 3 weeks prior.
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MateoBeach profile imageMateoBeach
2 years ago
perhaps that might be a favorable reversion???
BRAC1/2 mutations disable the encoded proteins from functioning correctly to facilitate repair of DNA (mismatch repair MMR) through the two repair processes of homologous repair HR, or non-homologous end joining NHEJ. And if the damaged DNA cannot be repaired, then triggering the death of the cell, apoptosis.
So while it is great to have these drugs for those whose cancer is caused or progresses due to the mutations in these genes. Is it not better to have non-mutated or reversion to properly functioning mechanisms?
I have not been clear on this question. Paul
en.m.wikipedia.org/wiki/BRCA1
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MateoBeach profile imageMateoBeachMateoBeach
2 years ago
BTW, that is a lot of chemo my friend. Hoping you are tolerating it well.
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HopingForTheBest1 profile imageHopingForTheBest1MateoBeach
2 years ago
Yes, tolerating well. Although, liver enzymes ALT & AST are high and red blood cells are low.
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Grandpa4 profile imageGrandpa4
2 years ago
I think there is increasing data these drugs work in some patients without known mutation in DNA repair. If it worked for you in the past seems worth a try.
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HopingForTheBest1 profile imageHopingForTheBest1
2 years ago
Unfortunately, re-challenging with a PARP is out of the question and will not be effective due to the reversion mutation. I did get 3 separate concurring opinions from different well known cancer centers.
Yes, you are right again, I had 18 months before PSA started to rise. What puzzles my MD and I is that Ola works so well with BAT, havn’t seen any reason for that. Too many SSB’s?
I studied the BAT/Ola trial, maybe this is the explanation: «We have previously reported that supraphysiological androgens (SPA) results in a substantial suppression of BRCA2 (4-fold reduction) and other DNA repair genes(3). Therefore, it seems plausible that BAT may induce an HRR-deficient phenotype and sensitize prostate cancer cells to olaparib. »
I believe hopingforthebest with BRCA mutation in his whole body (not just the cancer) was on olaparib for 18 months and reported that his whole body was cleaned from the BRCA mutation. He was happy with the results on olaparib but I believe he would be better of leaving parp inhibitors last.
You could see his posts.
I have already made a post about the BRCAAWAY trial, but here is a summarization
“Median progression-free survival was 39 months with olaparib plus abiraterone and prednisone (arm 3) vs 8.4 months in arm 1 (abiraterone plus prednisone) and 14 months in arm 2 (olaparib alone)”
ascopost.com/issues/march-1...
Good to know if you have a mutation. Therefore 39 months of progression free cancer.
Hopefully your life is also extended not just made miserable by low eritrocite levels etc. Parp inhibitors are very toxic medications. I would wait for the New generation of the parp inhibitors. Parp inhibitors could make you bedridden etc. I may don't have a mutation yet. Why they didn't allow crossover to Abi plus ola?
From what I have read I think they have allowed for crossover when the single agents were not effective. The mutations from the trial were germline from what she says, so in the whole DNA.
"Among the total study population, grade 3 adverse effects occurred in 19% of arm 3, 21% of arm 1, and 14% of arm 2. Common grade 3 adverse events included anemia and fatigue". So I would say that olaparib is not that worse compared abi alone, in fact (if to believe them) they consider it comparable.
The more you can wait the better it is, for a number of reasons:
- some new research found that PARPi are a sensible choice als for people with no mutations (even if they work better for people with HRR mutations)
- some new research found that they work discreetly well with ATM mutations and definitely better with BRCA mutations
- some new research found that with ATM a combination of PARP and ATR inhibitors work the best
- AZD5305 looks promising as it's greatly more selective (and we all want to be like the guy in the article!)
After all olaparib is been around for quite a while, so it's very likely that there will be something better soon (even if it will take ages to complete a study like Profound and similar).
"Patients were randomly assigned 1:1:1 to one of three treatment arms: arm 1 received abiraterone and prednisone (n = 19); arm 2 received 300 mg of olaparib (n = 21); and arm 3 received 300 mg of olaparib plus abiraterone and prednisone (n = 21). Crossover was allowed from arms 1 and 2 at disease progression, with eight patients crossing over from abiraterone plus prednisone to olaparib and eight, from olaparib to abiraterone."
They didn't say that it was possible to cross over to ABI plus OLA?
Only between arms 1 and 2 but not to the arm 3 (Abi plus ola). That is funny.
I am not sure they were not allowed, looks like their MD did not want to
“More interestingly, unlike the phase 3 trials, BRCAAway incorporated a crossover design, which allows us to gain insights into a combination ARPI/PARP inhibitor approach versus a sequential approach. The data presented suggest that an upfront combination is better than a sequential approach with an ARPI followed by a PARP inhibitor at progression,” or vice versa, Dr. Chi said.
Another pertinent detail observed by Dr. Chi is that approximately 60% of patients in the abiraterone-alone arm and in the olaparib-alone arm did not cross over to receive the alternative therapy at progression.
“This supports the supposition that many patients may not receive additional treatment beyond first-line mCRPC, especially those with BRCA2 who are known to have a poor prognosis and aggressive disease. Therefore, these individuals may miss an opportunity if a PARP inhibitor is reserved for after progression on an ARPI,” Dr. Chi remarked.
I don't like this logic. They should allow people to transfer from Abi to to parp inhibitors plus Abi. Otherwise how could they know that Abi plus ola from Start is better than crossing from Abi to ola plus Abi at progression.
Plus the cancer itself develops BRCA mutation later during the treatment so they should include that population also. Where did you see that only people with gremline BRCA mutation are included in this study? Could you point that to me? I should go to the inclusion and exclusion criterias but I don't see the link to the clinical trial information on the government site.
I believe EdBar has gremline BRCA mutation (I am not 100% sure) and he is alive for very long time without Abi plus parp inhibitors like ola. As I said we should save up the parp inhibitors for later because they may fail after some time. Again I don't really know that for sure but you can imagine that if the parp inhibitors reverse the mutation like in a hopingforthebest1 case.
it's written in the article
"In this open-label study, 165 eligible patients with metastatic castration-resistant prostate cancer were screened, and 61 patients were selected who had BRCA1/2 or ATM alterations; these genetic findings were identified by next-generation sequencing and germline testing. Patients were randomly assigned 1:1:1 to one of three treatment arms: arm 1 received abiraterone and prednisone (n = 19); arm 2 received 300 mg of olaparib (n = 21); and arm 3 received 300 mg of olaparib plus abiraterone and prednisone (n = 21). Crossover was allowed from arms 1 and 2 at disease progression, with eight patients crossing over from abiraterone plus prednisone to olaparib and eight, from olaparib to abiraterone."
But I interpret this like it was not possible to crossover to the combo. This would explain the data about single treatment and sequential treatment. They considered sequentials those who crossed from abi to olaparib and vice versa.
If only the cancer has a BRCA mutation would the results be the same? (39 months progression free cancer on ola plus Abi)
Strictly speaking we don't really know if the progression free survival would be still 39 months if only the cancer has a BRCA mutation because the trial participants had an inherited BRCA mutation identified from their blood. Therefore gremline (in whole body not just in the cancer.)
. 2023 Jan 4;29(1):81-91. doi: 10.1158/1078-0432.CCR-22-0931.
Detection of BRCA1, BRCA2, and ATM Alterations in Matched Tumor Tissue and Circulating Tumor DNA in Patients with Prostate Cancer Screened in PROfound
Kim N Chi 1, Alan Barnicle 2, Caroline Sibilla 3, Zhongwu Lai 4, Claire Corcoran 3, J Carl Barrett 4, Carrie A Adelman 4, Ping Qiu 5, Ashley Easter 6, Simon Dearden 3, Geoffrey R Oxnard 7, Neeraj Agarwal 8, Arun Azad 9, Johann de Bono 10, Joaquin Mateo 11, David Olmos 12, Antoine Thiery-Vuillemin 13, Elizabeth A Harrington 2
Affiliations expand
PMID: 36043882
PMCID: PMC9811161
DOI: 10.1158/1078-0432.CCR-22-0931
Abstract
Purpose: Not all patients with metastatic castration-resistant prostate cancer (mCRPC) have sufficient tumor tissue available for multigene molecular testing. Furthermore, samples may fail because of difficulties within the testing procedure. Optimization of screening techniques may reduce failure rates; however, a need remains for additional testing methods to detect cancers with alterations in homologous recombination repair genes. We evaluated the utility of plasma-derived circulating tumor DNA (ctDNA) in identifying deleterious BRCA1, BRCA2 (BRCA), and ATM alterations in screened patients with mCRPC from the phase III PROfound study.
Patients and methods: Tumor tissue samples were sequenced prospectively at Foundation Medicine, Inc. (FMI) using an investigational next-generation sequencing (NGS) assay based on FoundationOne®CDx to inform trial eligibility. Matched ctDNA samples were retrospectively sequenced at FMI, using an investigational assay based on FoundationOne®Liquid CDx.
Results: 81% (503/619) of ctDNA samples yielded an NGS result, of which 491 had a tumor tissue result. BRCA and ATM status in tissue compared with ctDNA showed 81% positive percentage agreement and 92% negative percentage agreement, using tissue as reference. At variant-subtype level, using tissue as reference, concordance was high for nonsense (93%), splice (87%), and frameshift (86%) alterations but lower for large rearrangements (63%) and homozygous deletions (27%), with low ctDNA fraction being a limiting factor.
Conclusions: We demonstrate that ctDNA can greatly complement tissue testing in identifying patients with mCRPC and BRCA or ATM alterations who are potentially suitable for receiving targeted PARP inhibitor treatments, particularly patients with no or insufficient tissue for genomic analyses.
They are toxic so waiting until needed is probably the best option. And there are newer PARP Inhibitors in the pipeline that are less toxic so that is also something to consider.
Good question. I have mHSPCa and if recurrence is proven my oncologist will put me on ola+abi+adt.TALAPRO 3 is addressing ola+abi for the hormone sensitive. I suppose many docs won't prescribe until those results are in.
This is great
Hey Ana, come here, you have to explain all of this to me. Not to worry I'll cook dinner tonight...(yep the usual, peanut butter and jelly sandwiches). Okay, on toast it is....What I do for love.........
Good Luck, Good Health and Good Humor.
j-o-h-n
From the inclusion criterias of the clinical trial:
"Agree to undergo a biopsy of at least one metastatic site (fresh biopsy of primary prostate only allowed if there is clear local disease and no other measurable disease site or biopsiable bone lesion.) to determine DNA repair defects. (Please refer to the Laboratory Manual for specific procedures). However:
Adequate archival metastatic or primary disease tumor tissue can be used if available in lieu of a new biopsy. These patients will only be eligible for protocol therapy if the biopsy has tumor that is positive for DNA repair defects.
Patients with known DNA damage repair defects based on prior appropriately validated metastatic or prostate tissue analysis may be used in lieu of new biopsy/analysis based on central site evaluation of quality of the biopsy and analysis.
Patients with known germline DNA repair defects are eligible without a biopsy. However it will be highly desirable that they undergo a metastatic (or fresh prostate biopsy if there is clear local disease and no other measurable disease site or biopsiable bone lesion) disease biopsy to better define the scope of the DNA repair defects in the current disease context."
I would say that you don't have to have an inherited BRCA mutation in order to qualify for the clinical trial. It is enough that your cancer has a BRCA mutation.
Here is the clinical trial link:
Official Title:
BRCAAway: A Randomized Phase II Trial of Abiraterone, Olaparib, or Abiraterone + Olaparib in Patients With Metastatic Castration-Resistant Prostate Cancer With DNA Repair Defects
Brief Summary:
This is a biomarker preselected, randomized, open-label, multicenter, phase II study in men with metastatic castration resistant prostate cancer (mCRPC). Patients with tumors that have ATM, BRCA1 and/or BRCA2 mutations/deletions/loss of heterozygosity will be randomized in a 1:1:1 fashion to each arm. Patients with mutations in noncanonical DNA repair genes including FANCA, PALB2, RAD51, ERCC3, MRE11, NBN, MLH3, CDK12, CHEK2, HDAC2, ATR, PMS2, GEN1, MSH2, MSH6, BRIP1, or FAM175A defects will be assigned to Arm IV with single agent olaparib.
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