I took a genetic germ-line test showing I have the BRCA2 mutation, thanks to advice from prostatecancer.news/2019/10... The link shows promising results from using PARP inhibitors, however on (metastatic) castration resistant men who have already been on e.g. Zytiga or Xtandi which is not the case with me.
In a thread from 3 months ago started by mrssnappy, the question was raised about the role of PARP inhibitors for the castration sensitive. The response on the thread was generally in favor of starting PARP inhibitors early for those with the BRCA2 mutation.
I was Dx with Gleason 4+5 in September last year, low PSA and with intraductal in two of 16 samples. After five months of Firmagon I will be visiting my clinic next week when suspected mets to the bones will probably be confirmed by PSMA and the next course of action will be decided. I had been aiming for a more aggressive approach with long-term ADT perhaps transdermal estrogen, plus either Zytiga or Docetaxel. However, after reading the thread and some studies, I understand that using a PARP inhibitor would eliminate the need for all of these making my choice rather easy.
E.g, from one of the two studies referred to in the thread on PARP and the castration sensitive, in an update from February clinicaltrials.gov/ct2/show... “For men with mHSPC, this trial would also provide an alternative to ADT. Identification of a non-hormonal based therapy is warranted as ADT is associated with a shorter time to castration resistance in men harboring a germline DNA repair mutation versus those with intact DNA repair”. Tantalizingly in my case, the primary completion date of this seemingly crucial study is next month May.
However there is also some evidence indicating the contrary: “A number of preclinical studies have suggested a synergistic effect of PARP inhibition and inhibition of the AR pathway in prostate cancer” from section 5 PARP inhibition and combination therapy in onlinelibrary.wiley.com/doi...
But when reading through that article, which refers to the castration resistant only , the evidence of the benefits of the combination don´t appear that strong.
From the thread, and in another prostate cancer newsletter, carboplatin + docetaxel have been suggested beneficial for men with DNA-repair defects. However there does not seem to be the volume of evidence as is the case for PARP inhibitors and the studies are on the castration resistant only.
My tentative conclusion is that medicating with only a PARP inhibitor, possibly complemented with low-dose Bicalutamide, would be the wisest course in my case. If I am cautious I should wait till the study completion date in May, but then I have to take ADT for another month or two.
Any comments would be appreciated.
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Prostate cancer is a heterogeneous condition . Meaning it differs in different men. But one fact remains constant and that is...Androgen Receptor plays a role in it..in some a lot of role and some small degree of role. Even in the most castration resistant tumor, there is always some Androgen sensitive cancer cells. Therefore, anti androgen therapy is required in almost all cases. But, ones who have BRCA2 ,just anti androgen therapy is not enough..and drugs like PARP inhibitors need to be added. In men, without a BRCA1 or BRCA2 mutations, there is no need to add PARP inhibitor drugs.I notice that you are already thinking this strategy...kill Androgen sensitive cells with Anti Androgens or Lupron like drugs...and kill BRCA2 mutated cells with PARP inhibitors,
If Bicalutamide does the job. .then you are lucky because it has least side effects of all.
But proof will be in the pudding...IOW.. fall in PSA,ALP and healed mets on Scans.
I understand - anti-androgen therapy has an important role even even with the BRCA2 mutation.
Yet I am a bit confused... Why would an apparently well-designed study (although I cannot really vouch on that) rule out ADT and only go for a PARP inhibitor? From clinicaltrials.gov/ct2/show... “For men with mHSPC, this trial would also provide an alternative to ADT. Identification of a non-hormonal based therapy is warranted as ADT is associated with a shorter time to castration resistance in men harboring a germline DNA repair mutation versus those with intact DNA repair”.
If the combination is better, how dare they do a trial only using the inhibitor? (Granted, if there is little efficacy or significant side effects for an individual, he will be switched to ADT)
LearnAll, I´m not questioning what you are saying, I am just trying to come to grips with this issue for my semi-annual meeting with doc five days from now.... the clinic is fine but has never suggested any germ-line testing possibly doc has never even prescribed a PARP inhibitor before.....
PARP inhibitors should not bee taken lightly - they are highly toxic and very unpleasant.
If you are metastatic, you should be using ADT, not bicalutamide, and either a 2nd line hormonal or docetaxel+carboplatin (which is briefer and possible less side effects than olaparib).
Thank you, TA. Indeed, the toxicity risk of a PARP inhibitor is high, as e.g. shown in the excerpt below.
Does your answer imply that the knowledge of having the BRCA2 mutation will in effect not have any treatment effect, if the inhibitor is avoided because of toxicity?
Still, the potential efficacy from the inhibitor appears higher than the alternatives. Can´t the mere fact of the existence of several studies on the inhibitor, including now on the castration sensitive, imply judgements that improved efficacy outweighs toxicity risks?
The first study mentioned below implies that possibly a lower dosage, 300 instead of 400 mg, gives significantly less adverse events.
Among all PARP inhibitors, olaparib is the most extensively studied compound with respect to safety and toxicity in prostate cancer patients. In the TOPARP‐B trial, the most common adverse events (AEs) of any grade were anemia, fatigue, and nausea in both dosage cohorts. The most frequent grade 3‐4 AE was anemia (31% of patients in the 300 mg cohort vs 37% in the 400 mg cohort). Dose reduction due to AEs was required in 37% of the patients in the 400 mg cohort and 12% of the patients in the 300 mg cohort, suggesting a dose dependent effect. A total of 19 serious adverse events in 13 patients (13.3%) were considered potentially drug‐related.24 In the PROfound trial, the frequency of adverse events ≥grade 3, dose reductions and discontinuation due to AEs was significantly higher in the olaparib group than in the abiraterone group: 51% vs 38%, 22% vs 4%, 18% vs 8%, respectively.27
Interestingly, comparing the safety data of the PROfound trial27 and a randomized phase II trial,37 the combination of olaparib with abiraterone was not leading to more AEs, dose reduction or discontinuation than with olaparib alone. One patient died due to treatment‐related pneumonitis, while receiving olaparib and abiraterone.27, 37
The preliminary results of the TRITON2 trial showed that the most common grade 3‐4 toxicities for rucaparib were anemia, fatigue and elevated liver enzymes.33 In the interim analyses of the GALAHAD trial, niraparib may seem to be the most myelotoxic PARP inhibitor. Besides anemia (29%), thrombocytopenia (15%) and neutropenia (7%) were the most common grade 3‐4 AEs.34 Safety data concerning talazoparib in prostate cancer are still awaited.
That is a personal decision. Like all treatment decisions, you have to weigh how you feel about the potential benefits against the potential risks. No one can do that for you.
I can tell you what my doctor said in a conversation about PARP inhibitors. He did say the side effects can be very difficult for some. He had one patient that told him he would prefer to go into hospice rather than continue with the PARP inhibitor.
He also said that if he had a patient with a BRCA mutation, he would try the PARP inhibitor before chemo, but only after second-line ADT (Xtandi or Zytiga) became ineffective.
PARP inhibitors have their place but there's a reason why it is reserved for use in a particular timeline fashion regarding advanced PCa patients. All noted above! The toxicity being #1! Also, PARP inhibition isn't a permanent fix, they fail after a time as well. So the morbidity consideration must be weighed seriously.
I have it (somatic changes) but my situation lent to me determining that I would go agressive systemic therapy (Docetaxel) and then to drugs later, reserving the use of chemo a 2nd or even 3rd time. And maybe somewhere in that timeline they'll figure out how to lessen the drastic or caustic effects of Immunotherapy!
This may be naive, but can't a try be made with a PARP inhibitor and if toxicity is high a switch is made to other medication? I believe not all suffer from high toxicity with the inhibitor. In your profile iDPCa is mentioned. Is this intraductal cancer?
I am debating between olaparib and docetaxel or possibly zytiga.
I came across some info indicating docetaxel may be inferior to zytiga when there is intraductal. Is that anything you have happened to have looked into? It may depend on prevalence and type of idc, complicated... I have intraductal in two out of 16 samples, in one 3+3 and one 4+3.
In any case I don't want to interfere with your docetaxel I am sure you are doing the right thing! I write just in case you have done some thinking on it!
It's all good, we are all different, so try to keep focused on exactly what your diagnosis is indicating.
I believe a lot of the early diagnosis is relavent up until there are metastasis. That in itself is a game changer. Very much so because the PCa has taken on agressive characteristics by metastasizing, rendering the associated poor prognosis of IDC-p to where it what when you've arrived at the "agressive" side of the patient spectrum? So then, I focused more on the mets and performance of therapies towards that, in itself. I'm also mHSPC, so tissue is still sensitive to ADT for the time being and that's important to consider as well. Do I want to jump some lines of therapy, skip ahead and ignore some that work, some that work well to try something that may or may not make a drastic change? With mets, thoughts on therapy, lines of therapy, sequence, effectiveness in particular orders, etc., all became relevant.
So then in my search, I didn't really find anything that stood out above others, it seemed all pretty much get you to the same place (kind of), maybe via different timelines. Consideration to using a agressive systemic therapy first before drugs, as the drugs will fail at some point. Hoping the Docetaxel will provide at least a little time where no treatment is necessary (except ADT). My presentation (mets) is RARE... So it's difficult to really try and differentiate between which therapies might work best. Diagnostics, Genetics, Studies will only provide some guidance for me, a lot is going to be rolling the dice and seeing how it works. Really not much different than all of us too. Just that I don't have others to follow other than some indicators. My choice was chosing between Docetaxel and ADT & Zytiga. Docetaxel it was...
I was looking at the the PARP inhibitors for a few reasons. BRCA1 & 2 deletions and MSI-h being present (although not HIGH) provided enough ammo to dive deep into this pool, to learn about and initiate discussions as well with my MO. I felt that although I wanted agressive therapy, that this could be put aside for another line of therapy to use later. There are real considerations to make with Immunotherapy. There are adverse events for many patients. PARP inhibitors also only work for a while, it isn't like it is a one pill fix.
So all that thrown into the computer (Brain) left me thinking it's ok to wait on that one and use it if/when the PCa starts getting ugly (mCRPC). Problem is that there really isn't any data for it's use earlier in PCa progression. It very well could be a great option to be used earlier, but without hard data available to look at, I felt it was prudent to use what's here now, and proven to work for this or that.
The fight now, in my opinion for my situation, is preventing micro metastasis and spread! Doing so while trying to forestall Androgen Deprivation resistance. I think this will be the battle and game... Fixing MMR and Genetic (Somatic) Mutations will come, but hopefully years from now and in that time... How will the therapies improve? And provide increased benefit to patients?
But the concern or impact of IDC-p although there, doesn't really make a lot of noise in my mind. I could be making a mistake, but it's a ticket that's punched and can't be used now that I've transferred to a different bus on my trip!
I may have mentioned the jaw dropping research out of U of Cardiff regarding the so called TCR’s... specialized killer T’s that discriminately target cancer cells. This was billed as a universal cancer therapy a lover a year ago which scans aberrant HLA receptors and targets them for death....such a comforting idea that we could see a day when these dutiful cells scour our innards for malignancies.
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