Anyone have any experience with Lynparza? If so what are they? SE's and results?
Lynparza: Anyone have any experience... - Advanced Prostate...
Lynparza
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mrscruffy
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I use Lynparza occasionally. I've talked to three MOs and one RO. Radiosensitizer - mechanism of action is to reduce DNA SSB repair and hence increase DSBs. Works very well with radiation. Also works well with SPT. Verified with specialists.
Side effects are minimal. I only use it in bursts of 1-4 days. My MO told me that in her clinical experience it is one of the easiest PCa drugs to handle.
I am assuming you are positive for BRCA2
No. Per Sartor, Flaherty, Denmeade, and the head of ASTRO, and BAT clinical trials, you don't need to be BRCA. BRCA is a big plus and HRR might be required for effect if you are using them outside of BAT, chemo, or RT.
I don't have any mutations.
This is fascinating. Thanks for sharing.
Been on ADT for 7+ years. Just beginning to show signs of failure
If you're not doing RT or BAT and are not HRR then olaparib might not do much for you.
It is effective for those who have defects in the SSB or DSB repair mechanisms or are using therapies that work by inducing DNA damage.
ADT supposedly creates a state of "BRCAness". If that is true then olaparib might be a good addition.
I don't do ADT but if I did, I would talk to my MO about using olaparib for a month to see what it does to my PSA. Do this experiment a few times.
However, since ADT might be failing you I think you're beyond the point of experimentation.
Perhaps ask your MO about adding it to ADT.
That is the plan, have the Lynparza already, just going to do some scans before taking so we have a baseline
How do you convince the insurance to cover the Lynparza or do you do this out of pocket? Your usage would be off label or does it fall under an FDA approved treatment?
Go to manufactures website. They have programs for financial assistance. I am receiving drug cost free.
Insurance couldn't give me a straight answer on price until I had scrip. I went to Astra Zeneca direct
I'm assuming since you are BCRA2 and CR, you are on label use (FDA Approved). The other individual just seems to be adding it experimentally, so I was curious how it was approved for off label use and if insurance covered the off label use.
I got a sample from an MO. I'm running out this week. If I can't get another sample I might go through indiamart.
Interesting...so your MO is supporting your off label use. How are you determining if it has any effect in non mutated PCA?
My MO supports it. I do not know how much of the therapy results to attribute to each component. I've asked several MOs and they all appear to think it is a no-brainer. But this in context of the therapies I do. I don't know how well olaparib will work with "non DNA-DSB" therapies.
My ctDNA decreased from mid-high to undetectable. The drop coincided with the use of olaparib. But it could have been other factors.
That's interesting that MOs you spoke with believe it's a no brainier. I meet with a MO researcher yearly who is actively researching PARP and ATR inhibitors. His position is only BRCA1/2 are no brainers, the others HRR mutation are not well understood. The addition of Lynparza with Abiraterone is encouraging though for HRR and non HRR mcrpc... unknown for nmhspc. You seem to be pushing to the treatment up even further.
One of the ROs I talked to is the head of ASTRO. He's performing SBRT on me. He thought olaparib was an excellent addition.
Sartor seconded his opinion.
I also talked to Denmeade. One of his recent trials combines BAT and olaparib.
"Testosterone enanthate 500 mg IM every 28 days. Olaparib 300 mg every day
Excellent results for synergy with PARP inhibitor Olaparib. 47% of those who had an HRR mutation as well as 47% of those without an HRR mutation had a PSA50 response. 76% had a PSA drop. 26% had a PSA90 response. 61.5% had a radiographic complete or partial tumor response.
A control group was not included (Olaparib and injections of saline solution) but the radiographic response rate appears to be 1-2x what would be expected from Olaparib monotherapy.
"
The use of a PARP inhibitor is influenced by your therapy. I don't use it except for when I use SPT. And all the SBRT sessions. Only one more left 
The Zytiga/PARP inhibitor trial is intriguing. Perhaps Zytiga induces a state of "BRCAness" so a PARP inhibitor becomes more effective.
Coming back to this post and your usage of Lynparza, I've read it can take 3-5 months for Lynparza to show results. Im inferring from your reply that you take it for less than that. Am I inferring incorrectly?
Showing results and starting the process of something having results are two different things. I just finished SBRT today. The tumors are "dead tumors walking" and for them to completely go away should take many months.
In the case of DNA damage, cells have 24-48 hours to repair the DNA damage. If they don't, cell dies or goes to sleep. Thus my connect-a-dots told me that I don't need to inhibit PARP longer than this. My limited sample of olaparib and my dislike of side effects spurred me on to figuring out ways to reduce the overall dose. If you inhibit CYP3A you get a 50-100% boost to olaparib. So, I limited the time and the dose and my 20-day sample lasted over a year.
I bounced the olaparib idea off some MOs and later some trials started with pulsed olaparib. I'm sure that the idea didn't come from me. Instead, I suspect that some researchers came to the same conclusions and want to test them out.
I'm attempting to understand your approach versus the approach that I get from clinical trials being conducted. There is a MO in St Louis who combined continuous Olaparib with BAT and seemed to get positive results. I read some trials with intermittent Olaparib with Chemo and the results are not quite as clear. From everything I've read, it will take several days of Olaparib to illicit a response...the approach you appear to be taking requires near perfect timing. If you feel you are getting positive results and your MO is satisfied I don't see an issue.
Anyway, good luck.
The approach to timing is straightforward. When I inject T-propionate, DNA DSBs will be created within minutes to a few hours. RT is similar. Creates DNA SSBs and DSBs. If DSBs are unrepaired, the result is therapeutic. If enough SSBs are unrepaired, the result is therapeutic. Repair must happen within 24-48 hours. With olaparib Tmax of < 4 hours and half-life of 4-10 hours, I only need to pulse it from a few hours before the injection and then maintain for another day or two at the most. With the half-life consideration BID dosing isn't doing a good steady state. That tells me that we are using a higher dose to compensate for the valleys. Inhibiting the elimination enzymes increases serum levels 75% according to the manufacturer and the government. I ran it all by my MO and three of the other MOs I respect the most. And then I talked to the RO I respect. No disagreement with my approach.
The reality is that with a 20-day sample there is no way I could take it continuously. So, if biology and the four experts I talked to are incorrect, then I'm relying on the known effects of BAT and RT.
It could be coincidence but two years ago my tumor mutational burden was 4.6 mut/MB. A few months later I started using olaparib with my initial T injections. Four months after that my TMB was 4.0 mut/MB. Six months after that it couldn't be measured (ctDNA was undetectable). Three months later, it was still undetectable. Used to have two mutations (not HRR), but they disappeared a couple of years ago.
If I had to guess I'd guess that it was BAT that did the pull. But whatever worked, worked.
Hi, could you point me to the research or studies that indicate Olaparib needs to be taken several days for PARP inhibition?
Thanks
That's an interesting question. I'm not sure, based on reading various trials and literature, there was ever an intent to "pulse" dose a PARP inhibitor. You may be the first. You imply you gained information from some of the MO's you follow\interact with that do "pulse" dose PARP inhibitors. Can you share the literature?
I didn't get the info from the MO's and RO's. I looked into research by Denmeade, Antonarakis, etc. and came up with the idea. It was my attempt to prolong my 20-day sample.
After I solidified operation non-BRCA-prolong-olaparib, I talked to the head of ASTRO, my MO, and another practicing MO who is involved in RT/radioligand/testosterone trials and research. I mentioned my use of olaparib to another MO but did not tell him my extension plan.
Research is lots of cell studies. RT/SPT - DNA DSBs. How long they last. How PARP repair works and what happens when it is inhibited (mostly nothing since HRR repair picks up - unless your therapy induces lots of DNA DSBs).
•• Olaparib inhibits PARP within an hour: (PDF) Pharmacological ascorbate induces ‘BRCAness’ and enhances the effects of Poly(ADP Ribose) polymerase inhibitors against BRCA1/2 wild type ovarian cancer
researchgate.net/publicatio...
1. CRPC, HSPC, Olaparib, Radiation, SPA level discussion and studies: Supraphysiological androgens suppress prostate cancer growth through androgen receptor–mediated DNA damage – PMC ncbi.nlm.nih.gov/pmc/articl...
ADT and PARP inhibitors: PARP Inhibitors: A New Horizon for Patients with Prostate Cancer - PMC
ncbi.nlm.nih.gov/pmc/articl... Olaparib begins working after the first dose.
• Olaparib synergizes with BAT. ADT induces DNA DSBs (double-strand breaks). SPT also induces DNA DSBs. Olaparib induces DNA DSBs via at least two mechanisms. Trapping PARP1 and impairing DNA single strand break repair. Role of the DNA damage response in prostate cancer formation, progression and treatment | Prostate Cancer and Prostatic Diseases nature.com/articles/s41391-...
• HSPC cells in an ADT environment produce DNA DSBs. Addition of olaparib inhibits HSPC cell growth: IJMS | Free Full-Text | Androgen Deprivation Freezes Hormone-Sensitive Prostate Cancer Cells in a Reversible, Genetically Unstable Quasi-Apoptotic State, Bursting into Full Apoptosis upon Poly(ADP-ribose) Polymerase Inhibition
• Most DNA repair occurs in 48 hours: Researchers clock DNA’s recovery time | Biochemistry and Biophysics
med.unc.edu/biochem/news/re....
• Most DNA repair occurs in 24 hours: Pathways of DNA Double-Strand Break Repair during the Mammalian Cell Cycle - PMC
ncbi.nlm.nih.gov/pmc/articl...
• Apoptosis occurs within 24-72 hours of DNA damage: Induction of apoptosis in cells | Abcam
abcam.com/protocols/inducti....
• ESMO 2021: Bipolar Androgen Therapy (BAT) Plus Olaparib in Men With Metastatic Castration-Resistant Prostate Cancer
urotoday.com/conference-hig...
• BAT and PARP inhibitor: Testosterone and Olaparib in Treating Patients With Castration-Resistant Prostate Cancer - Full Text View - ClinicalTrials.gov
clinicaltrials.gov/ct2/show...
• Olaparib induced cell death (responders: PC-3 androgen-independent, LNCaP androgen-sensitive, C4-2B. Non-responders: DU145 androgen-independent – some research indicates that native DU145 is Olaparib sensitive). Cells exposed to Olaparib 3 hours prior to RT start had PARP inhibition and cell reduction hours later. :Effects Inhibition of PARP1-dependent end-joining contributes to Olaparib-mediated radiosensitization in tumor cells - ScienceDirect
sciencedirect.com/science/a...
• 8 oz of grapefruit juice (also pomegranate juice and tomatoes) inhibit CYP3A and increase Olaparib serum levels. Avoid these interactions or reduce your dose of Olaparib “If a strong CYP3A inhibitor must be co-administered, reduce the Lynparza dose to 100 mg (one 100 mg tablet) taken twice daily“ – this is 1/3rd of standard 300 mg twice a day dosing: LYNPARZA (olaparib) tablets
accessdata.fda.gov/drugsatf...
• Olaparib plus high-dose testosterone shows promise in prostate cancer
urologytimes.com/view/olapa...
I have dozens of other studies linked in my book.
If I could get a script and didn't have side effects, I would take it continuously. I did not have that option.
Here is the BAT + Olaparib trial I mentioned.pubmed.ncbi.nlm.nih.gov/365...
But this used continuous Olaparib, not pulsed. Also, patients were mcrpc. Not sure if this trial can be extrapolated to nmcspca or even mcspca. I do know Dennemede pretty much says BAT should be considered in CR patients.
Anyway, I have somatic ATM mutation from the primary tumor (somewhat rare is my understanding) and am interested in the parp ATR Inhibitor trials. Maybe at some point in the future I'll give BAT try but not considering it at this point. I'm getting ready to add xtandi per the EMBARK trial. Hoping to get a lot of mileage from that protocol.
Thanks. I've seen that trial. I talk to Denmeade regularly. We have some decent data applying BAT for HSPC men. I'm watching eight or so guys who are doing it now. And then there is the BATMAN trial. Funding for another HSPC trial is an issue and the bar to entry is higher for HSPC therapies than it is for CRPC therapies.
EMBARK is a nice trial of adaptive therapy. Personally, I refuse to do Xtandi again. I was on it for 3 weeks and had my MO cancel my script. I handle Nubeqa fairly well I guess. But in my MO's clinical experience, most men seem to handle Xtandi better than Nubeqa. That's not what the trials indicate and she talked about this.
I hope it works out for you! I expect you'll handle Xtandi much better than I did (I have never heard of anyone who had more side effects than me).
Fantastic thread, I only see it now,.
Is there anything written yet on pulsed dosing of a PARP inhibitor? Even if not published - in your book? - it would help me in getting MO on board on action re my two newly discovered mets.
I am BRCA2+ but I imagine that does not lessen the potential of combining PARP + BAT. If I am wrong, please let me know. .
If you know of any more recent data (from Denmeade) on BAT for HSPC,than the BATMAN trial, perhaps you could share it.
Hi - I'm unfamiliar with your abbreviations SSB, DSB, and SPT. None of them are in the abbreviation list posted here. Help, please? Thanks.
Unfortunately there are some on this site who think it is a good idea to use masses of abbreviations - I have written on this before - makes any posting less readable and prone to be ignored. Its good you also raise the question - the more of us who protest the less abr (abreviations) there will be
When someone uses an abbreviation, rather than complain, I use google. Or I ask politely as HikerWife did.
A tip: if you don't like the way someone writes, don't read their info. We aren't being paid to write.
But you are correct, the more people complain when others post free info, the less likely they will be to post. So, less abbreviations
Single Strand Breaks. SSBDouble Strand Breaks DSB
Has to do with the DNA repair mechanism...which the PARP and ATR inhibitors
impact cell death. Complicated stuff.
Thank you.
SPT is just testosterone injection that raises a man's T levels above a certain level. Used in Bipolar Androgen Therapy....so normally if you see SPT, the context is BAT.
I have heard about Lynparza being taken only for a few days at a time....how does that work out?
If you use a therapy that induces DNA DSBs (e.g., BAT, RT, most types of chemo) then Lynparza will inhibit SSB repair and increase DSBs. There are numerous mechanisms of action, and it feels like you could spend weeks learning about PARP inhibitors and how they work. I didn't spend weeks; I primarily looked at the output of studies.
Most of the DNA damage from BAT and RT is done within 24 hours. Then the cells have another 24 hours or so to repair the DNA damage. If they don't the cell usually enters senescence or goes into apoptosis.
We can't use the SPT or RT continuously. RT - our bodies won't take it. SPT - androgen insensitive cells are "fueled" and we lose our edge. So, spike up the SPT or do the RT and add olaparib. When the DNA damage window is over, no need to continue olaparib. Anyway, that is my connect-a-dots SWAG approach.
I'm playing connect a dots. But in the words of an MO I recently talked to "the U.S. is way behind because our clinical trial process can slow things down". He seems to think that we have the tools available to extend PCa patients' lives.
Clinical trials are important but it does seem to me that we waste a lot of time demanding 100% proof before entertaining use. I cannot wait for 100% proof. Nice to have but my cancer isn't patient.
Anyway, I do not have proof but I there is a good possibility that olaparib could help HSPC and CRPC men who are using some type of hormone blockade.
I'm almost out of my limited supply of olaparib. If I can't get it here I'll look into Indiamart.
" In PROpel, all subgroup analyses for the HRRm and non-HRRm groups showed a benefit with the abiraterone + olaparib combination versus abiraterone + placebo [1]. In addition, results from the TALAPRO-2 trial were recently released by Pfizer [10]. The study aim was to demonstrate an improvement in radiographic PFS for talazoparib + enzalutamide versus enzalutamide + placebo for men with mCRPC with or without HRRm. According to the press release, a PFS benefit and a trend towards better OS have been demonstrated. Comparison of individual patient data on completion of both trials is warranted to assess whether a patient subgroup might eventually benefit from combination therapy. Data from the CASPAR trial will also add much to the current literature."
ncbi.nlm.nih.gov/pmc/articl...
Yes, all the FDA should be doing is making sure it's not going to kill or injure anyone. Efficacy should be determined by doctors and patients.
Been on it for month and a half. Have BRACA. Side effects have been very mild. Some stomach discomfort that can be handled by nausea drugs. Have not had follow up to see how it is working. Will let you know when I have follow up test n a couple of months.
How did your follow up test do?
Red and white blood cells are getting better and PSA is .14 down from 1.7 No new mets and cancer is not growing. I would say that is a good outcome
Is interesting (above)...
Certainly an issue to use off label as insurance will definitely bounce it back considering it's cost. ($20k per month)... And approval is for BRCA anomalies.
I'm BRCA 1 & 2 deleted, added Lynparza as a kicker a little while after Orgovyx began failing after just short of one year of use. Thinking metabolic issue, switches to Degarelix, which stabilized PSA, added 2nd generation lutamide (Darolutamide) and PSA and T dropped like a rock. Followed with Whack-a-mole RT to suspicious spots found on scans, and the icing was Lynparza post RT... Almost one year now with Lynparza.
Fatigue always present (ADT), muscle loss, and lately appetite issues not helping. Definitely some serious anemia borderline blood issues but not so low to cause for action. Not sure how much the Lynparza is problematic with stomach or intestinal discomfort as I'm also on metformin for blood sugar levels which causes the same. But I'll say it hasn't contributed to it that I can tell... For the most part, aside from blood changes, I didn't tell much difference after starting Lynparza and adding it to the Degarelix and Darolutamide.
Big question for me, is whether or not to ever stop the drugs, and take a peek to see if the RT was successful in getting rid of what may have been laying around to cause the recurrence. A conundrum because it occured just a year post Chemo. My MO has said, for me, that no, it wouldn't be such a good idea. I agree, but curiosity remains. Every time I've recurred, my PSA DT is <3 months... So it's like Russian Roulette if I ever want to do that. For now, the three drug cocktail is working. T below 8, and PSA undetectable (knocking on wood) lol.
Stepping back, I'm a rare case of PCa STG.IV which migrated to the peritoneal and appendix, last treated suspicious spots on the lung (and a few other spots) as well. So not your typical presentation or characteristics. Just a disclaimer... ;). Meaning "My" Cancer, isn't yours, I'll share my story but it doesn't mean we share a path on this journey!
Good Luck and Best Regards
Great read Coolone !
Your Lynparza journey combined with PCa Warrior give us insight into DNA Repair blockage of PCa cells allowing apoptosis.
You dudes are leading edge. Oncologists across the Country could learn a bundle from this website. Thanks guys!! Great post. Thanks Seasid for bringing to my attention. Mike
There is a Phase 1 clinical trial call LUPARP. I'm not in the trial, but my MO suggested trying it. I started on Oct 19. It consist of mixing pluvicto with lynparza. I take the lynparza 4 days before the pluvicto injection and 18 days after. I am in my first cycle. No side effects yet.
Please send updates after a few months. Thanks.
I’ve been on it for 2 years. Little nausea fort week I started it but don’t have any side effects after that.
Good news indeed
Do you take it with or without food and what dose
I take it at night before bed. I started with 600mg but it affected my blood so we dropped down to 450mg. May try 300 after next set of tests. I should add my MO is called the "Michael Jordan of Lynparza" He was part of the development team and knows it inside and out and what complications to look out for and how to deal with them
My husband has an ATM mutation and has been on Lynparza for three years. He takes 200mg twice a day. Initial starting dose was 400mg twice a day. He experiences fatigue with decreased blood counts and occasional digestive issues.
I have an ATM mutation. It was found in the tissue from my RP. Your husband, what ATM found in a germline test or somatic test? If somatic, was a tissue sample used or a liquid biopsy test?Do you happen to know what the actual mutation is?
Thanks in advance.
Did it reduce his PSA?
I too have the ATM Repair gene. This allows for less DNA double strand breaks, allowing the Ca to grow faster.
Did you read PCa Warrior statement above how most of the reversal with Lynparza happens in the first 24-48 hrs thinking lower doses for less days giving less side effects. Maybe Day 1-2-3 of each month vs daily?
It is early times, but what a wealth of information. Mike
Foundation One Liquid
AR-Abiraterone-failed within four months
ATM-Oliparib-present treatment-3years-remains undetectable
PIK3CA-none
PTEN-none
The above are the mutations found and the treatment the mutation is responsive to.
He remains on Lynparza and PSA remains undetectable.
I hope this helps!
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