Tumor can’t be removed: What are chances of survival now?

@pendesk8 , like you, I also don't understand why the PARP inhibitor is not given in conjunction with something else.

My understanding is that the PARP inhibitors prevent cancer cells from _repairing_ damaged DNA, while the traditional cytotoxic drugs (Folfirinox, GAC, etc) _cause_ the kind of DNA damage that slows cancer growth. So it sure seems like you'd want both.

One researcher I spoke with (more specifically about ATR inhibitors, as they more directly target ATM) said that they also caused some DNA damage as well as impeding the DNA repair, so maybe there's something to that.

Another oncologist told me combining the drugs (cytotoxic plus an inhibitor) would be more than my system could handle, but I'm handling the traditional cytotoxic (GAC) so well I'd be happy to give it a try, and then back off if necessary.

I'm not sure about all the legalities. My understanding is if a drug is approved for some other condition, it can be prescribed off-label for your condition, even outside of a clinical trial. But if not approved yet for any disease, then it can _only_ be used in the context of a trial.

In your particular case, because it's part of a trial, it has to follow whatever the trial protocol is, which sounds like they're testing out a PARP inhibitor as maintenance therapy for patients who are off the traditional cytotoxics. Since it has shown promise in BRCA1/2 and PALB, maybe they want to get more detailed data of PARP inhibition of ATM than past studies have revealed.

FWIW, MD Anderson has done some studies combining ATR and PARP inhibitors simultaneously. About halfway down this page: https://www.mdanderson.org/newsroom/results-fgfr-inhibitors-parp-atr-inhibitor-combinations.h00-159617856.html

I hope you'll keep us posted regarding the other trial you're hoping to get into.

Thanks and best wishes!

yes,I will.It still hasn't gotten into trial.I am now 4 months with no cancer growth.I'm happy to not be so sick this year for christmas .

My case is somewhat similar to yours. I'll be getting the "less effective" chemo this week for my reoccurrence though my metastasized very quickly to the liver , as it appears that my 5FU (what an appropriate name!) chemo after distal surgery didn't really work for me, or maybe should have been continued beyond the typical protocol of 12 sessions. Have you done any research about the effectiveness of oral chemo following systemic chemo?

@mnewland99 , Sorry to say I have not done any research into that. In fact, I started digging into it after your question, and now know less than I did when I started. (Or more accurately, I now realize how much I didn't know and how many of my assumptions were wrong.)

Head-to-head searches for terms like "capecitabine vs iv 5fu" and "capecitabine vs gemcitabine" and targeted searches like "capecitabine mechanism of action" return some useful hits, but with no real biochem education to my name, it takes me forever to read and understand them. Not to mention, those searches return papers addressing many types of cancer, and if there's enough variety, they need to be narrowed down as appropriate to pancreatic cancer.

The results make capecitabine sound (to me) like a somewhat attractive and viable alternative to intravenous 5FU, more convenient than infusions, but when I asked my oncologist about it last month as an oral-only maintenance alternative to gemcitabine infusions, she said their mechanisms of action were different enough that it might be risky to switch me since I'm doing so well on the current regimen, whereas capecitabine would be an unknown.

What I gather though, from the head-to-head papers of oral capecitabine vs intravenous 5FU is that they have a similar mechanism in the end:

1) https://pubmed.ncbi.nlm.nih.gov/15763604/
Capecitabine was developed as a prodrug of FU, with the goal of improving tolerability and intratumor drug concentrations through tumor-specific conversion to the active drug.

2) https://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20896lbl.pdf
"[capecitabine] ... is ... an orally administered systemic prodrug of 5’-deoxy-5-fluorouridine (5’-DFUR) which is converted to 5-fluorouracil."

My question for an oncologist would be whether it's the end product (5FU) that is not (or no longer) effective, or whether it's the current delivery method of getting the drug to the tumor that's not effective. In the latter case, switching to oral capecitabine sounds sensible (to me), but in the former, maybe a completely different drug is called for. I (non-medically trained) have no idea, but that's a question today's research would lead me to ask.

Best of luck, and please let us know what else you learn!

--mm

Clinical studies have concluded 5-FU by the IV route is more beneficial and why it is used as first -line therapy
https://pubmed.ncbi.nlm.nih.gov/30483908/
An interesting fact about cost reimbursement/insurance coverage of these two drugs. When given as an IV infusion in a clinic setting, the cost is fully covered. When it is taken as Capecitabine (Xeloda) in oral form outside of a clinic and more convenient for the patient, there is higher out-of-pocket expense to patients. It is referred to as oral drug disparity. I have been involved the past two years as a patient advocate as a member of the Hematology/Pharmacy Pharmacist Association (https://www.hoparx.org/) going to Capitol Hill with colleagues from HOPA and meeting with the Health Policy Legislative Aids to members of the House and Senate in support of getting the bill proposed by HOPA known as the Chemo Drug Parity Act. On our last meetings in September with Congressional staff, several more key legislators have signed on in supporting the act. It is hoped that in 2024, the proposed Bill will come up for a vote and improved for financial relief to patients taking oral forms of chemotherapy and not being financially penalized.

PARP’s are used as maintenance therapy after primary chemo has lowered the tumor burden. Chemo itself is sufficient in interrupting the DNA cycle and causing cells to go into irreversible apoptosis. Combination chemo like Folfirinox is interrupting the DNA cell cycle at more than one point making treatment efficient in those that it works in.

There are a number of side effects to PARP’s with suppression of the bone marrow with RBC precursor cells affected most. These are the cells that mature into RBC’s. Suppression leads to anemia that can become severe and result in chemo being suspended. PARP’s can also affect WBC’s and Platelets which would also cause a halt to standard of care chemo. WBC’s of the granulocyte lineage play an important role in protecting against bacterial infections. A drop in WBC’s can lead to sepsis and death. Platelets are responsible for coagulation. The liver makes a number of clotting factors and is already under stress having to metabolize chemotherapy agents. Adding a PARP inhibitor adds more strew to the functioning of the liver that is vital in metabolizing drugs, producing different enzymes and filtering toxins from the blood.

The most serious side effect that can be caused by PARP’s is Myelodysplasia Syndrome (MDS). It results in toxicity to precursor cells in the bone marrow of RBC’s, WBC’s and Platelets causing mutations that can become Acute Myelogenous Leukemia (AML) which is not curable and results in death.

Thanks to stageivsurvior for all of the very helpful information. I have the BRCA1 gene and Olaparib is known to be helpful in cancers related to the BRCA1 gene. I had a complete response to chemo. I went from borderline resectable to resectable and had a Whipple's surgery. The tumor was completely dead and no nodes seen.

I had an allergic reaction to oxaliplatin after the 11th treatment and developed neuropathy which worsened after treatment. My sister, also with BRCA1 gene, has esophageal cancer, and had the same response, Unfortunately, her cancer has progressed despite treatment with a combination which included the oxaliplatin

My second opinion oncologist, Dr David Kelsen at MSKCC (Sloan Kettering Memorial Cancer Center) recommended testing for ctDNA fragments. Mine were positive, but only weakly so. Survival does go down significantly when the ctDNA fragments are present. I have started with olaparib. I don't feel I have had any side effects.

Here are some articles discussion the results of the POLO trial

https://www.nejm.org/doi/full/10.1056/nejmoa1903387 2019
CONCLUSIONS
Among patients with a germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo. (Funded by AstraZeneca and others; POLO ClinicalTrials.gov number, NCT02184195. opens in new tab.)

FOLLOW UP AFTER POLO 2022
https://ascopubs.org/doi/full/10.1200/JCO.21.01604
Summary
CONTEXT
Key Objective

To present the final overall survival (OS) results of the POLO study of active maintenance therapy with olaparib relative to placebo in patients with metastatic pancreatic cancer and a germline BRCA mutation. We have previously reported that olaparib confers a significant progression-free survival benefit relative to placebo.

Knowledge Generated

No statistically significant OS (0verall survivor) benefit for olaparib relative to placebo was observed. Kaplan-Meier OS curves separated from approximately 24 months, and estimated 3-year survival rates were 33.9% for Olaparib and 17.8% for placebo. Statistically significant benefits were demonstrated for other key secondary end points, including time to treatment discontinuation and time to first and second subsequent therapies.

Relevance

Active maintenance therapy with olaparib confers a significant benefit for multiple clinically relevant end points relative to placebo, including increasing time free from subsequent chemotherapy use. The results also indicate a durable response to olaparib in a subset of patients.

Overall of Treatment for pancreatic cancer 2023
https://ascopubs.org/doi/full/10.1200/JCO.21.01604
Review Nat Rev Gastroenterol Hepatol
. 2023 Oct 5. doi: 10.1038/s41575-023-00840-w. Online ahead of print.

Therapeutic developments in pancreatic cancer (looks very interesting, access is not free for the general public but can be purchased for $29.99) This would be free for subscribers to the Journal or Institutional Subscribers. I don't have a free resource to get the article.

Z Ian Hu 1, Eileen M O'Reilly 2 3
Affiliations expand
PMID: 37798442 DOI: 10.1038/s41575-023-00840-w
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a rising incidence and is one of the most lethal human malignancies. Much is known regarding the biology and pathophysiology of PDAC, but translating this knowledge to the clinic to improve patient outcomes has been challenging. In this Review, we discuss advances and practice-changing trials for PDAC. We briefly review therapeutic failures as well as ongoing research to refine the standard of care, including novel biomarkers and clinical trial designs. In addition, we highlight contemporary areas of research, including poly(ADP-ribose) polymerase inhibitors, KRAS-targeted therapies and immunotherapies. Finally, we discuss the future of pancreatic cancer research and areas for improvement in the next decade.

Thank you! I will pull this. I harbor the KRAS G12-D mutation and so far I have found only a semi exciting trial at MD Anderson. Perhaps this will reveal more .

GEMZAR seems to be keeping my disease at bay but I intend to take a break for the month of February to be with first grandchild to be born! I don’t view Gemzar as maintenance drug for sure. Hoping to remain in maintenance mode and turn up something ! Olaparib and Xeloda have been mentioned.

Thank you all for sharing your excellent research.