Friday, 3 February 2017

Olaparib

Hello guys,

2 days ago a study about olaparib and IDH mutant gliomas appeared. Since olaparib is already an approved PARP inhibitor for treatment of ovarian cancer and trial for gliomas in the end of 2017 is expected, I thought someone might find it useful.

"The researchers tested several existing cancer drugs on the mutated cell lines. They found that tumor cells with the mutant genes were particularly sensitive to a drug, olaparib, recently approved for the treatment of hereditary ovarian cancer. The drug caused a 50-fold increase in brain tumor cell death."

https://www.sciencedaily.com/releases/2017/02/170202141211.htm

And link to the study:

2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity
http://stm.sciencemag.org/content/9/375/eaal2463 

Also I did a quick search for olaparib and glioma and there are already trials with olaparib and TMZ for recurrent GBM.
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23 comments:

  1. Stephen W3 February 2017 at 03:24

    This was a fascinating study, and I'm planning to do an Astrocytoma Options update on it. My main question in all of this is: does olaparib (or rucaparib, a second PARP inhibitor approved by the FDA just over a month ago) cross into the brain in therapeutically effective quantities? It was very interesting that the IDHmut subcutaneous xenograft mouse model in this study was responsive to olaparib, but the isogenic IDH wild-type model was unresponsive. Current or future trials testing PARP inhibitors for glioma should really pay attention to IDH1 status.

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  2. Stephen W4 February 2017 at 15:22

    I've just updated the Exploring Strategies for IDH1 Mutated Gliomas page at Astrocytoma Options with a summary of the new study. The summary is found at the top of the page.

    http://astrocytomaoptions.com/exploring-strategies-for-idh1-mutated-gliomas/

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  3. Matjaz5 February 2017 at 05:03

    Nice summary :)

    I did a quick search on olaparib and blood brain barrier, this presenatation came up:

    PARP inhibitors and TEMOZOLAMIDE in BRAIN TUMORS
    http://www.geino.es/wp-content/uploads/Symposium2015/Ponencia_InhibidoresPARP_Dra_MORILLA.pdf

    Where there are some conclusions from OPARATIC trial (olaparib+TMZ for rGBM):

    "Olaparib detected in 24/24 recurrent GBM specimens.
    Mean tumour concentrations in same range as those observed in previous breast cancer study (1).
    Tumour olaparib concentrations did not correlate with olaparib dose or plasma concentrations.
    100 mg once daily oral dosing delivered tumour concentrations associated with clinical responses (1)"

    And also "Olaparib is a substrate for MDR1 and does not cross the intact BBB under normal conditions."

    So to summarize, I guess olaparib gets to the tumor, if blood brain barrier is already disrupted (contrast enhancement on MRI)

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    Replies
    1. Stephen W5 February 2017 at 10:41

      Thanks Matjaz, I came to the same conclusion - that olaparib would probably not be as effective in lower grade tumors with little disruption of the blood-brain barrier, unless an effective inhibitor of MDR1 (P-glycoprotein) was also used to temporarily disable the drug efflux pump at the blood-brain barrier.

      See also:
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4674360/
      "Efficacy of PARP inhibitor rucaparib in orthotopic glioblastoma xenografts is limited by ineffective drug penetration into the central nervous system"

      Delete
    2. Melinda Voicu6 February 2017 at 06:01

      hello Matjaz,

      I have a question to you:

      how long did you get TMZ prescribed?

      because my husband is on 24 month taken after radiation.
      and I want to know if is anybody who is on same situation.

      thank you ,

      Melinda Voicu

      Delete
    3. Mike6 February 2017 at 07:34

      Hi Melinda,

      I am on my 26th cycle of TMZ. I have had a very well respected NO tell me to go a few more cycles and another very respected NO tell me that I should definitely stop now due to the risks associated with long term TMZ. There is no clear answer.

      In the latest Ben Williams update a Japanese study concluded that 12 cycles of TMZ were better than 6, but that 24 cycles were no better than 12. I don't think there is much information on going beyond 24 cycles.

      Mike B

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    4. Melinda Voicu6 February 2017 at 09:25

      Hi Mike,
      thank you for your input, I appreciate your opinion, yes we also going for more cycle of tmz , if our oncologist agree, I don't know yet, but we wish to continue. I will keep you all posted.
      Melinda.

      Delete
    5. Matjaz6 February 2017 at 23:18

      Hello Melinda,
      since I had complete resection of low grade oligodendroglioma, no chemotherapy was given to me at this time.

      Delete
    6. Melinda Voicu6 February 2017 at 23:51

      sorry Matjaz,

      I don't know why i supposed you have GBM,

      I wish you good health and get well.
      Melinda

      Delete
    7. Matjaz8 February 2017 at 09:35

      No problem melinda. I think oligodendroglioma is rather rare brain tumor.

      I wish you and your husband good health as well!

      Delete
  4. Matjaz10 February 2017 at 01:45

    I had some time waiting at the dentist and I found this:

    The PARP inhibitor, niraparib, crosses the blood brain barrier in rodents and is efficacious in a BRCA2-mutant intracranial tumor model

    http://mct.aacrjournals.org/content/14/12_Supplement_2/B168

    ReplyDelete
    Replies
    1. Matjaz10 February 2017 at 01:59

      I'm really spamming this thread, but another useful study on this matter:
      Poly-ADP-Ribose Polymerase as a Therapeutic Target in Pediatric Diffuse Intrinsic Pontine Glioma and Pediatric High-Grade Astrocytoma.
      https://www.ncbi.nlm.nih.gov/pubmed/26351319

      Delete
    2. Stephen W10 February 2017 at 08:50

      The niraparib study is interesting. The drug hasn't been approved yet, but is being fast-tracked so likely will be soon.

      Delete
    3. Stephen W10 February 2017 at 08:52

      You've never spammed this blog Matjaz, the intention of spam is to sell a product, not to inform. Thanks for the links.

      Delete
  5. Unknown17 February 2017 at 10:08

    I'm curious to see if used with resection and chemoradiotherapy if that could help increase efficacy for LGG since radiotherapy comprises the BBB.

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  6. Stephen W17 February 2017 at 15:24

    A second study showing PARP inhibitors can improve response in IDH1 mutant cells

    http://cancerres.aacrjournals.org/content/early/2017/02/15/0008-5472.CAN-16-2773

    "Chemosensitivity of IDH1 mutant gliomas due to an impairment in PARP1-mediated DNA repair"

    ReplyDelete
    Replies
    1. Stephen W17 February 2017 at 15:27

      This was only an in vitro study, whereas the Yale study I summarized on Astrocytoma Options also validated their findings in vivo.

      Delete
  7. Matjaz21 February 2017 at 02:36

    New studies unravel mysteries of how PARP enzymes work
    https://www.sciencedaily.com/releases/2017/02/170217012511.htm

    Link to the article in the bottom.

    To be honest I didn't read whole study, just the summary on ScienceDaily.

    "The second study reports how PARP-1 regulates embryonic stem cell self-renewal and pluripotency (ability to become different cell types), but without using its enzymatic activity. Instead, in this case, PARP-1 functions as a structural component of chromosomes in the nucleus, creating binding sites for the critical embryonic stem cell transcription factor Sox2. This action allows transcription of genes necessary to maintain the ability of embryonic stem cells to continue self-renewing, rather than becoming a specific cell type, the research shows."

    But if I understand correctly PARP inhibitors would be viable option against glioma stem cells, since SOX2 is associated with CSCs?

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  8. Semyon12 February 2018 at 02:31

    At the moment I'm considering the use of Olaparib and collect all information about possible dosages and schedules.

    SNO 2017, OPARATIC trial
    http://www.practiceupdate.com/content/sno-2017-olaparib-looks-promising-in-combination-with-temozolomide-in-relapsed-glioblastoma-and-is-well-tolerated-in-combination-with-short-course-radiation-in-elderly-patients-with-newly-diagnosed-disease/60787/13/1/2?usersourceid=2287&trendmd-shared=1

    "The expansion cohort dose was defined as temozolomide 75mg/m2 of body surface area daily + olaparib 150 mg once daily on days 1 - 3 weekly. In the expansion cohort, nine of 13 patients completed cycle 1, two of 13 completed cycle 2, and two of 13 completed cycle 3."

    I did not quite understand the information about the cycles in this trial.
    1 cycle = 1 week?
    This means that the maximum duration of taking Olaparib was 3 weeks (on days 1-3 of each week) ???

    2017-2018 https://clinicaltrials.gov/ct2/show/NCT03212742
    In this open-label study, for example, such a dose is proposed in combination with radiation therapy and temozolomide:
    "We propose 7 dose levels to reach the target dose of 400 mg per day (200 mg twice daily) of olaparib continuously DL1 (starting dose level) : Olaparib 50 mg Q12H Monday to wednesday DL2 : Olaparib 100mg Q12H Monday to wednesday DL3: Olaparib 100mg Q12H Monday to friday DL4 : Olaparib 200mg Q12H Monday to wednesday DL5: Olaparib 200mg Q12H Monday to friday DL6: Olaparib 200mg Q12H, continously."

    Have you seen other information about the doses / schedules of Olaparib in the trials for glioblastoma?

    ReplyDelete
    Replies
    1. Stephen W12 February 2018 at 17:50

      I think a cycle in the OPARATIC trial is considered to be 8 weeks: 42 days of TMZ (6 weeks), plus a two week break.

      "After recovery from surgery, patients receive oral olaparib once or twice daily and oral temozolomide once daily on days 1-42. Treatment repeats every 8 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity."

      Olaparib given on days 1-3 each week. Olaparib on days 1-5 per week in the OPARATIC trial was apparently too myelosuppressive so was reduced to day 1-3 every week.

      A much simpler schedule is used when olaparib is given alone: twice daily every day of a 28 day schedule.
      https://clinicaltrials.gov/ct2/show/NCT03212274

      Delete
    2. Stephen W12 February 2018 at 18:01

      More details on OPARATIC trial here:
      https://clinicaltrials.gov/ct2/show/NCT01390571

      They don't call it "OPARATIC" in this clinicaltrials.gov entry, but according to this ASCO abstract it is the same trial.
      https://meetinglibrary.asco.org/record/146706/abstract

      Delete
    3. Semyon14 February 2018 at 05:27

      Stephen, thanks a lot for your help!

      In the end, I consider adding an olaparib to our cocktail on days 1-3 of each week for 100-150 mg. I'm afraid that as a single agent the olaparib will not work and probably it needs to be added while there is an effect from Avastin + Lomustin.

      Unfortunately, I'm not a doctor, and not even a nurse. I am a lawyer. But I have to make decisions, because the standard decision of doctors is just a few standard drugs without any hope. I have to decide something and this is a big responsibility, and it's terrible.

      By the way, strangely, in this study, one of the conditions for participation is the presence of IDH1/2 mutations.
      https://clinicaltrials.gov/ct2/show/NCT03212274
      "Patients with previously identified IDH1/2 mutations can be enrolled on the trial, but must be verified in the central study laboratory"
      And there are no conditions for PTEN.

      Delete
    4. Stephen W14 February 2018 at 10:27

      This trial is being run at Yale by Ranjit Bindra, whose lab identified sensitivity to PARP inhibitors in IDH1 mutant gliomas.
      https://www.ncbi.nlm.nih.gov/pubmed/28148839

      So that is the hypothesis they're testing in this particular trial.

      Delete

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