Olaparib in treatment of men with mCRPC and selected HRR gene mutations


According to a media release issued by AstraZeneca and Merck on Friday evening, olaparib (Lynparza) has shown “a statistically significant and clinically meaningful improvement in … overall survival (OS)” in men with metastatic, castration-resistant prostate cancer (mCRPC) and BRCA1/2 or ATM gene mutations (homologous repair gene mutations or HRRm).

The Phase III PROfound trial had previous shown that olaparib was effective in delaying radiographic disease progression in the same group of men with HRRm (see this media release). It is hoped that Lynparza will be approved by the US Food and Drug Administration for the treatment of prostate cancer in this group of men later this year (see here).

The 387 patients enrolled in the PROfound trial all had mCRPC and had all progressed on treatment with one of the new hormonal agent treatments, e.g., enzalutamide (Xtandi) and abiraterone acetate (Zytiga). The patients were divided into two cohorts based on the type of HRRm they exhibited on genetic testing:

  • Cohort A included 245 patients with alterations in BRCA1BRCA2, or ATM.
  • Cohort B included 142 men with any of 12 other HRR alterations.

The 387 patients were then randomly assigned in a 2:1 fashion to treatment with either olaparib (at 300 mg twice daily) or the treating physician’s choice of enzalutamide or abiraterone acetate + prednisone.

The results available to date seem to indicate that olaparib is effective only in the men with the three HRRm specified (BRCA1/2 and ATM).

For additional information, see this report on the Cancer Network web site.

11 Responses

  1. On a follow-up tack, it is of interest to many of us whether “second line” PARP inhibitors (e.g., rucaparib, talozaparib, etc.) are more effective or can be used when olaparib fails.

    The late Professor Bill Burhans, who studied PARP inhibitors at Roswell Park, and was himself BRCA2+ and got almost 2 years from olaparib before it failed him, was of the opinion that the second-line PARP inhibitors could be used for follow up. He even discussed this with his UK-based colleague, Johann DeBono.

  2. Rick:

    If the rumors are true, then the real question is going to be whether talozaparib will become the PARP inhibitor of choice once it gets to market. If it is that much more effective than the other PARP inhibitors, then it seems unlikely (at least to me) that any of the earlier products are going to be effective for most patients once they progress on talozaparib.

    And if talozaparib isn’t that much more effective than the other PARP inhibitors, then Pfizer will have paid an awful lot of money to buy Medivation!

  3. I have been on an investigator-initiated clinical trial of Lynparza (Olaparib) for NON-metastatic PCa at Johns Hopkins for about a year and a half with truly wonderful results with aggressive cancer.

    My medical summary:

    Age 82 and in otherwise good health

    BRCA2 positive.

    Diagnosed March 2008; prostatectomy in April 2008; Gleason 4 + 5 = 9; small tumor and encapsulated; clean pathology findings. Recurrence 3 years later: radiation (28 sessions) and ADT (6 months). Interim episode of bladder cancer (in remission). Renewed PSA rise 2 years after radiation/ADT. No progression (metastasis) noted on bone and PSMA scans

    Entered Hopkins study when PSA reached 1.0 ng/ml, the minimum PSA inclusion criterion for study participation.

    After a month of daily olaparib pills (300 mg, 2 pills, twice daily) PSA started slow but linear decline. Side effects very minimal and totally tolerable (loss of appetite — good! I was happy to lose the extra weight; mild neuropathy in toes which I mostly don’t notice).

    PSA has declined from the 1.0 at start to 0.20 ng/ml as of April 2020.

    Results in the study cohort have favored the BRCA-positive participants.

    This is not intended to be curative, but continues to nadir with an endpoint of how long from nadir (lowest PSA reached and start of increase) until doubling of original PSA of 1.0 — so 2.0 ng/ml. At 82 that can be a lot of good years and a bus — or COVID-19 — can get to you first.

    Olaparib is not FDA approved for prostate cancer so forget about Medicare or insurance. At $15,000 (approx.) a month, planning should include winning the lottery. Cannot say enough good things about my care at Hopkins; a two-day trip each month, but FedEx drug refill dispensation for the time being because of pandemic. Physician and study principal investigator (PI) is fabulous. Dr. Emmanuel Antonorakis.

  4. Hi Steve … Glad to hear that the olaparib/Lynparza has been working for you. I expect to see this drug approved for the treatment of at least some prostate cancer patients in the near future.

  5. Thank you.

    Steve

  6. Meant to add that, by good fortune (three’s a charm), my physician wife is a Principal Investigator with her site doing mostly CNS trials. So monthly blood draws and lab work plus day-of-visit Vitals are all done at her site and faxed/e-mailed to Baltimore. A huge advantage at this particular time.

  7. Great results, Steven.

    While none of the PARP inhibitors are yet approved for prostate cancer, we are aware of several BRCA+ men , whose insurance has approved the use of a PARP inhibitor, most often olaparib.
    We would encourage any BRCA+ man to speak to his doctor about going on a PARP inhibitpr, and ask the doctor to make the case to the insurance company … they are receptive, both Medicare and pre-Medicare. The insurers understand the pan-cancer relationship of the PARP to the BRCA mutation.

    Steven … How are your blood counts holding up?

  8. Rick:

    Thanks for your comments and kind words. I am on Medicare at 82 plus a supplement plan with United Healthcare / AARP so I would guess that Medicare either would or would not approve. Not the kind of organization prone to individual determination. They are policy driven. On the other hand, as long as there is a positive benefit I would think I would remain in the study. If olaparib stops working for me and I am out of the study it would — I guess — serve no purpose post-study. Will face that at the time. Prostate cancer used to keep me awake and sweating. Amazing how 82 puts things and life in perspective.

    As to blood count, I had two experiences of anemia. Their minimum was 10 and I was there for one; Hopkins decided on a transfusion. For the next visit, my brilliant wife had me on the treadmill for an hour before the subsequent blood draw. I hate exercise, which is not helpful. That was quite a few months ago. Since then my blood work has been perfect, but I do try to watch Netflix in our home gym to ease the dislike of regular exercise. Olaparib has been very tolerable and my wife said she wishes my labs on most of her patients

    Actually all my monthly lab reports have been unremarkable, especially for my age.

  9. Your wife should be available to every man with advanced PCa, Steven. … Exercise can be so helpful, as you have witnessed.

    Come join us on one of our advanced prostate cancer virtual support groups. We’ll introduce you to a couple of other BRCA+ men who have had done well on olaparib outside a trial — and their insurance is paying for the drug. And to another remarkable 82-year-old, going on 65! You’ll find more info at https://ancan.org.

  10. Rick:

    Thank you for that nice note. I will share it with my wife. I don’t know if she has so far saved my life but 11 years with Gleason 9 and — as of yesterday — a PSA of 0.021 in a Hopkins olaparib trial certainly illustrates my good fortune in having my care managed so well by my wife, who is a Primary Investigator in CNS studies.

    Just got off the phone after a tele visit with my Hopkins physician. Great technology. My wife took my vital signs before leaving for her practice and Hopkins had them by e-mail minutes later. Hopkins too feels olaparib will be approved shortly for prostate cancer in a metastatic setting, which I happily do not face, but I have to assume that piece of luck won’t last forever.

  11. Rick:

    I did sign up for the group. Thanks.

    Steve

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