Olaparib for resistant prostate cancer

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In what is the first (and hopefully one of many) example of using modern genomic methods to match treatments to the molecular defects in prostate cancer, the FDA has just granted “breakthrough designation” to olaparib, a drug made by AstraZeneca. This followed a publication in the NEJM with nearly as many authors as patients, illustrating the power of team science and international collaboration.

Cancer cells develop numerous mutations that provide them with the ability to divide, metastasize, escape immune surveillance and so forth. One of the drivers of this mutation cascade is genetic instability, in part due to the accumulation of mutations that keep the cells from correcting DNA alterations. These mutations in DNA-repair enzymes can leave the cancer susceptible to additional inhibitors of DNA repair, one of which is PARP, an enzyme found in the nucleus that detects DNA strand breaks and initiates repair. When olaparib interferes with this enzyme, cells can become so genetically unstable they die.

In the TOPARP-A trial, 50 patients who had castrate resistant prostate cancer and had progressed on second generation anti-androgen treatment and docetaxel were given olaparib. 16 of 49 evaluable patients responded, however the exciting finding was that because these patients participated in the clinical trial and allowed the investigators to biopsy their tumors, it was possible to relate response to the presence of defects in the DNA repair genes. For this subgroup, 14 of 16 responded, indicating that using the repair defects as a biomarker you could predict high response rates, while at the same time, patients without such genetic defects had a much lower response rate (2/33). There is an excellent video that illustrates the results accompanying the publication that you can find by clicking here.

Although this is terrific news for prostate cancer patients, it brings a number of challenges. Testing for genetic mutations is a growing (and somewhat expensive) process. When compared to giving patients a drug that predictably won’t work, however, it can be very cost effective. Second, when you biopsy a tumor, the results can vary depending on where you biopsy as I discussed in this previous blog. “Liquid biopsies” of circulating DNA or tumor cells may provide some help in meeting this challenge.  Third, responses to targeted therapies such as olaparib tend to be rather short-lived, as the cancer cells continue to mutate to find ways around the new agent. The hope would be that combining a targeted treatment like olaparib with an immune approach might bring more prolonged responses. Finally, we must find a way to deal with the extraordinary costs of the new oncology drugs. The actual cost of olaparib is $13,440/month according to this article in the ASCO post. I have previously opined on this issue and invite you to join the discussion by clicking here.

3 Comments

Filed under General Prostate Cancer Issues, Prostate cancer therapy, Targeted treatment

3 responses to “Olaparib for resistant prostate cancer

  1. Marshall

    Keep up your work and evaluations!

  2. Bob Lederer

    Excellent information. This is so exciting to see, as you predicted last year, that we are on the cusp of more tumor specific treatments. I agree with you that at this point in a man’s life, cost will be a deal breaker. We certainly need a new, sustainable and affordable health care system.

  3. Bryce

    Great blog entry. Glad I found this site. Good stuff. I’m a big fan of genomic sequencing and using that to pinpoint the molecular abnormalities that an advanced cancer patient has. Does it really matter what the tumor of origin is anymore? In Jan ’15 I pushed for genomic sequencing to find molecular abnormalities that fueled my advanced aggressive prostate cancer. Sequencing showed hyperactivity along Pi3k signaling pathway (P53, pi3k and PTEN loss) and i used that data to get on a pi3k inhibitor clinical trial drug. 14 months later cancer still shut down (progression free). If my cancer starts growing again, I’ll just sequence the met (blood biopsy most likely) and go after the new culprit. If sequencing had shown that i had DNA repair pathway alterations like BRCA1/BRCA2 I would have went after PARP inhibitors as well. Thanks for sharing this!

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