Olaparib for Resistant Prostate Cancer

Olaparib for Resistant Prostate Cancer

L. Michael Glode, MD, FACP, FASCO

Feb 16, 2016

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 U.S. FDA has just granted “breakthrough designation” to olaparib. 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. Sixteen 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 of 33). There is an excellent video that illustrates the results accompanying the publication.

Although this is terrific news for patients with prostate cancer, 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, testing 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 post. “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 per month according to this article in The ASCO Post. I have previously opined on this issue and invite you to join the discussion.

This post originally appeared on prost8blog, a blog to help patients and their families understand various aspects of prostate cancer, and is republished here with permission from Dr. Glodé.


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Robert A. Herve, MD

Feb, 19 2016 9:14 PM

Is liquid biopsy really more representative of the all tumor than tissue biopsy, ie is it possible with this technique to show mabny circulating sub types of the initial tumor?

L. Michael Glode, MD, FACP, FASCO

Feb, 22 2016 7:08 PM

Since single cell molecular analysis is certainly a reality, I suspect that this becomes a math problem: i.e. how many single cell analyses (with true and potentially false "hits" as regards sequencing or expression) do you have to do to adequately characterize the total picture in a patient who theoretically (and almost certainly) has more than one metastatic clone contributing in a dynamic fashion to the overall liquid biopsy sample. Since I am very weak at math, let alone truly understanding the complexities involved in the technology, the best I can do is refer you to this commercial site:https://www.qiagen.com/us/resources/knowledge-area/single-cell-resource/single-cell-knowledgehub/

Disclaimer: I have no relationship to qiagen and I did not do a comprehensive search to see what other sites might be out there to assist in understanding the technology better.

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