A complete, sustained response of mCRPC to treatment with ABT-888

A newly published report in Frontiers in Oncology is likely to be of considerable interest to many patients currently battling progressive and advanced forms of prostate cancer … but we emphasize that its promise may be limited to a relatively small subset of such patients.

VanderWeele et al. have described the response of a very specific patient to long-term treatment with a drug called veliparib (also known as ABT-888), which is a so-called PARP inhibitor and is still in development. Basically, one 82-year-old patient with metastatic, castration-resistant prostate cancer (mCRPC) has exhibited a complete and sustained response to initial chemotherapy (with carboplatin, gemcitabine, and veliparib) followed by long-term treatment with 38 cycles of veliparib alone. The complete text of this case report is accessible on line.

What do we mean by a “complete and sustained response”? We mean that all signs of the metastases originally evident in his lungs, liver, abdomen, and bowel have vanished, there is no other evidence of prostate cancer, and he continues to be treated on veliparib maintenance therapy some 30 months after initially being enrolled into a Phase I clinical trial of this drug. As far as both the authors of the paper and The “New” Prostate Cancer InfoLink are aware,  “this is the first report of complete response to PARP inhibitor-based therapy for a patient with prostate cancer.”

Having said that, it is also clear that this patient had some very specific characteristics that would suggest that he is “different” from the average man with advanced prostate cancer: he had only visceral (i.e., soft tissue) metastases, along with a BRCA2 deletion as well as other molecular markers for prostate cancer (TMPRSS2-ERG rearrangement and TP53 alteration). He initially exhibited only a partial response to the treatment with chemotherapy + veliparib; it was only after several months of maintenance therapy with veliprib alone — and 10 months after he started chemotherapy + veliparib — that he exhibited a complete response.

The authors are very clear that “It is unknown if discontinuing veliparib would result in disease recurrence or continued durable response.” And unfortunately the paper does not give us information about the patient’s PSA levels over the course of his chemotherapy and subsequent maintenance therapy on veliparib, but …

What this paper does show us is that targeted therapy that includes a PARP inhibitor very definitely can induce complete responses with long-term survival benefit in at least some men with mCRPC. It seems likely, at this time, that this may be limited to men with BRCA1/2 deletions. It is also clear that it will take some time to see where else a finding like this can lead us.

Last but not least we should note that this patient had been through a great deal to achieve such a response during this clinical trial. At 73 years of age he was initially treated for a Gleason 3 + 4 prostate cancer with external beam radiation. Some 3 years later he started androgen deprivation therapy (ADT) because of a rising PSA but he still needed multiple surgical procedures for continued urinary retention. When he was about 79, the latest TURP demonstrated the recurrence of prostatic adenocarcinoma with sarcomatoid features that led to a complete radical cystoprostatecomy (surgical removal of the prostate and the bladder). Pathological examination of the surgical tissues showed high-grade prostatic adenocarcinoma with extensive sarcomatoid and focal neuroendocrine differentiation — stage pT4N0 with 20 regional lymph nodes negative for cancer. He continued to be treated with ADT after the cystoprostatectomy, with an undetectable PSA, but his disease recurred again, with evidence of metastasis within the pelvis and his lungs. After enrollment in the above-mentioned trial, he had a significant series of side effects to treatment (including rectal bleeding, diarrhea, thrombocytopenia, anemia requiring transfusion, and fatigue) but with some modifications to his drug regimen he was able to recover from these.

It is not clearly stated in the paper, but we suspect that this patient has remained on ADT throughout the period of chemotherapy and long-term maintenance on veliparib.

4 Responses

  1. Just to clarify for the uneducated like myself, Mike — by BRCA2 deletion, do you mean the BRCA2 gene is present in a mutant form where some of its genomic characteristics have been deleted?

    Tx, rd

  2. Rick:

    Frankly, it wasn’t precisely clear to me what the authors meant by “BRCA2 deletion.” I therefore used exactly the term that they had used in the paper.

  3. Mike,

    As I understand it, mutations of BRCA1 and BRCA2 are identified by gene sequencing. This patient’s BRCA2 mutation was identified by a more specific (not specified) BRCA2 detetion test. No question that this patient was more predisposed to get prostate cancer and he did. Still this is a very impressive response to ABT-888! It would be nice to know that it works without chemotherapy at a earlier stage of the disease in such predisposed patients.

    Ralph V

  4. All of the PARP inhibitors under development (and there are five or six companies working on PARP inhibitors) are going to be approved (if approved) to be used in conjunction with at least one companion diagnostic test. Olaparib, by AstraZeneca, has been approved for certain breast and ovarian cancers. It is also being tested against prostate cancer.

    The PARP gene provides a backup DNA repair system. The BRCA genes provide the primary DNA repair mechanism. If there are certain types of defects in the BRCA genes, DNA repair won’t always happen correctly (which is why certain types of BRCA mutations result in cancer in the first place.) By inhibiting the working of the backup system (PARP gene), the idea is that the DNA repair process will be too broken to produce usable DNA, and the cancer cells will be unable to reproduce and will die. You (or your tumor) would have to have certain BRCA mutations in order for the drug to work (testing is being done on both germline cells and tumor cells).

    There are also tests called HRD (homologous recombination deficiency) tests which determine how badly a given cancer cell’s ability to repair DNA has been degraded (possibly by some means other than BRCA defects). Drug companies are hopeful that this type of testing may identify other patients (other than those with specific BRCA mutations) who may respond to PARP inhibitors and/or platinum drugs.

    Most new cancer drugs are usually tested (and initially approved) for patients who have already tried everything else. If these drugs prove to be effective, they will probably move to first-line treatment pretty quickly (for patients determined to be likely to respond). Considering how aggressive BRCA-related cancers can be, this offers some real hope for those folks. (Consider that Angelina Jolie had her breasts removed proactively because of her BRCA status. Sergey Brin, cofounder of Google, had his prostate removed proactively because of his BRCA status).

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