A small subgroup of patients with mCRPC responds to carboplatin + everolimus


There is an increasing level of evidence about our ability to identify small and carefully selected groups of patients with advanced disease who, despite the fact that they no longer respond to standard treatments, may respond well to other forms of therapy.

A new paper by Vaishampayan et al., published on line in Urology (the so-called “Gold Journal”) has recently indicated that two of 10 patients who had metastatic, castration-resistant prostate cancer (mCRPC) and were unresponsive to treatment with docetaxel-based chemotherapy, but who demonstrated negative nuclear pAkt staining on immunohistochemistry, exhibited significant responses to treatment with carboplatin + prednisone + everolimus.

pAkt is a regulator of the expression of the androgen receptor, and so men who are immunohistologically negative for nuclear pAkt have a different cancer biochemistry than men who express pAkt and are therefore immunohistologically positive for this protein. (Understanding these signalling pathways and how they affect growth of specific cancers is very complex, and we certainly aren’t going to try to explain this in detail but those who are interested in the pAkt signally pathway could have a look here.)

Vaishampayan et al. carried out a small, Phase II clinical trial of the combination of carboplatin + prednosine + everolimus among 26 men who were mCRPC; had already progressed after treatment with docetaxel-based chemotherapy; had a good performance status; and had good bone marrow, renal, and liver function. The primary study endpoint was time to PSA progression or clinical progression of their disease.

Here is what they found:

  • The average (median) age of the patients was 69 years.
  • Most patients gained little benefit from their treatment.
    • Average (median) time to progression was 2.5 months.
    • Average (median) overall survival was 12.5 months.
  • Among 10 patients tested for expression of nuclear pAkt
    • 8/10 patients were positive and progressed within 9 weeks
    • 2/10 patients were negative and only progressed at 30 and 48 weeks respectively.

In other words, it is possible that carefully selected patients who do not express nuclear pAkt may be unusually responsive to carboplatin-based chemotherapy together with everolimus (Afinitor®).

Now the degree of response is still small (about 6 to 12 months) and we are going to need to see if this response can be replicated in larger numbers of men with pAkt-negative disease, but it may well be that testing for expression of nuclear pAkt offers an opportunity for at least a select group of men with mCRPC who are more likely to respond to treatment with carboplatin + everolimus. We would also note that only 2/26 men being treated (about 8 percent) had this type of response, so we aren’t taking about even a quarter of all the men with mCRPC. However, …

This is yet another example of how individualized care (so-called “personalized” medicine) may well offer opportunities for some carefully characterized and selected patients in the future.

5 Responses

  1. Problem being unless you get plugged into a trial you are unlikely to get tested for nuclear pAkt.

    Even if tested and you’re part of the small percentage, unless it’s a phase III trial getting an off-label approval from insurance is a pain. I have a DNA alteration that could respond to olaparib and I am having having a bear of a time.

  2. Dear Dominic:

    No one was implying that any of this was going to be easy … but much of it will become easier with time as the data become clearer. I understand and grant that this may not help you in the short term.

  3. Yikes! The thought of that much carboplatin makes me want to throw up. OK … well I am still nauseous from last week’s cabazitaxel. (My oncologist talked me into trying another cycle.)

    Do we know how many cycles they did? I wonder what type of quality of life they had during treatment.

    Bill Manning

  4. Dear Bill:

    If you look at the trial protocol summary on ClinicalTrials.gov it may have been only two cycles, but it is not exactly clear. To your point, however, what is clear is that the initial drug dose levels given to the first few patients were higher than most could deal with, and had to be lowered.

    I have only seen the abstract of this paper and the summary protocol for the trial. I would assume that some of your questions would be answered in the full text of this paper if one wanted to track down a copy.

  5. There is good evidence going back some time that carboplatin can be effective for mutated/neuroendocrine disease. It was recently described to me as a “PARP inhibitor light”.

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