What to do first for men with mCRPC

The currently “great unanswered” question in the management of advanced prostate cancer is the order of agents to be used in the treatment of men who are receiving first-line therapy for metastatic prostate cancer after it becomes castration-resistant.

What we are going to need will be data from head-to-head trials.

In the interim, what we do have is a new paper by Sonpavde et al. in BJU International based on a retrospective analysis of data from > 1,000 men being treated for metastatic, castration-resistant prostate cancer (mCRPC) within the US Veterans Administration health system between October 2012 and September 2014. And we will begin with our usual caution that retrospective analyses of this type always have to be treated with caution. They are “hypothesis generating” as opposed to “practice changing” data.

So Sonpavde et al. were able to look at data from a group of 1,445 men with metastatic prostate cancer who became castration resistant during the above-mentioned time period. Of those 1,445 men,

  • 1,108 (76.7 percent) were first treated with one of the new anti-androgenic agents — either abiraterone acetate/Zytiga or enzalutamide/Xandi (Group A)
  • 337 (23.3 percent) were first treated with taxane-based chemotherapy (Group B).

Here is what the authors report:

  • There was no significant difference in overall survival (OS) between the men in Group A and Group B.
  • Time to discontinuation of initial treatment was shorter for the men in Group B compared to the men in Group A (hazard ratio [HR] = 2.339; P < 0.0001).
  • Time on standard ADT above the median, prior to initiation of treatment for mCRPC, was associated with
    • Longer OS in Group A as compared to Group B (HR = 0.566; P < 0.0001)
    • Longer time to discontinuation of initial treatment in Group A as opposed to Group B (HR = 0.831; P = 0.0363)
  • Time on standard ADT below the median, prior to initiation of treatment for mCRPC was associated with
    • A higher PSA response rate in Group B as compared to Group A (61.5 vs 51.1 percent; P = 0.0241).
  • Treatment-free interval following discontinuation of first-line treatment for mCRPC was longer for patients in Group B than for patients in Group A (mean, 53 vs 39 days; P = 0.0303).

Sonpavde et al. conclude that:

OS was similar for first-line chemotherapy versus anti-androgen therapy after adjusting for key prognostic factors in this large mCRPC dataset, despite shorter time to discontinuation with chemotherapy and longer treatment-free interval after first-line chemotherapy. These hypothesis-generating data also suggest that duration of prior ADT may assist in the selection of patients for chemotherapy versus anti-androgen therapy.

However, we are going to repeat that people have to be cautious about how they interpret these data. Here are just a couple of the reasons why:

  • Treatment with taxane-based chemotherapy is usually given for a specific number of cycles of therapy (e.g., six cycles), whereas there is no time limit on how long a patient may remain on either abiraterone or enzalutamide.
  • It is probable that patients had some degree of choice in how they got treated in this setting, and many of them may well have selected anti-androgen therapy in order to “avoid” early chemotherapy (whether that was really a good idea or not).

Your sitemaster thinks that the best way to interpret the data from this study is to appreciate that:

  • If you have responded better than average to standard ADT for metastatic prostate cancer, you may well respond better than average to  another anti-androgen as opposed to chemotherapy (but we can’t be sure about that yet).
  • Conversely, if you responded worse that average to standard ADT for metastatic prostate cancer, you may well respond a little better than average to chemotherapy as opposed to another anti-androgen (but we can’t be sure about that either, yet).
  • If there is a difference in overall survival between men who get chemotherapy first for mCRPC as opposed to a drug like abiraterone acetate or enzalutamide (or vice versa), it may not be a very big difference for most patients.

4 Responses

  1. Did this study indicate whether men waited for PSA to rise to a level (2.0) which enabled scans to determine whether their metastases were oligomets in order to treat with spot radiation? Or did they start second level systemic treatment as soon as their PSA started increasing while on primary ADT?


  2. Dear Bob:

    I would suspect the latter. This was a study done at the VA. But I have only seen the abstract, not the entire paper.

  3. I do wish they would have factored in PROVENGE (sipuleucel-T). The data would have been very helpful, and it is an option for first choice for patients once they are mCRPC. Since PROVENGE was FDA approved in 2010, it looks to me like it was available during this study period. It just leaves us with another “I don’t know”, that’s all. Wishful thinking. …

  4. Dear Jan:

    Any patient in this trial could have been given Provenge once they progressed and became metastatic, but Provenge is only approved for mCRPC, and not for nmCRPC. By the time any of the patients in this trial had become metastatic, they were only being followed for survival. It may well be that a lot of them got Provenge after they progressed.

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