Is there ANY role for estramustine phosphate in treatment of CRPC today?

The appropriate, individual treatment of men with metastatic and non-metastatic forms of castration-resistant prostate cancer (CRPC) has become vastly more complicated over the past 5 years.

After the approval of docetaxel (Taxotere)-based chemotherapy in 2004, which was the first time any drug had been shown to be extend survival in the treatment of CRPC, we successively saw the additional approvals of

  • Sipuleucel-T (Provenge) in 2010
  • Cabazitaxel (Jevtatna) in 2010
  • Abiraterone acetate (Zytiga) in 2011
  • Enzalutamide (Xtandi) in 2012
  • Radium-223 dichoride (Xofigo) in 2013

Other agents for which there had been significant hope failed to meet predefined endpoints in clinical trials, but there may well be more drugs on the way over the next 2 or 3 years (e.g., rilimogene galvacirepvec/rilimogene glafolivec [Prostvac] and ARN-509). But at present there is very little real clarity about the most appropriate combinations and sequencing of the treatments we already have in the management of CRPC.

The question therefore arises whether there is really any role at all for older forms of chemotherapy like mitoxantrone and estramustine phosphate in the management of late stage prostate cancer.

Mitoxantrone was initially approved for the palliation of pain in men with hormone-refractory prostate cancer back in 1996. (It had been approved for other uses years earlier.) Some data appear to suggest that it can still be used for men with bone pain in very late stage disease, but this use of of mitoxantrone has largely been superseded by the availability of radium-223.

Estramustine phosphate is an even older type of orally administered chemotherapy that had historic use in the treatment of men with very late stage prostate cancer back in the 1970s — before even the LHRH agonists were available. It was usually used at a total dose of 560 mg/day, and such use was associated with significant risk for severe thromboembolic events and related complications that could lead to patient deaths.

A newly published, small, single-arm trial by a group of Japanese researchers (Inoue et al.) has suggested — and we would emphasize that this is only a suggestion — that estramustine phosphate may still have some value in the treatment of late stage prostate cancer when it is given at a significantly lower dose (140 mg twice a day, p.o).

The paper in Clinical Genitourinary Cancer indicates that the researchers were able to give this drug relatively safely and at a low dose to 31 patients who were followed until death (and received a variety of other drugs either before or, more usually, after treatment with estramustine, including things like docetaxel, steroids, abiraterone, and enzalutamide). The authors further report that:

  • 4/31 patients were treated with docetaxel before they were treated with estramustine phosphate.
  • 10 patients (32 percent) had a decrease of ≥ 50 percent in their PSA level, of whom two had received docetaxel chemotherapy prior to treatment with estramustine.
  • The median time to PSA progression was 140 days (range, 117 to 260 days).
  • The median progression-free survival was 213 days (range, 167 to 422 days).
  • The 3-year disease-specific survival rate was 68.6 percent.
  • The 3-year overall survival rate was 59.9 percent.
  • Side effects included grade 1 and grade 2 nausea, vomiting, anorexia, and gynecomastia (but no thromboembolic complications)

The potential value of estramustine phosphate for the majority of men with CRPC here in the USA is probably very limited today. However, it is worth remembering that older drugs like this do still exist, and they may still have uses alone or in combination with other and newer drugs. What Inoue and his colleagues have shown us is that it  may be possible to use this drug with greater safety than previously recognized, which does at least reinforce the possibility. They also note that the cost of treatment with estramustine phosphate (at least in Japan) is very low — which is increasingly becoming a factor in the management of late stages of many disorders (prostate cancer specifically included).

Editorial comment: The “New” Prostate Cancer InfoLink thanks Dr. Takahiro Inoue and Prof. Osamu Ogawa of Kyoto University Graduate School of Medicine for promptly providing us with a copy of the full text of this article for our review.

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