When is radiopharmaceutical therapy most appropriately initiated in men with mCRPC?

A newly published paper by a team of Italian researchers has added a wrinkle to the critical questions about the most effective current and future forms of sequential therapy for men with metastatic, castration-resistant prostate cancer (mCRPC).

Three different “bone-seeking” radiopharmaceuticals have now been approved pretty much world-wide for the treatment of men with mCRPC. Two of them (strontium-89 choride/Metastron and samarium-153 lexidronam/Quadramet) are so-called β-particle emitters approved exclusively for the palliation of bone pain associated with skeletal metastases; the third (radium-223 dichoride/Xofigo) is an α-particle emitter that has been shown to reduce pain and to extend survival.

One of the concerns about the use of all three of these agents has long been the degree to which the toxic side effects of systemic radiation therapy using injectable radioactive agents may have downsides that counteract the upsides of pain relief. This concern is valid to some degree whether the drugs are used alone or in combination with other agents, although it certainly appears that it should be less of a concern with the newer α-emitter radium-223.

This is where the results of the small pilot study just published by Borsò et al. become relevant.

Borsò et al. wanted to know whether, when standard docetaxel-based chemotherapy was given to patients after treatment with samarium-153 lexidronam (also known as samarium-153-labeled ethylenediamine tetramethylene phosphonic acid  or Sm-EDTMP), there was evidence of either increased toxicity and/or evidence of reduced clinical effectiveness on the patients’ oncologic outcomes. So they put together a small, pilot study to test this.

They enrolled men with mCRPC who had clearly evident skeletal metastases. These men were initially treated with a single dose of Sm-EDTMP ( at 37 MBq/kg). About 6 weeks later, they were then started on standard docetaxel-based chemotherapy (75 mg/m2 intravenously every 21 days for at least six cycles).

Here is what the authors report:

  • 30 men with mCRPC were enrolled into the pilot trial.
  • > 80 percent of the patients indicated favorable biochemical responses to treatment (i.e., a drop in their PSA levels).
  • Average times to clinical progression were
    • A median of 9.1 months
    • A mean of 9.8 months
  • Average overall survival times were
    • A median of 19.9 months
    • A mean of 24.5 months
  • 5/24 patients (21 percent) were still alive at > 5 years after enrollment.
  • No additional hematological toxicities were observed when docetaxel was administered after Sm-EDTMP — other than those expected when administering docetaxel-based chemotherapy alone.

The authors conclude that

Prior administration of Sm-EDTMP does not cause additional toxicities for subsequent treatment with docetaxel and does not reduce the antitumor efficacy of the latter.

Borsò et al. also suggest that their data justify “further investigations on the possible synergistic effects of combined strategies” with Sm-EDTMP and docetaxel. However, The “New” Prostate Cancer InfoLink would argue that what these data really justify is intense investigation into when we should be initiating treatment with radium-223 prior to or in combination with docetaxel-based chemotherapy in men with mCRPC.

We already know that treatment with radium-223 extends life (for a median of about 2 months), and we also know that α-emitters should have fewer risks as systemic therapeutic agents than β-emitters. At least in theory, some men with bone metastases might be eligible for sequential treatment with radium-223 after abiraterone acetate or enzalutamide (or both) and immediately prior to initiation of chemotherapy; others might be appropriate candidates for treatment with a combination of a drug like abiraterone acetate or enzalutamide and radium-223 prior to chemotherapy. In addition, there is the simpler possibility of initiating combination treatment with radium-223 started immediately prior to docetaxel-based chemotherapy (but presumably after progression on abiraterone acetate or enzalutamide or both) in men with painful bone metastasis. In the last-mentioned case, a small pilot trial in 60 patients is, in fact, under way, and the initial results are expected late next year.

This new study by Borsò et al. should help the urology and medical oncology communities to work more closely with the nuclear medicine community to find the optimal ways in which to apply treatment with “bone-seeking” radiopharmaceuticals for those men with mCRPC who have or are at very high risk for serious bone pain after failure of standard forms of androgen deprivation therapy, either before or in combination with chemotherapy.

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