Monday, September 5, 2016

Testosterone to TREAT prostate cancer - are they crazy? No - it just may work. (mHSPC)

This is Part 2. In Part 1 we saw why bipolar androgen therapy (BAT) may be effective for men with metastatic castration-resistant prostate cancer (mCRPC), and the evidence so far in support of that. In this part, we'll look at what we know about BAT in men with metastases who are still hormone sensitive (mHSPC). As you recall, BAT is an experimental therapy for metastatic prostate cancer involving the administration of rapidly alternating treatments of androgen deprivation (ADT) with high-dose testosterone.

In theory, the high doses of testosterone will help the patient feel better and perhaps offset some of the symptoms of ADT (e.g., loss of libido, hot flashes, bone loss, lean muscle loss, mental symptoms).

In pilot trials so far, BAT was able to restore sensitivity to second-line hormone therapy, like Zytiga or Xtandi, in some men who had become resistant to their effects. If it can reverse castration resistance, can it also slow down the development of castration resistance? 

Schweizer et al. report on 29 patients:
  • None of the men in the study had started on androgen deprivation yet.
  • None had symptoms.
  • 10 had a low burden of metastases.
  • 19 had no detectable metastases, but had recurrent disease after an attempt at a cure (i.e., their cancer was micrometastatic)
  • They were all hormone sensitive. That means their PSA went down to less than 4 ng/ml after 6 months of ADT

They then received 3 months of testosterone injections, and then 3 months of ADT. Those cycles continued for a total of 18 months. 
  • They report that 17 men (59%) were still able to achieve their PSA goal (<4 ng/ml) at the end of 18 months. That is, they were still hormone sensitive.
  • Of the 10 patients with detectable metastases at the start, metastases had shrunk completely in 4, and partially in 4. So 8 in 10 (80%) had a positive radiographic response to BAT.
  • Six patients had metastatic progression. 
  • So, 13-15 of the 19 (68-79%) men with recurrent PC with no detectable metastases at the start still had no detectable metastases after 18 months of BAT.
  • Evaluations of quality of life improved.
Since the CHAARTED and STAMPEDE clinical trials, the new standard of care for mHSPC is the combination of ADT and docetaxel chemotherapy. Where would BAT fit in? We saw in Part 1 that BAT may work particularly well in conjunction with chemotherapy that targets the DNA responsible for cell replication. Docetaxel is usually administered in 6 three-week cycles. It may turn out that after an ADT induction period of 6 months, patients may be optimally treated by a high dose of testosterone and docetaxel concurrently. Testosterone would help the chemo patient feel better, and would also tend to raise his red blood cell counts, counteracting any chemo-induced anemia.

Another consideration is whether radiation ought to be included in the mix of early treatments. A few recent studies (see this link and this one) suggest that prostate radiation might still be beneficial to the metastatic patient. Moreover, a lab study suggests that radiation and BAT may be a particularly potent combination.

At this point, all of this is pure speculation. Future expanded clinical trials will have to determine whether BAT is useful for men with mHSPC, and what the optimal sequencing of therapies should be.

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