Repetitively dosed docetaxel and ¹⁵³samarium-EDTMP as an antitumor strategy for metastatic castration-resistant prostate cancer

Abstract

Background: β-emitting bone-seeking radiopharmaceuticals have historically been administered for pain palliation whereas docetaxel prolongs life in patients with metastatic castration-resistant prostate cancer (mCRPC). In combination, these agents simultaneously target the bone stroma and cancer cell to optimize antitumor effects. The toxicity and efficacy when each agent is combined at full, recommended doses, in a repetitive fashion is not well established.

Methods: Patients with progressive mCRPC and ≥ 3 bone lesions received (153) Sm-EDTMP (samarium-153 ethylene diamine tetramethylene phosphonate) at a dose of 1.0 mCi/kg every 9 weeks and docetaxel at a dose of 75 mg/m(2) every 3 weeks. In the absence of unacceptable toxicity, patients were allowed to continue additional cycles, defined by 9 weeks of treatment, until intolerance or biochemical/radiographic disease progression.

Results: Of the 30 patients treated, approximately 50% were considered to be taxane-naive, 36.7% were taxane-refractory, and 13.3% had previously been exposed to taxanes but were not considered refractory. Patients received on average 2.5 cycles of treatment (6.5 doses of docetaxel and 2.5 doses of (153) Sm-EDTMP). Twelve patients (40%) demonstrated a decline in their prostate-specific antigen level of ≥ 50%. The median progression-free survival (biochemical or radiographic) was 7.0 months and the overall survival was 14.3 months. Nine patients (30%) did not recover platelet counts >100 K/mm(3) after a median of 3 cycles to allow for additional treatment, with 4 patients experiencing prolonged thrombocytopenia. The most common reasons for trial discontinuation were progressive disease and hematologic toxicity.

Conclusions: The results of the current study indicate that (153) Sm-EDTMP can be safely combined with docetaxel at full doses on an ongoing basis in patients with mCRPC. Although thrombocytopenia limited therapy for some patients, preliminary efficacy supports the strategy of combining a radiopharmaceutical with chemotherapy, which is an appealing strategy given the anticipated availability of α emitters that can prolong survival.

Keywords: 153Sm-EDTMP (samarium-153 ethylene diamine tetramethylene phosphonate); chemotherapy; docetaxel; prostate cancer; radiopharmaceutical.

Figure 1

Treatment schedule for expansion cohort. ¹⁵³Sm-EDTMP 1 mCi/kg and docetaxel 75mg/m².

Figure 2 a and 2b

Taxane-naïve patients received the most ¹⁵³Sm-EDTMP and docetaxel with comparable rates among men with prior taxane exposure who were not considered refractory. Patients considered taxane-refractory prior to trial entry received the fewest cycles of therapy.

Figure 2 a and 2b

Taxane-naïve patients received the most ¹⁵³Sm-EDTMP and docetaxel with comparable rates among men with prior taxane exposure who were not considered refractory. Patients considered taxane-refractory prior to trial entry received the fewest cycles of therapy.

Figure 3

Waterfall graphs of best PSA response stratified by prior taxane exposure. Although PSA declined for all groups, the largest degree of change was seen in taxane-naïve patients.

Figure 4

Overall Survival and Progression-Free Survival (defined by PSA, imaging, or death). The median overall PFS was 7·0 months and OS was 14·3 months.

Figure 5

Waterfall plots of bone markers at week 3 following the first dose of ¹⁵³Sm-EDTMP 1.0 mCi/kg and docetaxel 75 mg/m². Median value labelled in green. Serum and urine N-telopeptide (NTx) declined in the majority of patients. The largest declines were seen with osteocalcin; there was a variable effect on bone-specific alkaline phosphatase (BSAP).