Changes in prostate cancer circulating tumor cell (CTC) numeration and gamma H2AX positivity before and after treatment with radium 223 for metastatic castrate resistant prostate cancer.

Abstract

211 Background: As an alpha-particle emitting radiopharmaceutical, R is indicated for symptomatic mCRPC patients with bone predominant metastases and no visceral metastases. The current R administration dose was calculated based on body weight and decay factor. This may not be an ideal dose to individual patient (pt) with different body mass and different burdens of bone metastases. We hypothesize that changes in CTC # and the DNA damage marker, γH2AX, could serve as readout for on target effects of R and conducted a pilot prospective biomarker study. Methods: Pts who received R as standard of care for mCRPC and had a baseline CTC # of ≥ 2 were eligible. CTC samples were collected prior to and between 24 and 96 hours post dose 1, 3 and 6 of R. CTC # and γH2AX positivity were performed by Janssen Diagnostics Lab. Results: 10 pts were enrolled and all had > 15 bone metastases at enrollment. 7/10 pts had prior Taxane-based chemotherapy. The median CTC # and γH2AX positivity prior to R were 21 (range: 3-250), and 33% (range: 3% to 80%) respectively. 8 pts completed all 6 doses of R; 2 pts completed 2 doses then elected to hospice due to rapid clinical decline. Among pts completed R, 4 (50%) had bone scan progression within 1 month. No decline in ALKP, PSA, CTC # or increase in gamma H2AX positivity were seen during treatment with R in these 4 pts. 2 pts had CTC # conversion to 0 after dose 3 R at week 9. Both pts had ALKP decline, but no PSA decline during treatment. 1 of these 2 pts had 100% positivity for gamma H2AX after dose 6 R and had prolonged post R PSA response with stable bone scans at last follow up 24 months after the first dose of R. Increases in CTCs’ γH2AX positivity, and > 50% decline of ALKP were observed in 2 pts with germline deleterious mutations in BRCA2 and PALB2. Both pts, however, had a rapid surge in CTC # and PSA after dose 3. Despite stable bone scans, both proceeded with chemotherapy within 2 months after completing dose 6 R. Conclusions: Increase in CTC # and no increase in γH2AX positivity were associated with lack of response to R. The lack of increase in the DNA damage marker, γH2AX, in pts without declines in ALKP, PSA, and CTC # suggests their R doses may need to be increased. Clinical trial information: NCT02981797.