Circulating Tumor Cell Number as a Response Measure of Prolonged Survival for Metastatic Castration-Resistant Prostate Cancer: A Comparison With Prostate-Specific Antigen Across Five Randomized Phase III Clinical Trials

Abstract

Purpose Measures of response that are clinically meaningful and occur early are an unmet need in metastatic castration-resistant prostate cancer clinical research and practice. We explored, using individual patient data, week 13 circulating tumor cell (CTC) and prostate-specific antigen (PSA) response end points in five prospective randomized phase III trials that enrolled a total of 6,081 patients-COU-AA-301, AFFIRM, ELM-PC-5, ELM-PC-4, and COMET-1- ClinicalTrials.Gov identifiers: NCT00638690, NCT00974311, NCT01193257, NCT01193244, and NCT01605227, respectively. Methods Eight response end points were explored. CTC nonzero at baseline and 0 at 13 weeks (CTC0); CTC conversion (≥ 5 CTCs at baseline, ≤ 4 at 13 weeks-the US Food and Drug Administration cleared response measure); a 30%, 50%, and 70% decrease in CTC count; and a 30%, 50%, and 70% decrease in PSA level. Patients missing week-13 values were considered nonresponders. The discriminatory strength of each end point with respect to overall survival in each trial was assessed using the weighted c-index. Results Of the eight response end points, CTC0 and CTC conversion had the highest weighted c-indices, with smaller standard deviations. For CTC0, the mean (standard deviation) was 0.81 (0.04); for CTC conversion, 0.79 (0.03); for 30% decrease in CTC count, 0.72 (0.06); for 50% decrease in CTC count, 0.72 (0.06); for 70% decrease in CTC count, 0.73 (0.05); for 30% decrease in PSA level, 0.71 (0.03); for 50% decrease in PSA level, 0.72 (0.06); and for 70% decrease in PSA level, 0.74 (0.05). Seventy-five percent of eligible patients could be evaluated with the CTC0 end point, compared with 51% with the CTC conversion end point. Conclusion The CTC0 and CTC conversion end points had the highest discriminatory power for overall survival. Both are robust and meaningful response end points for early-phase metastatic castration-resistant prostate cancer clinical trials. CTC0 is applicable to a significantly higher percentage of patients than CTC conversion.

Fig 1.

CONSORT diagram for the five randomized clinical trials combined. bCTC, baseline CTC; bPSA, baseline PSA; CTC, circulating tumor cell; PSA, prostate-specific antigen.

Fig 2.

Discriminatory power of post-therapy circulating tumor cell (CTC) and prostate-specific antigen (PSA) response measures for survival in metastatic castration-resistant prostate cancer registration trials. CTC0, CTC count ≥ 1 at baseline and 0 at week 13; CTCconv, CTC conversion (CTC count ≥ 5 at baseline and ≤ 4 at week 13); CTC30, CTC count ≥ 5 at baseline and a 30% decline from baseline to week 13; CTC50, CTC count ≥ 5 at baseline and a 50% decline from baseline to week 13; CTC70, CTC count ≥ 5 at baseline and a 70% decline from baseline to week 13; PSA30, PSA level ≥ 5 ng/mL at baseline and a 30% decline from baseline to week 13; PSA50, PSA level ≥ 5 ng/mL at baseline and a 50% decline from baseline to week 13; PSA70, PSA level ≥ 5 ng/mL at baseline and a 70% decline from baseline to week 13. SD, standard deviation. ClinicalTrials.gov identifiers for the trials are: COU-AA-301, NCT00638690; AFFIRM, NCT00974311; ELM-PC-5, NCT01193257; ELM-PC-4, NCT01193244; COMET-1, NCT01605227.

Fig 3.

Kaplan-Meier estimates of responders versus nonresponders along with 95% CIs for the circulating tumor cell count ≥ 1 at baseline and 0 at week 13 (CTC0) and prostate-specific antigen level ≥ 5 ng/mL at baseline and a 50% decline from baseline to week 13 (PSA50) response end points at 13 weeks, for the five metastatic castration-resistant prostate cancer registration trials. (A) COU-AA-301 (ClinicalTrials.gov identifier: NCT00638690). (B) AFFIRM (ClinicalTrials.gov identifier: NCT00974311). (C) ELM-PC-5 (ClinicalTrials.gov identifier: NCT01193257). (D) ELM-PC-4 (ClinicalTrials.gov identifier: NCT01193244). (E) COMET-1 (ClinicalTrials.gov identifier NCT01605227). wt C, weighted c-index.

Fig A1.

CONSORT diagram for COU-AA-301 (ClinicalTrials.gov identifier: NCT00638690). bCTC, baseline CTC; bPSA, baseline PSA; CTC, circulating tumor cell; PSA, prostate-specific antigen.

Fig A2.

CONSORT diagram for AFFIRM (ClinicalTrials.gov identifier: NCT00974311). bCTC, baseline CTC; bPSA, baseline PSA; CTC, circulating tumor cell; PSA, prostate-specific antigen.

Fig A3.

CONSORT diagram for ELM-PC-5 (ClinicalTrials.gov identifier: NCT01193257). bCTC, baseline CTC; bPSA, baseline PSA; CTC, circulating tumor cell; PSA, prostate-specific antigen.

Fig A4.

CONSORT diagram for ELM-PC-4 (ClinicalTrials.gov identifier: NCT01193244). bCTC, baseline CTC; bPSA, baseline PSA; CTC, circulating tumor cell; PSA, prostate-specific antigen.

Fig A5.

CONSORT diagram for COMET-1 (ClinicalTrials.gov identifier: NCT01605227). bCTC, baseline CTC; bPSA, baseline PSA; CTC, circulating tumor cell; PSA, prostate-specific antigen.