Burden of Metastatic Castrate Naive Prostate Cancer Patients, to Identify Men More Likely to Benefit from Early Docetaxel: Further Analyses of CHAARTED and GETUG-AFU15 Studies

Abstract

Background: Docetaxel (D) at the time of starting androgen deprivation therapy (ADT) for metastatic castrate naive prostate cancer shows a clear survival benefit for patients with high-volume (HV) disease. It is unclear whether patients with low-volume (LV) disease benefit from early D.

Objective: To define the overall survival (OS) of aggregate data of patient subgroups from the CHAARTED and GETUG-AFU15 studies, defined by metastatic burden (HV and LV) and time of metastasis occurrence (at diagnosis or after prior local treatment [PRLT]).

Design, setting, and participants: Data were accessed from two independent phase III trials of ADT alone or ADT+D-GETUG-AFU15 (N=385) and CHAARTED (N=790), with median follow-ups for survivors of 83.2 and 48.2 mo, respectively. The definition of HV and LV disease was harmonized.

Outcome measurements and statistical analysis: The primary end point was OS.

Results and limitations: Meta-analysis results of the aggregate data showed significant heterogeneity in ADT+D versus ADT effect sizes between HV and LV subgroups (p=0.017), and failed to detect heterogeneity in ADT+D versus ADT effect sizes between upfront and PRLT subgroups (p=0.4). Adding D in patients with HV disease has a consistent effect in improving median OS (HV-ADT: 34.4 and 35.1 mo, HV-ADT+D: 51.2 and 39.8 mo in CHAARTED and GETUG-AFU15, respectively; pooled average hazard ratio or HR (95% confidence interval [CI]) 0.68 ([95% CI 0.56; 0.82], p<0.001). Patients with LV disease showed much longer OS, without evidence that D improved OS (LV-ADT: not reached [NR] and 83.4; LV-ADT+D: 63.5 and NR in CHAARTED and GETUG-AFU15, respectively; pooled HR (95% CI) 1.03 (95% CI 0.77; 1.38). Aggregate data showed no evidence of heterogeneity of early D in LV and HV subgroups irrespective of whether patients had PRLT or not. Post hoc subgroup analysis was based on aggregated data from two independent phase III randomized trials.

Conclusions: There was no apparent survival benefit in the CHAARTED and GETUG-AFU15 studies with D for LV. Across both studies, early D showed consistent effect and improved OS in HV patients.

Patient summary: Patients with a higher burden of metastatic prostate cancer starting androgen deprivation therapy (ADT) have a poorer prognosis and are more likely to benefit from early docetaxel. Low-volume patients have longer overall survival with ADT alone, and the toxicity of docetaxel may outweigh its benefits.

Keywords: Androgen deprivation therapy; Chemotherapy; Docetaxel; High volume; Low volume; Metastatic castrate naive prostate cancer; Metastatic prostate cancer; Prostate cancer; Volume disease.

Fig. 1

Disposition of patients in the CHAARTED and GETUG-AFU15 studies. ADT = androgen deprivation therapy; D = docetaxel; HV = high volume; LV = low volume. ^aIncluding nonevaluable patients.

Fig. 2

Overall survival in (A) patients with high-volume disease and metastases at initial diagnosis of prostate cancer, (B) patients with high-volume disease and prior local treatment (no metastases at initial diagnosis of prostate cancer), (C) patients with low-volume disease and metastases at initial diagnosis of prostate cancer, and (D) patients with low-volume disease and prior local treatment (no metastases at initial diagnosis of prostate cancer). ADT = androgen deprivation therapy; D = docetaxel.

Fig. 2

Overall survival in (A) patients with high-volume disease and metastases at initial diagnosis of prostate cancer, (B) patients with high-volume disease and prior local treatment (no metastases at initial diagnosis of prostate cancer), (C) patients with low-volume disease and metastases at initial diagnosis of prostate cancer, and (D) patients with low-volume disease and prior local treatment (no metastases at initial diagnosis of prostate cancer). ADT = androgen deprivation therapy; D = docetaxel.

Fig. 2

Overall survival in (A) patients with high-volume disease and metastases at initial diagnosis of prostate cancer, (B) patients with high-volume disease and prior local treatment (no metastases at initial diagnosis of prostate cancer), (C) patients with low-volume disease and metastases at initial diagnosis of prostate cancer, and (D) patients with low-volume disease and prior local treatment (no metastases at initial diagnosis of prostate cancer). ADT = androgen deprivation therapy; D = docetaxel.

Fig. 2

Overall survival in (A) patients with high-volume disease and metastases at initial diagnosis of prostate cancer, (B) patients with high-volume disease and prior local treatment (no metastases at initial diagnosis of prostate cancer), (C) patients with low-volume disease and metastases at initial diagnosis of prostate cancer, and (D) patients with low-volume disease and prior local treatment (no metastases at initial diagnosis of prostate cancer). ADT = androgen deprivation therapy; D = docetaxel.