Prediction of survival following first-line chemotherapy in men with castration-resistant metastatic prostate cancer

Purpose: We sought to evaluate predictors of overall survival following progression after systemic chemotherapy in men with metastatic castration-resistant prostate cancer. Experimental Design: For our study population, we used the TAX327 multicenter randomized phase III trial comparing administration of docetaxel and prednisone every 3 weeks, weekly administration of docetaxel and prednisone, and administration of mitoxantrone and prednisone every 3 weeks. Progression was defined as the earliest of prostate-specific antigen (PSA), tumor, or pain progression. We analyzed predictors of postprogression survival according to both prechemotherapy and postchemotherapy variables with adjustment for potential confounders. Results: Among 1,006 men, 640 had evaluable information on protocol-defined progression leading to further therapy. Median postprogression survival was 14.5 months. In the multivariable analysis, several pretreatment factors were associated with postprogression survival: pain, performance status, alkaline phosphatase, number of sites of metastatic disease, liver metastases, hemoglobin, PSA, and time since diagnosis. In addition, we found that the number of progression factors (PSA, pain, and tumor size), the duration of first-line chemotherapy, and whether progression occurred during chemotherapy independently predicted postprogression survival. We found evidence for the benefit of continuation of chemotherapy beyond progression only for men who had isolated worsening of pain. A nomogram was constructed and internally validated with a concordance index of 0.70. Conclusions: An internally validated model to predict postchemotherapy survival was developed. Evaluation of men in the postdocetaxel setting should consider the type of progression, duration of therapy, and known pretreatment prognostic factors. Definitions of progression in castration-resistant prostate cancer that include pain should also consider composite measures of tumor or PSA progression. External validation is planned

Tolerability and efficacy of docetaxel in older men with metastatic castrate-resistant prostate cancer (mCRPC) in the TAX 327 trial

Objective: Prostate cancer is a disease of older men. Weekly docetaxel (DPq1w) is often favored over the standard three-weekly regimen (DPq3w) due to concerns about safety and tolerability in this population. Materials and Methods: Two subgroup analyses of TAX 327 were conducted. Among patients receiving DPq3w, tolerability and efficacy were compared between three age groups: < 65, 65-74 and ≥ 75. years. For men ≥ 75. years, these outcomes were compared between DPq3w, DPq1w, and mitoxantrone (MP) arms. Tolerability outcomes included dose delivery, grade 3/4 adverse events and quality of life. Efficacy outcomes included overall survival and tumor response. Results: Of 1006 men with metastatic castrate-resistant prostate cancer (mCRPC) in the trial, 335 received DPq3w. Among these, 20% were age ≥ 75. years. For DPq3w, there were non-significant associations of worse tolerability and efficacy with advancing age. Twenty-eight percent of men age ≥ 75. years had an objective pain response, compared to 38% and 34% of patients 65-74 and < 65. years, respectively. There were no significant differences in prostate-specific antigen (PSA) response (43-48%, p = 0.74) or measurable tumor response (7-17%, p = 0.30) according to age. Among men ≥ 75. years, DPq3w resulted in more dose reductions than DPq1w (22% versus 8%, p = 0.007), but tolerability was otherwise comparable. Both were associated with more favorable efficacy than mitoxantrone. Conclusions: Tolerability and efficacy of DPq3w appear less favorable with advancing age. Compared to DPq1w, DPq3w is associated with better survival outcomes, but similar tolerability, and remains the standard first-line chemotherapy option in mCRPC. Toxicity is substantial, therefore careful patient selection, close monitoring and early management of toxicities is advised