End points and outcomes in castration-resistant prostate cancer: from clinical trials to clinical practice

Abstract

New therapeutic approaches for castration-resistant prostate cancer (CRPC) introduce new treatment dilemmas: how best to sequence these options to maximally benefit patients, what tests to perform before and after treatment to assess disease status, and how to interpret the test results and use them to guide treatment. New and specific end points for different classes of drugs are needed to provide the information to guide these treatment decisions. In 2008, the Prostate Cancer Working Group 2 consensus criteria for early-phase clinical trials redefined clinical trial end points as first, to control, relieve, or eliminate disease manifestations present when treatment is started and second, to prevent or delay future disease manifestations. Disease manifestations include prostate-specific antigen (PSA), soft-tissue disease (nodes and/or viscera), bone disease (most common site of spread), and symptoms. Recent US Food and Drug Administration (FDA) approvals for CRPC therapies have been based on the prevent/delay end points that reflect unequivocal benefit to a patient: prolongation of life or reduction in skeletal-related events (SREs). For the practicing oncologist, the control/relieve/eliminate outcomes should serve primarily to inform the decision of whether to continue therapy. In this review, we consider individual end points such as PSA, imaging, and patient-reported outcomes in the context of the control/relieve/eliminate and prevent/delay framework. We address the time-to-event end points of metastasis prevention, SRE, time to progression, and overall survival in the context of regulatory approvals. We also discuss circulating tumor cells measured with the CellSearch assay, recently cleared by the FDA for monitoring CRPC.

Fig 1.

Prostate cancer clinical states model; framework for patient management and drug development. PSA, prostate-specific antigen. Data adapted.^,

Fig 2.

(A) Prostate-specific antigen drift: A slow rise in PSA after an initial rapid decline with no evidence of radiographic or clinical progression for 28 months while receiving MDV3100; (B) an initial rapid rise in PSA with subsequent decline above baseline on a second value in a patient who remained biochemically, radiographically, and clinically stable for 22 months on abiraterone acetate.

Fig 3.

Flare on bone scan. Two new lesions at 8 weeks were not followed by subsequent additional lesions, so patient remained on study; bone scan markedly improved over 18 months. POD, progression of disease; PSA, prostate-specific antigen; RECIST, Response Evaluation Criteria in Solid Tumors.