Post-Therapy Changes in PSA as an Outcome Measure in Prostate Cancer Trials
Post-Therapy Changes in PSA as an Outcome Measure in Prostate Cancer Trials
To the investigator and clinician, prostate-specific antigen (PSA) level is a seemingly perfect outcome measure because it is easily assessable, quantitative, reproducible, and inexpensive. Whether post-therapy decline in PSA reflects true clinical benefit, and whether post-therapy declines can be used as an intermediate endpoint for accelerated drug approval is still open to question. At present, no drug has been approved strictly on the basis of a post-treatment decline in PSA, as it is unproven that such PSA changes are surrogates for true clinical benefits. Post-therapy PSA changes have been associated with improved survival in patients with castrate metastatic disease. The role of PSA changes as potential surrogates of clinical benefit have only been explored to a limited degree because to date, only two prospective randomized trials showing a survival benefit have been reported. Such trials are necessary, but not a sufficient pre-requisite to explore the potential role of any outcome measure as an intermediate endpoint. The clear demonstration that a post-therapy PSA change can account for all of the treatment effects seen is not yet available. A cytotoxic drug that does not produce any PSA decline is unlikely to be effective, but the converse is not always true because not all PSA rises represent a treatment failure. It is important to recognize that there are a range of clinical benefits to patients that can improve the quality and possibly the duration of survival, independent of PSA.
Serum prostate-specific antigen (PSA) levels play a crucial role in the diagnosis and management of prostate cancer, from assessing illness prediagnosis to death. As a framework for patient counseling, treatment recommendations, and outcome assessments, the clinical spectrum of prostate cancer can be divided into a series of states or clinical milestones. For individuals without a prostate cancer diagnosis, the absolute level and changes in PSA over time are used in the surveillance of patients on cancer prevention strategies. These measurements are also used to enhance the specificity and sensitivity of diagnostic algorithms that determine who should undergo procedures to establish a diagnosis. For men with localized disease, PSA levels are an integral part of the statistical models used to predict disease extent and the probability of cure with surgery or radiation therapy alone or as part of a combined modality approach. A detectable and/or rising PSA after surgery or radiation therapy, the state of a rising PSA, signals treatment failure, and changes in PSA levels over time are the key indicators that determine whether an intervention should be considered. The situation is similar for patients with progressive rising PSA castrate and castrate metastatic disease, where rates of rise in PSA expressed as PSA doubling times provide important prognostic information regarding risk of metastatic progression or death from the disease.
The use of preintervention changes in the level of PSA as a prognostic indicator must be distinguished from the use of post-treatment changes in PSA as an outcome measure to assess the clinical benefit to a patient or the effect of an intervention on the status of the disease. While it is true that in clinical practice or in a clinical trial, treatments are rarely stopped when PSA levels are decreasing, or continued when they rise, there are many situations where reliance on PSA kinetics alone is misleading. Indeed, declining PSA values may not indicate that an intervention is working, and rising values may not indicate that it is failing.
In this regard, the present discussion will focus on the group of patients for whom early indicators of treatment efficacy would allow the early identification of a favorable treatment effect, and in turn, might lead to an earlier approval by regulatory agencies, which would make a drug available sooner. We focus on patients with progressive disease despite castrate levels of testosterone. Such patients are the most likely to have, or to develop, symptoms of metastatic disease or to die of their cancers, and include those with and without radiographic evidence of metastatic disease. The symptoms represent some of the most feared complications of cancer, ranging from bone pain, bone fractures, spinal cord compression, and the sequelae of general bone marrow failure. In fact, prostate cancer is the primary cause of death for patients with progressive metastatic disease on androgen depletion, and accounts for the majority of the prostate cancer deaths in the US.
Summary and Introduction
Summary
To the investigator and clinician, prostate-specific antigen (PSA) level is a seemingly perfect outcome measure because it is easily assessable, quantitative, reproducible, and inexpensive. Whether post-therapy decline in PSA reflects true clinical benefit, and whether post-therapy declines can be used as an intermediate endpoint for accelerated drug approval is still open to question. At present, no drug has been approved strictly on the basis of a post-treatment decline in PSA, as it is unproven that such PSA changes are surrogates for true clinical benefits. Post-therapy PSA changes have been associated with improved survival in patients with castrate metastatic disease. The role of PSA changes as potential surrogates of clinical benefit have only been explored to a limited degree because to date, only two prospective randomized trials showing a survival benefit have been reported. Such trials are necessary, but not a sufficient pre-requisite to explore the potential role of any outcome measure as an intermediate endpoint. The clear demonstration that a post-therapy PSA change can account for all of the treatment effects seen is not yet available. A cytotoxic drug that does not produce any PSA decline is unlikely to be effective, but the converse is not always true because not all PSA rises represent a treatment failure. It is important to recognize that there are a range of clinical benefits to patients that can improve the quality and possibly the duration of survival, independent of PSA.
Introduction
Serum prostate-specific antigen (PSA) levels play a crucial role in the diagnosis and management of prostate cancer, from assessing illness prediagnosis to death. As a framework for patient counseling, treatment recommendations, and outcome assessments, the clinical spectrum of prostate cancer can be divided into a series of states or clinical milestones. For individuals without a prostate cancer diagnosis, the absolute level and changes in PSA over time are used in the surveillance of patients on cancer prevention strategies. These measurements are also used to enhance the specificity and sensitivity of diagnostic algorithms that determine who should undergo procedures to establish a diagnosis. For men with localized disease, PSA levels are an integral part of the statistical models used to predict disease extent and the probability of cure with surgery or radiation therapy alone or as part of a combined modality approach. A detectable and/or rising PSA after surgery or radiation therapy, the state of a rising PSA, signals treatment failure, and changes in PSA levels over time are the key indicators that determine whether an intervention should be considered. The situation is similar for patients with progressive rising PSA castrate and castrate metastatic disease, where rates of rise in PSA expressed as PSA doubling times provide important prognostic information regarding risk of metastatic progression or death from the disease.
The use of preintervention changes in the level of PSA as a prognostic indicator must be distinguished from the use of post-treatment changes in PSA as an outcome measure to assess the clinical benefit to a patient or the effect of an intervention on the status of the disease. While it is true that in clinical practice or in a clinical trial, treatments are rarely stopped when PSA levels are decreasing, or continued when they rise, there are many situations where reliance on PSA kinetics alone is misleading. Indeed, declining PSA values may not indicate that an intervention is working, and rising values may not indicate that it is failing.
In this regard, the present discussion will focus on the group of patients for whom early indicators of treatment efficacy would allow the early identification of a favorable treatment effect, and in turn, might lead to an earlier approval by regulatory agencies, which would make a drug available sooner. We focus on patients with progressive disease despite castrate levels of testosterone. Such patients are the most likely to have, or to develop, symptoms of metastatic disease or to die of their cancers, and include those with and without radiographic evidence of metastatic disease. The symptoms represent some of the most feared complications of cancer, ranging from bone pain, bone fractures, spinal cord compression, and the sequelae of general bone marrow failure. In fact, prostate cancer is the primary cause of death for patients with progressive metastatic disease on androgen depletion, and accounts for the majority of the prostate cancer deaths in the US.
