Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group

Abstract

Purpose: To update eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone.

Methods: A committee of investigators experienced in conducting trials for prostate cancer defined new consensus criteria by reviewing previous criteria, Response Evaluation Criteria in Solid Tumors (RECIST), and emerging trial data.

Results: The Prostate Cancer Clinical Trials Working Group (PCWG2) recommends a two-objective paradigm: (1) controlling, relieving, or eliminating disease manifestations that are present when treatment is initiated and (2) preventing or delaying disease manifestations expected to occur. Prostate cancers progressing despite castrate levels of testosterone are considered castration resistant and not hormone refractory. Eligibility is defined using standard disease assessments to authenticate disease progression, prior treatment, distinct clinical subtypes, and predictive models. Outcomes are reported independently for prostate-specific antigen (PSA), imaging, and clinical measures, avoiding grouped categorizations such as complete or partial response. In most trials, early changes in PSA and/or pain are not acted on without other evidence of disease progression, and treatment should be continued for at least 12 weeks to ensure adequate drug exposure. Bone scans are reported as "new lesions" or "no new lesions," changes in soft-tissue disease assessed by RECIST, and pain using validated scales. Defining eligibility for prevent/delay end points requires attention to estimated event frequency and/or random assignment to a control group.

Conclusion: PCWG2 recommends increasing emphasis on time-to-event end points (ie, failure to progress) as decision aids in proceeding from phase II to phase III trials. Recommendations will evolve as data are generated on the utility of intermediate end points to predict clinical benefit.

Fig. 1

Prostate cancer clinical-states model, a framework for patient management and drug development. Modified from Scher et al^, with permission. PSA, prostate-specific antigen.

Fig. 2

Eligibility based on prostate-specific antigen (PSA) changes. The reference value (#1) is the last PSA measured before increases are documented, with subsequent values obtained a minimum of 1 week apart. If the PSA at time point 3 (value #3A) is greater than that at point 2, then eligibility has been met. If the PSA is not greater than point 2 (value #3B), but value #4 is, the patient is eligible assuming that other criteria are met, if values 3A or #4 are 2 ng/mL or higher, a reduction from the 5 ng/mL specified in the previous guidelines. Reprinted from Bubley et al.

Fig. 3

Waterfall plot showing the maximal (at 12 weeks or at any time point) prostate-specific antigen (PSA) post-therapy change from baseline. Note that the proportion of patients showing any defined degree of decline is readily assessable.

Fig. 4

Prostate-specific antigen (PSA) progression. An increase of 25% and absolute increase of 2 ng/mL or more above the nadir. Values A, B, and C show rising PSA values that do not meet the criteria. Value D is the first PSA value that is greater than 25% and more than 2 ng/mL above the nadir, confirmed with a further rise in PSA shown by value E. For reporting purposes, PSA progression would be recorded on the date value D was obtained.

Fig. 5

Serial bone scans and prostate-specific antigen (PSA) values from a patient treated with cytotoxic treatment showing (B) two new areas of tracer uptake at week 13 relative to (A) the pretreatment baseline with (C) no additional new lesions on the week-25 scan. The patient did not meet the criteria for progression because no additional new lesions were documented on the week 25 scan. (D) Note that the PSA values continued to decrease through this interval.