Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3

Abstract

Purpose: Evolving treatments, disease phenotypes, and biology, together with a changing drug development environment, have created the need to revise castration-resistant prostate cancer (CRPC) clinical trial recommendations to succeed those from prior Prostate Cancer Clinical Trials Working Groups.

Methods: An international expert committee of prostate cancer clinical investigators (the Prostate Cancer Clinical Trials Working Group 3 [PCWG3]) was reconvened and expanded and met in 2012-2015 to formulate updated criteria on the basis of emerging trial data and validation studies of the Prostate Cancer Clinical Trials Working Group 2 recommendations.

Results: PCWG3 recommends that baseline patient assessment include tumor histology, detailed records of prior systemic treatments and responses, and a detailed reporting of disease subtypes based on an anatomic pattern of metastatic spread. New recommendations for trial outcome measures include the time to event end point of symptomatic skeletal events, as well as time to first metastasis and time to progression for trials in the nonmetastatic CRPC state. PCWG3 introduces the concept of no longer clinically benefiting to underscore the distinction between first evidence of progression and the clinical need to terminate or change treatment, and the importance of documenting progression in existing lesions as distinct from the development of new lesions. Serial biologic profiling using tumor samples from biopsies, blood-based diagnostics, and/or imaging is also recommended to gain insight into mechanisms of resistance and to identify predictive biomarkers of sensitivity for use in prospective trials.

Conclusion: PCWG3 moves drug development closer to unmet needs in clinical practice by focusing on disease manifestations most likely to affect prognosis adversely for therapeutics tested in both nonmetastatic and metastatic CRPC populations. Consultation with regulatory authorities is recommended if a trial is intended to seek support for drug approval.

Fig 1.

Prostate cancer clinical states model, a framework for patient treatment and drug development, updated for the Prostate Cancer Clinical Trials Working Group 3. Combination therapy is considered one line of therapy. mCRPC, metastatic castration-resistant prostate cancer; nmCRPC, nonmetastatic castration-resistant prostate cancer; PSA, prostate-specific antigen.

Fig 2.

Controlling for flare by applying the 2+2 rule using the first post-treatment scan as baseline.

Fig 3.

Swim lanes illustrating the patient experience on a trial. For early-phase trials, the swimmers plot is used to track individual patients on a trial, including time on and off therapy, adverse events, progression events, and the point at and the reason for which therapy is stopped. Progression in individual disease manifestations and other significant events are recorded, including those that did not lead to trial discontinuation and those that did. Pragmatically, each line shows the duration on therapy. Note that this particular example depicts a trial in progress. NLCB, no longer clinically benefiting; PSA, prostate-specific antigen; rPFS, radiographic progression-free survival; SAE, serious adverse event.

Fig A1.

Three patterns of biomarker (eg, PSA) response to agents that effect cell kill. Shown are a substantial and durable decline consistent with marked sensitivity (gray line); a decline followed by a slow rise, indicative of partial sensitivity followed by acquired resistance (gold line); and a transient drop (or none at all) followed by an immediate rise, consistent with either de novo or intrinsic resistance (blue line). PSA, prostate-specific antigen.

Fig A2.

Radionuclide bone scan, sodium fluoride PET scan, and FDG PET scan of the same patient. Only FDG PET is tumor directed; Tc-99 MDP and NaF PET are bone directed. Note that neither the target of the tracer nor the clarity of the image necessarily implies a superior biomarker, and each modality must be validated analytically and clinically. ^99mTc MDP, ^99mTc methylene diphosphonate; NaF, sodium fluoride; FDG, fluorodeoxyglucose; PET, positron emission tomography.

Fig A3.

Bone scan assessment form.

Fig A3.

Bone scan assessment form.

Fig A3.

Bone scan assessment form.

Fig A3.

Bone scan assessment form.