Castarion Not Running for State Assembly Again

INTRODUCTION

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In 1999, the Prostate Cancer Clinical Trials Working Group 1 issued recommendations for standardizing prostate-specific antigen (PSA) outcomes in phase II castration-resistant prostate cancer (CRPC) trials.¹ In 2008, when docetaxel was the only drug proven to prolong survival in metastatic CRPC (mCRPC),^2,3 the successor group, the Prostate Cancer Clinical Trials Working Group 2 (PCWG2), outlined more extensive principles of clinical trial conduct for this disease.⁴ Incorporating the earlier recommendations on the use of PSA measurements in clinical investigations, PCWG2 applied a clinical states framework in which trial objectives, design, and outcomes were based on (1) early measures of response that represented the control, relief, or elimination of existing disease manifestations and (2) later time-to-event measures that represented the delay or prevention of manifestations that may occur as disease progressed (Appendix, online only).

The Prostate Cancer Clinical Trials Working Group 3 (PCWG3) is an international working group of clinical and translational experts in prostate cancer that convened in June 2012 and worked through February 2015 to update the recommendations of PCWG2 in light of a changing therapeutic landscape^5-11 and advances in the understanding of disease biology. The two chairs (H.I.S. and A.J.A.) developed an outline and convened eight meetings that included many of the PCWG2 investigators and 20 additional investigators. A synthesized document was developed and approved by all PCWG3 members. Key principles of trial design and conduct from PCWG3 are shown in Tables 1–5 with comparisons to the prior recommendations of PCWG2.

Table 1. Summary of Major Changes in PCWG3 Recommendations Compared With PCWG2

Table 2. Standard Baseline Disease Assessments Recommended by PCWG3 in Comparison With PCWG2 Recommendations

Table 3. Criteria for Progression at Trial Entry by Disease Manifestation

Table 4. Suggested Frequency of Assessment for Commonly Used Measures in Metastatic Prostate Cancer Clinical Trials

Table 5. Suggested Outcome Measures for Clinical Trials in Metastatic Prostate Cancer: Report by Disease Manifestation

CONCEPTUALIZING THE DISEASE

The decision milestones in PCWG2 were based on disease states defined by the status of the primary tumor, the presence or absence of distant disease on imaging (metastatic versus nonmetastatic), testosterone levels, and prior chemotherapy exposure.

PCWG3 presents a revised disease states model that, like its predecessor, defines trial objectives on the basis of state-specific clinical needs (Fig 1 ). Emphasis is placed on designing clinical trials within a biomarker context, and focusing on how biomarkers can be developed to predict outcome, guide management, and influence clinical decision making. The revised model aligns with the indications and uses of the currently approved drugs (see Appendix Table A1, online only) and provides the framework for a decision tree that closely follows contemporary clinical practice. Key new recommendations of the decision tree include (1) distinguishing adenocarcinomas from other histologies including pure small-cell carcinomas and variants with neuroendocrine differentiation; (2) replacing the pre- versus postchemotherapy distinction with a dynamic classification that considers the lines of therapy a patient has received independent of the mechanism of action, the order in which they were administered, and the sensitivity of the tumor to each; (3) designing dedicated trials for the different CRPC phenotypes defined by the pattern of spread; (4) adding recommendations for trials in the nonmetastatic CRPC (nmCRPC) state, formerly defined as the rising PSA castrate state; (5) emphasizing the importance of serial biologic profiling of the disease using minimally invasive blood-based assays of tumor material, imaging, or biopsy of a metastatic tumor site to identify and target mechanisms of primary or adaptive resistance and to better enable treatment selection to be based on disease biology; (6) including clinically relevant time-to-event end points such as symptomatic skeletal events (SSEs); and (7) with our increased recognition of disease heterogeneity and emerging resistance, focusing more on determining when a treatment should be discontinued when the patient is no longer clinically benefiting (NLCB) rather than strictly at the first evidence of progression.

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.

OBJECTIVES

The objectives of the PCWG3 recommendations are to identify subsets of patients for whom specific agents are most (or least) appropriate, ensure that the determination of dose and schedule for noncytotoxic treatments is mechanism specific, develop intermediate end points to support regulatory submissions, assess pre- and post-treatment disease biology, demonstrate the best use of agents to maximize patient benefit, and introduce the concept of a new time-to-event measure, NLCB, as the indicator that a change in therapy is necessary.

ELIGIBILITY FOR ENROLLMENT

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Eligibility criteria define the population to be considered for enrollment as one that has a high likelihood of demonstrating the hypothesized effect of a treatment. The criteria may be based on clinical features and laboratory measures that are prognostic, predictive, or important from a safety perspective.

PATIENT DEMOGRAPHICS AND PATHOLOGY

Baseline Assessment

The baseline disease assessment recommendations of PCWG2 are expanded in PCWG3 (Table 2) to include histology; prior radiation therapy; the timing and duration of, and (if available) response to all prior systemic treatment(s); a standardized assessment of blood-based biomarkers; patient-reported outcomes (PROs); imaging; profiling disease by a repeat biopsy that also determines changes in histology or through blood-based assays for molecular markers/determinants of prognosis and drug sensitivity.

Prior Systemic Treatment

To better define and characterize a patient's disease at the time of trial enrollment and to explore potential favorable or unfavorable interactions among therapies, PCWG3 recommends recording all lines of therapy (represented as a single agent or combination) in the order they were administered. Ideally, reporting should include the start and stop dates, or at least the duration, for each prior line of therapy; the dose and schedule of the agent(s); the disease state in which it was administered; and the type of progression (biochemical [ie, a rising PSA], radiographic, and/or symptomatic). Response (resistant versus sensitive) should be categorized on the basis of the post-therapy PSA or radiographic change pattern for agents that reduce tumor burden. For example, Appendix Fig A1 (online only) shows that post-therapy PSA change patterns with agents that effect cell kill allow one to categorize response as resistant versus sensitive. Similar response patterns to prior therapy that were based on other clinical biomarkers such as imaging or pain may be considered and reported, recognizing the challenges in obtaining such historical data.

The definition of a prior hormonal intervention is changed to include only the addition of a hormonal therapy that had the intent of treating the cancer. Assessing for a withdrawal response to an antiandrogen is no longer considered an intervention and is not required, but should be considered for 4 to 6 weeks for patients who have been on long-term antiandrogen therapy with apparent benefit. A response, if it was observed on discontinuation, should be recorded.

Prior Radiation Treatment

Details of the dates, portals, number of fractions, dose per fraction, and total administered dose by portal should be recorded for all courses of radiation therapy, including those directed at the primary and metastatic site(s). Details of prior radioisotope therapy should also be recorded.

Histology and Pathologic Subtype

To better inform future decision making, PCWG3 encourages the direct biologic characterization of the tumor at the time a new treatment is being considered by performing a biopsy of a metastatic site or with blood-based diagnostics such as circulating tumor cells (CTCs), circulating nucleic acids, or host factors (eg, markers of bone turnover or immune function).

Although a number of prostate cancer histologic subtypes have been described, only the pure small-cell phenotype is a distinct entity that is diagnosed consistently.^12,13 It represents less than 1% of newly diagnosed prostate cancers but leads directly to treatment with cytotoxic regimens similar to those used to treat small-cell lung carcinomas of the lung and should thus be noted specifically. Treatment-emergent histologic variants that contain nonadenocarcinomatous elements are still being defined but are anticipated to differ from the de novo small-cell phenotype.¹³

BLOOD-BASED BIOMARKERS

Baseline Measures

A baseline assessment of hematologic, hepatic, and renal function is essential to assess prognosis, to predict response to therapy, and for safety. Multivariable analyses suggest that hemoglobin, alkaline phosphatase, albumin, and lactate dehydrogenase are established prognostic factors for survival¹⁴ and should be included in all studies.

Testosterone.

PCWG3 retains the definition of castrate as ≤ 50 ng/dL of testosterone (or ≤ 0.50 ng/mL or 1.73 nmol/L) but encourages investigators to consider using ultrasensitive testosterone assays with a sensitivity to 1 to 2 ng/dL when evaluating a drug known or suspected to change androgen levels.

Bone biomarkers.

Biochemical markers of osteoblast and osteoclast activity are often reported but rarely used for eligibility in most clinical trials.¹⁵ Although not required, they may be measured as a prognostic and pharmacodynamic marker in certain contexts.¹⁶

Immune function.

Assays of immune function such as serum cytokines, antibody response, T-cell subsets, function and antigen specificity are increasingly included in trials. Most have not achieved the necessary level of analytical validity, with the exceptions of the absolute lymphocyte count and neutrophil-to-lymphocyte ratio, which are obtained from a complete blood count.^17,18

PSA and other tumor markers.

A rising PSA is typically the first sign of tumor regrowth, followed later by worsening of disease by imaging and the development of clinical symptoms.¹⁹ PSA should be assessed in all trials, and in particular for those with PSA change as a primary end point, in a central laboratory to minimize interassay variability. PCWG3 retains the PCWG2 criteria for PSA progression.^5,6,10,11 For nmCRPC, PCWG3 advises recording PSA doubling times (PSADTs) and focusing drug development efforts on patients with shorter times who have the greatest risk of developing detectable metastatic disease or symptoms, and dying of their cancers.^20,21 The preferred method for calculating PSADT is described in the Appendix. Other markers in the blood, such as chromogranin A, neuron-specific enolase, and carcinoembryonic antigen, have not been validated in prospective studies (Table 2).

CTC number.

The usefulness of CTC analyses at baseline and during treatment is an area of active research. Although multiple platforms are under development,²² CellSearch (Janssen Diagnostics, Raritan, NJ), which reports the number of cells captured from whole blood with an EpCAM-positive immunomagnetic ferrofluid, is the only US Food and Drug Administration–cleared CTC assay at the present time.²² Baseline CTC count, reported as favorable or unfavorable (< 5 versus ≥ 5 CTC/7.5 mL of blood, respectively), has been shown to be an independent prognostic factor for survival in CRPC both before and after treatment.^22-24 Although the strengths and limitations of CTC enumeration as an indicator of antitumor effects require further study, CTCs may be considered for use as a screening end point for activity in patients with unfavorable counts at baseline.²⁵ CTCs can also serve as a source of tissue for biologic profiling.^26-28

PROs

PCWG3 recognizes the importance of patient-centered drug development and reporting the patient experience on study.²⁹ Pain is the most established PRO in this population and is associated with inferior survival and diminished quality of life.^30-33 When pain is an important component or primary end point of a study, PCWG3 recommends a baseline assessment using serial measurements, including pain intensity, pain interference with activities, and opiate intake, over several days before starting treatment, using methods described by the US Food and Drug Administration.³⁴ The average score over those days is used as the baseline pain value.³⁵ Pain questions using numerical rating scales (0 to 10) can be used, eliciting worst pain intensity and interference over the previous 24 hours.³⁴

Physical functioning should also be assessed and can be measured at baseline and during treatment using an established multi-item questionnaire such as the physical function measure of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 or Patient-Reported Outcomes Measurement Information System (PROMIS) instruments. Collection of patient-reported adverse events should be considered at baseline and during treatment using the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).³⁶

IMAGING

Imaging provides critical information on disease distribution, prognosis, extent, biology, and host reaction to the tumor.

Baseline by Site of Disease

PCWG3 retains the PCWG2 recommendations with modifications that include developing, recording, and validating measures of disease burden. Imaging of the chest, abdomen, and pelvis using a contrast-enhanced computed tomography (CT) scan with ≤ 5-mm axial slices is advised for all patients. For those intolerant of contrast, a cross-sectional magnetic resonance imaging (MRI) scan of the abdomen and pelvis, with a noncontrast CT scan of the chest, may be considered. In phase I and II trials, recognizing that individual lesions may be biologically distinct, PCWG3 recommends reporting whether progression on entry was in the growth of pre-existing lesions, the development of new lesions, or both. PCWG3 advises following Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for extraskeletal disease but recommends that up to five lesions per site of metastatic spread (eg, lung, liver, lymph nodes as separate sites) be recorded to address disease heterogeneity and to track patterns of metastatic progression. Bone lesions should be recorded separately (see Bone section on this page).

Prostate or prostate bed.

Specific imaging of the prostate or prostate bed is not required for every patient. If there is a question of locally persistent or recurrent disease, a directed MRI of the prostate or prostate bed and/or biopsy of the site is recommended.

Nodes or viscera.

PCWG3 advises that nodal disease be measured in the short axis and recorded by location: pelvic disease should be classified as locoregional, and extrapelvic disease (retroperitoneal, mediastinal, thoracic, or other) as metastatic. Nodes ≥ 1.5 cm in the short axis are considered pathologic and measurable. As per RECIST 1.1, lymph nodes that are ≥ 1.0 cm but less than 1.5 cm in the short axis may be pathologic and can be considered nonmeasurable/nontarget lesions.³⁷ Visceral disease in metastatic patients should be designated separately as lung, liver, adrenal, or CNS and is considered measurable if an individual lesion is ≥ 1 cm in its longest dimension. Given that lung metastases are relatively frequent in mCRPC trials (7% prevalence), chest CT imaging is recommended.³⁸

PCWG2 did not formally address trials in the nmCRPC population, where the aim is to delay/prevent the development of radiographically evident metastatic disease and death. To establish nonmetastatic status, note that nodes less than 1.0 cm in the short axis are nonpathologic; nodes 1.0 to less than 1.5 cm may be considered pathologic, but with clinical discretion; and nodes ≥ 1.5 cm are both pathologic and measurable. PCWG3 advises that trial entry be based on PSADT, and that the same standard imaging modalities (eg, bone scan, CT, and/or MRI) used to determine eligibility be used for monitoring the patient receiving treatment.

Bone.

The use of ^99mTc-methylene diphosphonate radionuclide bone scintigraphy as the standard for bone imaging is retained in PCWG3, with the presence or absence of metastasis recorded first. A quantitative measure of disease burden, such as lesional number,³⁹ the bone scan index,^40,41 or lesion area,⁴² is also suggested, recognizing that these measures require further analytical and prospective clinical validation. Changes in lesions considered metastatic on bone scintigraphy should be followed and assessed serially using a bone scan assessment form (Appendix Fig A3 , online only). Areas/lesions on bone scintigraphy that are suggestive can be assessed further with CT or MRI and followed separately, but such supplemental imaging should not be used to establish indicator lesions for the purposes of a trial.

Different modalities for imaging bone metastases can provide different information for the same patient (Appendix Fig A2 ). However, because of the lack of standards for reporting disease presence or changes after treatment, positron emission tomography imaging with sodium fluoride, fluorodeoxyglucose, choline, or prostate-specific membrane antigen, bone marrow MRI (body MRI), and other modalities that are in use to image bone, should be approached as new biomarkers subject to independent validation.

Neurologic.

PCWG3 upholds the PCWG2 recommendation to perform an MRI or CT of the brain for patients with small-cell/neuroendocrine tumors and to maintain a low threshold for performing an MRI of the base of the skull or spine to diagnose and/or detect impending neurologic compromise. Routine imaging of the brain for adenocarcinoma is not recommended.

Type of progression at entry into a trial.

PCWG3 advises recording whether progression was manifested by PSA alone, bone ± nodes by location, nodes by location only, or viscera (± other sites), and the proportion of patients who progress in each of these categories, because this is prognostic.^5,6,10,11 PCWG3 also advises reporting whether progression by imaging at study entry involved the growth or enlargement of pre-existing lesions, the development of new lesions, or both. The criteria for progression can be found in Table 3.

Clinical subtypes of CRPC that are based on pattern of spread.

The five clinical subtypes defined in PCWG2 on the basis of the pattern of spread in individual patients are retained with modifications: (1) locally recurrent CRPC after radical prostatectomy or persistent disease in the prostate or prostate bed after radiation therapy on ADT, with no evidence of metastases on imaging; (2) nonmetastatic (nmCRPC): a rising PSA with no detectable disease in the primary site, in lymph nodes beyond the true pelvis by CT/MRI (lymph nodes ≤ 1.5 cm in the short axis in the pelvis are eligible), in bone by radionuclide bone scan or CT, or in visceral organs; (3) nodal spread within the pelvis (lymph nodes > 1.0 cm) and/or beyond the pelvis (specify) and no evidence of bone or visceral disease⁴³; (4) bone disease with or without nodal disease and no evidence of visceral spread; (5) visceral disease with or without spread to other sites; includes spread to lung, liver, or adrenal and CNS sites, each reported separately. It is recommended that research studies report the proportion of patients in each subtype. Stratification by pattern of metastatic spread is also encouraged.

MOLECULAR AND BIOLOGIC SUBTYPES

With the report of the CRPC genotypic landscape,⁴⁴ PCWG3 strongly endorses incorporating detailed molecular assessments of tumors into clinical trial strategies to better understand the disease biology and to identify predictors of sensitivity to a specific therapy. This requires the molecular characterization of an individual patient's tumor at the time treatment is considered. A profile of the primary tumor obtained at diagnosis may not be sufficiently informative for a castration-resistant metastatic site, because the biologic drivers of growth and cell-surface targets can change as the disease progresses through various treatments. Molecular biomarkers in metastatic lesions can be assessed through a directed biopsy^45,46 or by using blood-based assays of CTCs or cell-free nucleic acids (RNA or DNA or proteins), recognizing that the biologic profiles of different lesions and blood-based assays in the same patient may not be the same. The number of tumor cells within a single metastatic site that harbor a specific alteration may also vary and, as such, simply detecting its presence at a low frequency may not predict sensitivity.

ASSESSING PROGNOSIS

Prognosis indicates the likelihood that a patient or patient group will develop a disease manifestation if left untreated. Predicted survival time is one measure estimated commonly by using nomograms. Validated prognostic tools such as nomograms include patient demographics and clinical measures to estimate outcomes at a trial-based level as risk-stratification tools.^16,33,47-51 Adding a measure of metastatic disease burden and type of radiographic progression (new lesions versus growth of existing lesions) on the basis of physician assessment or computer-based assessments of bone or other disease sites may permit more reliable prognostication.^42,52 The incorporation of prognostic molecular biomarkers is an active area of research.

INTERVENTION

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In PCWG3, the term intervention includes both the therapy itself and the post-treatment assessments to determine dose, schedule, and antitumor effects. PCWG3 emphasizes the importance of developing trials that provide the following information tailored to the mechanism and postulated therapeutic target(s) of the agent: population-specific pharmacokinetics in the castrate state, the use of pharmacodynamic measures specific to the postulated effect of a particular agent on the malignant process to confirm or refute the hypothesized mechanism of action, and the optimal timing to assess the pharmacodynamic measures and to inform the determination of the optimal dose and schedule to study in future trials. The optimal time to assess for antitumor effects, which can be delayed for many types of treatment including those that affect immune function, should also be determined by assessing disease status at fixed intervals.

MEASURING OUTCOMES AND REPORTING

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PCWG3 reaffirms the recommendation to use control/relieve/eliminate end points to assess antitumor effects of therapies that are anticipated to kill tumor cells, particularly in early clinical development. For therapies not expected to kill tumor cells, delay/prevent end points should be used. PCWG3 discriminates between activity-estimating end points in early-phase trials (such as declines in PSA, changes in CTCs, and time to progression) where the objective is to demonstrate sufficient antitumor activity to justify further study, versus registration trials for regulatory approval where clinical benefit is the objective. For instance, in early-phase trials, time to progression, which censors deaths, may be used, whereas in registration trials, progression-free survival, which includes deaths as events, is preferred. The suitability of efficacy end points to demonstrate clinical benefit is context dependent, and consultation with regulatory authorities is strongly recommended when selecting and defining end points for a trial intended to support drug approval.⁵³ Although demonstrating overall survival may be challenging as a primary end point, it is assumed that all trials will continue to follow patients for survival and analyze and report survival results, particularly in randomized clinical trials. PCWG3 also recommends that all therapies administered subsequent to the intervention, including start and stop dates when available, be recorded, until death. This is essential because the availability and use of life-prolonging treatments post protocol may reduce the ability to demonstrate the survival benefit of an effective treatment.

On-treatment evaluations should include physical examinations, symptom assessments, and laboratory studies to assess safety, with appropriate attribution to the disease or therapy. Imaging should include cross-sectional imaging of the chest, abdomen, and pelvis, as well as bone scintigraphy, regardless of whether patients have involvement of those sites at baseline. Imaging strategies restricted to known sites of disease risk missing disease progression at new sites.

PCWG3 advises that disease assessments be performed at fixed intervals to better understand when antitumor effects occur (Table 4). To minimize patient exposure to ineffective treatment, and to better assess the timing of the antitumor effects of an agent for which the optimal timing is not known, an 8- to 9-week assessment interval for the first 6 months and every 12 weeks thereafter is advised. This recommendation is based on the findings of several trials.^5,10,54 The shorter interval also helps clarify bone scan flare (the development of new lesions on a first follow-up scan that may actually represent a favorable response to treatment). Using the shorter interval will also inform the optimal assessment interval in subsequent trials, particularly important for biologic therapies whose antitumor effects may be delayed. Notable is that the applicability of the immune-modified RECIST criteria to prostate cancer has not been established, in particular, whether an early increase in the size of a nodal or visceral lesion represents the recruitment of immune effector cells or tumor growth.⁵⁵ It is also noteworthy that neither the RECIST criteria nor the immune-modified RECIST criteria address changes in osseous disease.

APPLYING THE CONTROL/RELIEVE/ELIMINATE VERSUS DELAY/PREVENT FRAMEWORK

PCWG3 retains the recommendation to report outcomes by manifestation (eg, host or tumor biomarkers, symptoms, site of spread) and not to report grouped categorizations of response such as complete response, partial response, or progression on the basis of multiple manifestations. In patients who show evidence of benefit, PCWG3 advises continuing therapy in the case of an isolated PSA rise after an initial decline until radiographic or clinical progression is manifest. Table 5 describes the updated PCWG3 recommendations for reporting outcomes by disease manifestation. Of particular note is the use of the 2+2 rule to distinguish flare from true progression in patients with osseous disease at baseline (Fig 2 ).^4,6 Also recommended are reporting the proportion of patients who have not progressed at fixed time intervals (eg, 6 or 12 months) and reporting separately the time receiving treatment.

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

RADIOGRAPHIC PROGRESSION-FREE SURVIVAL

Radiographic progression-free survival (rPFS) is the time interval from random assignment to the date when the first site of disease is found to progress (using a manifestation-specific definition of progression), or death, whichever occurs first. To better understand the effect of therapy on an individual site of disease, PCWG3 advises the date of progression in all specific sites be reported independently whether it is bone, nodes (pelvic or extrapelvic), visceral (lung, liver, adrenal, or CNS), or other. Reporting the proportion of patients who remain radiographic progression free at fixed time points (eg, 6 and 12 months) is also advised.

PCWG3 also emphasizes the importance of analytically and clinically validating the definitions of progression for each site of disease, as was performed for the bone scan progression end point proposed in PCWG2 that became part of the rPFS definition in the phase III registration trials of abiraterone (NCT00887198), enzalutamide (NCT01212991), and orteronel (NCT01193244). Noteworthy is that in all three trials, the local radiology interpretations were highly concordant with the centralized interpretation. The association between rPFS and overall survival is still being investigated, but an association was demonstrated in at least one of these trials.⁵⁶

SKELETAL-RELATED EVENTS AND SYMPTOMATIC SKELETAL EVENTS

Delay/Prevent

PCWG2 did not consider skeletal-related events (SREs), which include asymptomatic nonclinical fractures ascertained by serial imaging, clinical pathologic fractures, spinal cord compression, and surgery or radiation therapy to bone. Reduction in the frequency of SREs is an approvable end point in its own right, used in several trials to support the approval of zoledronic acid and denosumab.^57,58 The registration study of radium-223 used a composite bone end point, symptomatic skeletal events (SSEs), defined as symptomatic fracture, radiation or surgery to bone, or spinal cord compression.^9,59

PCWG3 advises reporting SSEs that include only symptomatic events of clear clinical significance, in contrast to SREs, which also include asymptomatic fractures. The prospective evaluation of composite end points such as SSEs that incorporate rPFS and clinical progression is warranted, to determine which end point may be most associated with clinical benefit and/or survival after treatment with a specific agent class.

PROs

Control/Relieve/Eliminate

PCWG3 supports standardizing an approach for reliable and quantitative assessment of the patient experience in prostate cancer trials. PCWG3 reaffirms that demonstrating pain palliation requires a patient population with clinically meaningful pain at baseline (eg, ≥ 4 on a 10-point pain intensity scale) and a response defined as a clinically meaningful score improvement at a subsequent time point (eg, a 30% relative or 2-point absolute improvement from baseline at 12 weeks, confirmed at least 2 weeks later, without an overall increase in opiate use).³⁴ Serial (eg, daily) assessments at each time point can improve the stability of values. These principles may be extended to any patient-reported disease-related symptom end point for which a clinically meaningful baseline score has been determined, together with a responder definition that is based on a sustained clinically meaningful score improvement.⁶⁰ Physical functioning should be assessed serially using a validated instrument (eg, EORTC QLQ-C30 or PROMIS).

Delay/Prevent

For a time-to-pain-progression analysis, patients with any level of baseline pain are eligible. Those without pain are followed for development of pain, whereas those with baseline pain are followed for pain progression (eg, a 2-point increase without an overall decrease in opiate use). A pain assessment should be administered at treatment discontinuation and once again if feasible (eg, 2 to 4 weeks later). When product labels are correct, they should include time-to-pain-progression end points, such as the time to development of opiate-dependent pain.⁶¹ Time to deterioration of physical function should also be included, with a priori thresholds defining clinically meaningful deterioration score changes.

Description of Adverse Events

Collection of patient-reported symptoms related to adverse events from treatment should be considered using the National Cancer Institute's PRO-CTCAE.³⁶ Inclusion of PRO-CTCAE should be considered in both early- and late-phase clinical trials. Results from PRO-CTCAE analyses can help determine optimal dosing and tolerability and can inform the risk:benefit evaluation of treatments.

PROGRESSION FROM nmCRPC TO mCRPC

Lymph Nodes

PCWG3 recommends that lymph nodes that were previously normal in size (< 1.0 cm) or pathologic in size must have grown by at least 5 mm in the short axis from baseline or nadir and be ≥ 1.0 cm in the short axis to be considered to have progressed. If the node progresses to ≥ 1.5 cm in the short axis, it is pathologic and measurable. Nodes that have progressed to between 1.0 and less than 1.5 cm are pathologic subject to clinical discretion and are nonmeasurable. These guidelines apply to studies involving patients with both metastatic and nonmetastatic disease. For existing pathologic adenopathy, progression is defined per RECIST 1.1.

Visceral

The date of first metastasis is the date on which an unequivocal visceral lesion by RECIST 1.1 is determined. No confirmatory scan is required unless the protocol uses modified criteria for immunotherapy.⁶² Visceral disease should be reported as being with or without other patterns of spread (node, bone).

Bone

Documentation of radiographic evidence of metastatic disease should include the time of the unequivocal development of new sites on bone scintigraphy. Given the earlier disease setting, it is advised that the scanning interval be increased to 16 weeks rather than the 8 weeks recommended for trials in mCRPC (Table 4). With 8-week intervals, it is less clear whether the detection of new sites of disease on a first follow-up bone scan represents flare of a pre-existing subclinical metastatic lesion(s) or a true transition from a nonmetastatic to a metastatic state.

In such cases, PCWG3 advises that the event be recorded, and that both the treatment and serial radiographic assessments be continued until two additional new lesions are detected, assuming the treatment is being tolerated well and there is no clinical reason to discontinue it. Both the date of the initial detection of metastatic disease and the date of subsequent progression should be recorded and both intervals, metastasis-free survival (MFS) and rPFS, should be reported. Because the optimal method to confirm new metastatic bone disease is uncertain at this time, the definition of MFS should be discussed with regulatory authorities if the MFS end point is being considered for a trial intended to support drug approval.

Use of Confirmatory Scans With Other Modalities

For patients who develop equivocal bone lesions while on study, PCWG3 discourages the use of other scanning modalities, including MRI, positron emission tomography, or other investigational scans that were not used to determine eligibility for the study. Supplemental scanning using imaging modalities with varied sensitivity that were selected by personal preference or regional practice may introduce bias.

MIXED RESPONSES

Individual metastatic foci in a particular site of disease or in the patient as a whole may be biologically distinct. Such biologic heterogeneity can result in a mixed response to treatment, wherein one site responds favorably and another unfavorably. This phenomenon has been considered historically as disease progression that requires a change in therapy. PCWG3 advises focusing on the entirety of disease rather than on a subset of index lesions. A review of the disease as a whole using each modality used at baseline is recommended. Biopsies of these growing, nonresponding, and new lesions may provide insights into mechanisms associated with resistance.

Control/Relieve/Eliminate

Whether favorable changes are occurring in all lesions in an organ or disease site, or in a subset of lesions, should be reported; whether they are occurring in one organ site or across sites of involvement should be reported separately.

Delay/Prevent

Progression may not occur in all sites. PCWG3 encourages reporting whether worsening represents the growth of one to two existing foci in an organ or disease site, or the development of new lesions in an organ or disease site that was previously uninvolved.

NLCB: PROGRESSION VERSUS THE DECISION TO DISCONTINUE THERAPY

PCWG2 encouraged the continuation of treatment if a rising PSA or worsening of an isolated disease site that was not clinically significant was the sole indicator of disease progression and the patient was otherwise tolerating therapy. Now, recognizing the biologic heterogeneity of individual metastatic lesions, PCWG3 draws the distinction between documenting progression for consistency of reporting (eg, recording the date of documented progression in a site of disease such as a lymph node that is unlikely to adversely affect prognosis) versus the decision to stop therapy.

To address this, PCWG3 introduces the no longer clinically benefiting (NLCB) reporting metric defined as the date and the specific reason(s) a therapy was ultimately discontinued. This end point permits individualized provider-patient decisions to continue or discontinue a treatment based on the primary therapeutic objective for which it is being administered and assessed, be it quality of life, PROs, or survival. As an example, in cases in which multiple sites of disease continue to respond but one to two sites grow, focal therapy such as radiation or surgery could be administered to the resistant site(s) and systemic therapy continued. Similarly, therapy may be continued if progression by PSA or imaging is slow and the disease-related symptoms that were present at baseline remain controlled. Important here is to record in detail the specific reasons why a therapy was ultimately discontinued, which may include clinical deterioration (clarifying whether it is disease or therapy related) or need for a change in systemic therapy. PCWG3 cannot define the risks/benefits at the individual level for continuation of therapy beyond progression, but sets the goal of prospectively defining the circumstances in which scenarios are identified where continuing a therapy is justified. Clinical trials evaluating whether therapy A should be stopped and a new one started, continued alone, or continued with a new one added, are ongoing.

To illustrate the concept of NLCB, we recommend use of a swimmers plot (Fig 3 ), in which each lane documents the individual patient experience on a trial over time. This plot includes significant adverse events encountered, treatment discontinuations, and the points at which the criteria for progression by a specific disease manifestation were met while treatment was continued up through the time treatment was ultimately discontinued. The information in each swim lane can also be used to record the dates a focal therapy (eg, external beam radiation) was used to treat nonresponding sites in cases in which multiple other sites of disease are still responding. In both cases, the patient may still be benefiting overall from a treatment, justifying its continuation. These plots are suggested for phase I and II studies and may be particularly useful in trials designed to assess the patient experience across treatment groups.

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.

SUMMARY

Section:

PCWG3 seeks to move the drug development process closer to common clinical scenarios encountered in routine practice. It also aims to allow a more complete characterization of the host and his disease, not only at the start of therapy, but also over time as it evolves under treatment, which may help establish the value and the benefit of continuing a therapy when there are signs that the disease is beginning to progress.

PCWG3 emphasizes the distinction between adenocarcinomas and other histologies, moves away from the pre- and post-taxane categorization, and recommends eligibility on the basis of prior therapies received. This should result in a greater focus on developing specific protocols for the distinct clinical phenotypes. An important addition to PCWG3 is the recommendation to describe the percentage of patients with a specific disease pattern; in some cases, stratification for a specific pattern of disease may be indicated. Focusing PROs on core concepts of disease-related symptoms, physical functioning, and adverse events of therapy is advised, with the goal of improving the standardization of PRO in prostate cancer clinical trials.

Serial biologic profiling of the disease before treatment, while receiving treatment, and at progression is also advised. To establish clinical significance, PCWG3 advises evaluating the strength of the association between early changes in individual outcome measures, be they clinical, biochemical, PROs, imaging, CTCs, or other molecular determinants, and later events such as rPFS or clinical progression-free survival and/or overall survival. Standards for the interpretation of outcomes for therapies that affect the immune system are also needed. Although improvements in symptoms and/or functional status can be clinical benefits in their own right, determining the clinical significance of a statistically significant change in a PRO measure is another area of focus. Finally, PCWG3 underscores the distinction between the need to consistently report progression by individual disease manifestation in the order in which they occur (be it PSA, imaging, or other surrogate) from the need to terminate a treatment because the patient is NLCB from the therapy he is currently receiving.

AUTHOR CONTRIBUTIONS

Section:

Conception and design: Howard I. Scher, Michael J. Morris, Walter M. Stadler, Celestia Higano, Ethan Basch, Karim Fizazi, Emmanuel S. Antonarakis, Tomasz M. Beer, Michael A. Carducci, Kim N. Chi, Paul G. Corn, Johann S. de Bono, Robert Dreicer, Daniel J. George, Elisabeth I. Heath, Maha Hussain, Wm. Kevin Kelly, Glenn Liu, Christopher Logothetis, David Nanus, Mark N. Stein, Charles J. Ryan, Oliver Sartor, Eric J. Small, Matthew Raymond Smith, Cora N. Sternberg, Mary-Ellen Taplin, George Wilding, Peter S. Nelson, Lawrence H. Schwartz, Susan Halabi, Philip W. Kantoff, Andrew J. Armstrong

Provision of study materials or patients: Howard I. Scher, Michael J. Morris

Collection and assembly of data: Howard I. Scher, Michael J. Morris, Celestia Higano, Tomasz M. Beer, Lawrence H. Schwartz, Susan Halabi, Andrew J. Armstrong

Data analysis and interpretation: Howard I. Scher, Michael J. Morris, Walter M. Stadler, Ethan Basch, Emmanuel S. Antonarakis, Tomasz M. Beer, Michael A. Carducci, Robert Dreicer, Daniel J. George, Maha Hussain, Dana E. Rathkopf, Susan F. Slovin, Charles J. Ryan, Oliver Sartor, George Wilding, Lawrence H. Schwartz, Susan Halabi, Andrew J. Armstrong

Manuscript writing: All authors

Final approval of manuscript: All authors

© 2016 by American Society of Clinical Oncology

Acknowledgment

Supported by National Cancer Institute (NCI) Grant No. P50-CA92629 SPORE in Prostate Cancer, NCI Cancer Center Support Grant No. P30 CA008748, the Department of Defense Prostate Cancer Research Program (PC071610), the Prostate Cancer Foundation, the Sidney Kimmel Center for Prostate and Urologic Cancers, and funds provided by David H. Koch through the Prostate Cancer Foundation. We thank the following institutions and individuals for their input into these recommendations: the US Food and Drug Administration, the Prostate Cancer Clinical Trials Consortium (which is supported by the US Department of Defense and the Prostate Cancer Foundation), and other international investigators in prostate cancer drug and biomarker development.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.

Howard I. Scher

Consulting or Advisory Role: Astellas Pharma, Bristol-Myers Squibb, Ferring Pharmaceuticals, OncologySTAT, Pfizer, Sanofi, Takeda Pharmaceuticals, WIRB-Copernicus Group, Medivation, BIND Therapeutics, Janssen, Roche/Genentech, Blue Earth, Celgene

Speakers' Bureau: WebMD

Research Funding: BIND Biosciences, Exelixis, Janssen Pharmaceuticals, Medivation, Janssen Diagnostics, Innocrin Pharmaceuticals

Travel, Accommodations, Expenses: Janssen Pharmaceuticals, Sanofi, AstraZeneca, Genentech, Pfizer, Takeda Pharmaceuticals, Ferring Pharmaceuticals, WIRB-Copernicus Group, Astellas Pharma, BIND Therapeutics, Roche, Medivation

Michael J. Morris

Consulting or Advisory Role: Astellas Pharma, Bayer, Millennium, Progenics, Tokai Pharmaceuticals

Research Funding: Bayer, Sanofi, Takeda Pharmaceuticals, Janssen Oncology, Agensys

Travel, Accommodations, Expenses: fujifilm

Walter M. Stadler

Honoraria: Bayer, Caremark, Medpacto, Johnson & Johnson, Merck, Sotio

Consulting or Advisory Role: Bayer, Caremark, Medpacto, Sotio, Johnson & Johnson, Merck

Research Funding: Active Biotech, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Dendreon, Exelixis, Novartis, Genentech/Roche, GlaxoSmithKline, Medivation, Pfizer, Merck, Millennium Pharmaceuticals

Other Relationship: UpToDate

Celestia Higano

Employment: CTI Biopharma

Leadership: CTI Biopharma

Stock or Other Ownership: CTI Biopharma

Consulting or Advisory Role: Dendreon, Bayer, Medivation, Ferring Pharmaceuticals, AbbVie, Genentech, Pfizer, BHR Pharma, Orion Corporation, Sanofi, Emergent BioSolutions, MorphoSys, Churchill Pharmaceuticals, Clovis Oncology

Research Funding: Algeta/Bayer, Aragon Pharmaceuticals, AstraZeneca, Dendreon, Genentech, Medivation, Millennium, Sanofi, Teva, Exelixis, Oncogenex, Emergent BioSolutions

Travel, Accommodations, Expenses: Bayer, Medivation, Dendreon, Ferring Pharmaceuticals, Pfizer, Johnson & Johnson, AbbVie, Genentech, Amgen, Orion Pharma, Ockham, Teva, Sanofi, Astellas Pharma, Emergent BioSolutions, MorphoSys, Churchill Pharmaceuticals, Clovis Oncology

Ethan Basch

No relationship to disclose

Karim Fizazi

Consulting or Advisory Role: Astellas Pharma, Sanofi, Janssen, Amgen, Orion Pharma, Novartis, AstraZeneca, Bayer

Emmanuel S. Antonarakis

Honoraria: Sanofi, Dendreon, Medivation, Janssen Biotech, ESSA

Consulting or Advisory Role: Sanofi, Dendreon, Medivation, Janssen Biotech, ESSA

Research Funding: Janssen Biotech, Johnson & Johnson, Sanofi, Dendreon, Aragon Pharmaceuticals, Exelixis, Millennium Pharmaceuticals, Genentech, Novartis, Tokai Pharmaceuticals

Travel, Accommodations, Expenses: Sanofi, Dendreon, Medivation, Tokai Pharmaceuticals

Tomasz M. Beer

Stock or Other Ownership: Salarius Pharmaceuticals

Consulting or Advisory Role: Astellas Pharma, Bayer, Dendreon, Janssen Japan, Novartis, Sotio

Research Funding: Astellas Pharma, Bristol-Myers Squibb, Dendreon, Janssen Research & Development, Medivation, Oncogenex, Sotio

Michael A. Carducci

Consulting or Advisory Role: Medivation, Astellas Pharma, Blue Earth, AstraZeneca, Clovis Oncology

Kim N. Chi

Honoraria: Sanofi, Janssen Pharmaceuticals, Astellas Pharma

Consulting or Advisory Role: ESSA, Astellas Pharma, Janssen Pharmaceuticals, Sanofi, Lilly/ImClone, Amgen, Bayer, Takeda Pharmaceuticals

Research Funding: Janssen Pharmaceuticals, Astellas Pharma, Amgen, Bayer, Novartis, Sanofi, Exelixis, Tokai Pharmaceuticals, Oncogenex, Teva

Paul G. Corn

Honoraria: Sanofi

Consulting or Advisory Role: Sanofi

Travel, Accommodations, Expenses: Sanofi

Johann S. de Bono

Honoraria: AstraZeneca, Sanofi, Astellas Pharma, Pfizer, Genentech/Roche

Consulting or Advisory Role: AstraZeneca, Sanofi, Genentech/Roche, Astellas Pharma

Research Funding: AstraZeneca, Genentech, Sanofi

Patents, Royalties, Other Intellectual Property: Abiraterone Rewards to Inventors

Travel, Accommodations, Expenses: AstraZeneca, Astellas Pharma, GlaxoSmithKline, Orion Pharma, Sanofi, Genmab, Taiho Pharmaceutical, QIAGEN, Vertex

Robert Dreicer

Consulting or Advisory Role: Medivation, Roche, Merck, Asana Biosciences, Tokai Pharmaceuticals, Churchill Pharma

Research Funding: Progenics

Daniel J. George

Honoraria: Dendreon, Novartis, Sanofi

Consulting or Advisory Role: Bayer, Dendreon, Exelixis, Medivation, Novartis, Pfizer, BIND Biosciences, Sanofi, GlaxoSmithKline, Astellas Pharma, Progenics, Innocrin Pharma, Genentech, Clovis Oncology, Merck, Bristol-Myers Squibb

Speakers' Bureau: Dendreon, Novartis, BiPar Sciences/Sanofi

Research Funding: Exelixis, Genentech/Roche, Janssen Oncology, Novartis, Pfizer, Progenics, Astellas Pharma, Bristol-Myers Squibb, GlaxoSmithKline, Millennium Pharmaceuticals, Innocrin Pharma

Travel, Accommodations, Expenses: Astellas Pharma, Bayer, Dendreon, Pfizer, Sanofi, Progenics, Bristol-Myers Squibb, Merck, BIND, Medivation

Elisabeth I. Heath

Honoraria: Bayer Diagnostics, Dendreon, Sanofi

Research Funding: Tokai Pharmaceuticals, Seattle Genetics, Agensys, Dendreon, Genentech/Roche, Millennium Pharmaceuticals, Celldex, Inovio Biomedical, Celgene

Maha Hussain

Consulting or Advisory Role: Johnson & Johnson, Synthon

Research Funding: Astellas Pharma, Bayer, Genentech, Medivation, Millennium Pharmaceuticals, Pfizer

Patents, Royalties, Other Intellectual Property: Method of Treating Cancer, Serial No. 61/481/671

Wm. Kevin Kelly

Honoraria: Sanofi

Consulting or Advisory Role: Sanofi, Churchill Pharmaceuticals, Johnson & Johnson

Research Funding: Sanofi, Novartis, Bayer HealthCare Pharmaceuticals, Tesaro

Glenn Liu

Stock or Other Ownership: AIQ Services

Research Funding: Johnson & Johnson, Novartis, Millennium Pharmaceuticals, Cellectar, Pfizer

Patents, Royalties, Other Intellectual Property: Patent US 9161720B2 System and Method for Evaluation of Disease Burden

Other Relationship: AIQ Services

Christopher Logothetis

Honoraria: Bayer, AstraZeneca, Pfizer, Helsinn Therapeutics, Bristol-Myers Squibb, Janssen, Sanofi, Novartis, Medivation/Astellas Pharma

Consulting or Advisory Role: Astellas Pharma, Bristol-Myers Squibb, Johnson & Johnson, Pfizer, Novartis, Helsinn Therapeutics, Bayer, AstraZeneca, Sanofi, Exelixis, Churchill Pharmaceuticals, Clovis Oncology

Research Funding: Astellas Pharma, Bristol-Myers Squibb, Johnson & Johnson, Exelixis, Pfizer, Novartis, Karyopharm Therapeutics, Cougar Biotechnology, AstraZeneca, Medivation, Bayer, GlaxoSmithKline, Sanofi

Travel, Accommodations, Expenses: Bayer, AstraZeneca, Bristol-Myers Squibb, Pfizer, Janssen, Astellas Pharma, Novartis, Churchill Pharmaceuticals, Clovis Oncology, Sanofi

David Nanus

No relationship to disclose

Mark N. Stein

Research Funding: Janssen Oncology, Oncoceutics

Dana E. Rathkopf

Consulting or Advisory Role: Janssen Oncology

Research Funding: Janssen Oncology, Medivation, Celgene, Takeda Pharmaceuticals, Millennium Pharmaceuticals, Ferring Pharmaceuticals, Novartis

Susan F. Slovin

No relationship to disclose

Charles J. Ryan

Honoraria: Janssen Oncology, Astellas Pharma

Consulting or Advisory Role: Bayer, Millennium Pharmaceuticals, Astra Zeneca, Medivation

Research Funding: BIND Biosciences, Karyopharm Therapeutics, Novartis

Oliver Sartor

Consulting or Advisory Role: Astellas Pharma, Bavarian Nordic, Bayer, Bellicum Pharmaceuticals, Biscayne Pharmaceuticals, Johnson & Johnson, Medivation, Oncogenex, Sanofi, Teva, Tokai Pharmaceuticals

Research Funding: Bayer, Johnson & Johnson, Progenics, Sanofi, Sotio, Endocyte

Eric J. Small

No relationship to disclose

Matthew Raymond Smith

Consulting or Advisory Role: Bayer, Janssen Oncology, Astellas Pharma, Medivation, Gilead Sciences

Cora N. Sternberg

Consulting or Advisory Role: Astellas Pharma, Bayer, Janssen Pharmaceuticals, Sanofi

Mary-Ellen Taplin

Honoraria: Medivation, Janssen-Ortho, Dendreon, Tokai Pharmaceuticals, Bayer

Consulting or Advisory Role: Medivation, Janssen-Ortho, Tokai Pharmaceuticals, Sanofi, Bayer, Guidepoint Global, Best Doctors, Gerson Lehrman Group, Dendreon, UpToDate

Research Funding: Janssen-Ortho, Medivation, Bayer

Travel, Accommodations, Expenses: Medivation, Janssen Oncology, Tokai Pharmaceuticals, Dendreon

George Wilding

No relationship to disclose

Peter S. Nelson

Honoraria: Janssen Research & Development

Consulting or Advisory Role: Janssen Research & Development, Medivation/Astellas Pharma, AstraZeneca

Lawrence H. Schwartz

Honoraria: Novartis, Celegene

Patents, Royalties, Other Intellectual Property: Varian Medical Systems

Other Relationship: ICON Clinical Research, BioClinica

Susan Halabi

Consulting or Advisory Role: Bayer, Genentech/Roche

Travel, Accommodations, Expenses: Bayer

Philip W. Kantoff

Consulting or Advisory Role: Aragon Pharmaceuticals, Amgen, Bayer, Bavarian Nordic, Celgene, Exelixis, Genomic Health, GTx, Janssen Pharmaceuticals, Millennium Pharmaceuticals, Pfizer, Teva, Astellas Pharma, Auven Therapeutics, Bellicum Pharmaceuticals, BIND Biosciences, Blend Therapeutics, Roche, Metamark Genetics, Medivation, Merck, MTG Therapeutics, OncoCellMDX, Oncogenex, Progenics, Sotio, Sanofi, Tokai Pharmaceuticals

Research Funding: Aragon Pharmaceuticals, Amgen, Astellas Pharma, Bayer, Bavarian Nordic, Dendreon, Exelixis, Janssen Oncology, Medivation, Sanofi, Oncogenex

Travel, Accommodations, Expenses: Sanofi, Janssen Pharmaceuticals, BIND Biosciences, Bavarian Nordic, Millennium Pharmaceuticals, Progenics

Andrew J. Armstrong

Honoraria: Dendreon, Sanofi

Consulting or Advisory Role: Bayer, Sanofi, Novartis, Dendreon, Medivation, Janssen Biotech

Speakers' Bureau: Dendreon, Sanofi

Research Funding: Dendreon, Sanofi, Bayer, Pfizer, Novartis, Bristol-Myers Squibb, KangLaiTe, Janssen Oncology, Medivation, Astellas Pharma, ImClone Systems

Patents, Royalties, Other Intellectual Property: Circulating tumor cell novel capture technology

Travel, Accommodations, Expenses: Dendreon, Medivation, Janssen Biotech

Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

The Dual-Objective Framework for Therapeutic Objectives

The Prostate Cancer Clinical Trials Working Group 3 (PCWG3) retains the dual-objective structure described by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2), categorizing therapeutic objectives as control/relieve/eliminate versus delay/prevent. Delay/prevent objectives include manifestations that are clinically significant trial end points in their own right, such as symptomatic skeletal events or prolonged survival. This model aligns with the indications and uses of the currently approved drugs (see Appendix Table A1). Notable is that pain is the only control/relieve/eliminate end point for which therapies are approved or indicated.

The Biomarker Context of PCWG3

Drug development programs are designed to demonstrate clinical benefit with acceptable safety in well-controlled studies.⁶³ Optimally, the clinical benefit should fulfill an unmet need. PCWG3 considers all aspects of the clinical trial process within a biomarker context, from discovery or definition, to analytical assay validation, to clinical validation.^64,65 The biomarker may be a clinical measure (eg, functional status), patient-reported outcome, tumor or host biochemical measure, imaging parameter, or molecular determinant. PCWG3 encourages defining and evaluating biomarkers for specific contexts of use during the early phases of drug development to enable validation in later-phase trials. The demonstration of a biomarker's clinical usefulness (which shows that the risk/benefit outcome for the patient is improved when the biomarker test result is used in making the therapeutic decision) is also emphasized.⁶⁶

Calculating Prostate-Specific Antigen Doubling Time

Prostate-specific antigen (PSA) doubling time should be calculated using a linear regression model of the normal logarithm of PSA and time.⁶⁷ The calculation should be based on (1) at least three consecutive PSA values with each value ≥ 0.2 ng/dL, (2) inclusion of the most recent PSA values during androgen deprivation therapy, and (3) interval between first and last PSA values of ≥ 8 weeks but ≤ 12 months.^20,21,67

Table A1. Indications and Regulatory Labels for the Currently Approved Drugs for CRPC, Aligned With the PCWG3 Manifestation-Specific Outcome Framework

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.

REFERENCES

Section:

1.	GJ Bubley, M Carducci, W Dahut, etal: Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: Recommendations from the Prostate-Specific Antigen Working Group J Clin Oncol 17:3461–3467,1999 Link, Google Scholar
2.	IF Tannock, R de Wit, WR Berry, etalTAX 327 Investigators: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer N Engl J Med 351:1502–1512,2004 Crossref, Medline, Google Scholar
3.	DP Petrylak, CM Tangen, MH Hussain, etal: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer N Engl J Med 351:1513–1520,2004 Crossref, Medline, Google Scholar
4.	HI Scher, S Halabi, I Tannock, etalProstate Cancer Clinical Trials Working Group: 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 J Clin Oncol 26:1148–1159,2008 Link, Google Scholar
5.	TM Beer, AJ Armstrong, DE Rathkopf, etalPREVAIL Investigators: Enzalutamide in metastatic prostate cancer before chemotherapy N Engl J Med 371:424–433,2014 Crossref, Medline, Google Scholar
6.	JS de Bono, CJ Logothetis, A Molina, etalCOU-AA-301 Investigators: Abiraterone and increased survival in metastatic prostate cancer N Engl J Med 364:1995–2005,2011 Crossref, Medline, Google Scholar
7.	JS de Bono, S Oudard, M Ozguroglu, etalTROPIC Investigators: Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial Lancet 376:1147–1154,2010 Crossref, Medline, Google Scholar
8.	PW Kantoff, CS Higano, ND Shore, etalIMPACT Study Investigators: Sipuleucel-T immunotherapy for castration-resistant prostate cancer N Engl J Med 363:411–422,2010 Crossref, Medline, Google Scholar
9.	C Parker, S Nilsson, D Heinrich, etalALSYMPCA Investigators: Alpha emitter radium-223 and survival in metastatic prostate cancer N Engl J Med 369:213–223,2013 Crossref, Medline, Google Scholar
10.	CJ Ryan, MR Smith, JS de Bono, etalCOU-AA-302 Investigators: Abiraterone in metastatic prostate cancer without previous chemotherapy N Engl J Med 368:138–148,2013 Crossref, Medline, Google Scholar
11.	HI Scher, K Fizazi, F Saad, etalAFFIRM Investigators: Increased survival with enzalutamide in prostate cancer after chemotherapy N Engl J Med 367:1187–1197,2012 Crossref, Medline, Google Scholar
12.	R Aggarwal, T Zhang, EJ Small, etal: Neuroendocrine prostate cancer: Subtypes, biology, and clinical outcomes J Natl Compr Canc Netw 12:719–726,2014 Crossref, Medline, Google Scholar
13.	H Beltran, S Tomlins, A Aparicio, etal: Aggressive variants of castration-resistant prostate cancer Clin Cancer Res 20:2846–2850,2014 Crossref, Medline, Google Scholar
14.	HI Scher, X Jia, JS de Bono, etal: Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: A reanalysis of IMMC38 trial data Lancet Oncol 10:233–239,2009 Crossref, Medline, Google Scholar
15.	PJ Saylor, AJ Armstrong, K Fizazi, etal: New and emerging therapies for bone metastases in genitourinary cancers Eur Urol 63:309–320,2013 Crossref, Medline, Google Scholar
16.	K Fizazi, C Massard, M Smith, etal: Bone-related parameters are the main prognostic factors for overall survival in men with bone metastases from castration-resistant prostate cancer Eur Urol 68:42–50,2015 Crossref, Medline, Google Scholar
17.	P Nuhn, AM Vaghasia, J Goyal, etal: Association of pretreatment neutrophil-to-lymphocyte ratio (NLR) and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with first-line docetaxel BJU Int 114:E11–E17,2014 6b Crossref, Medline, Google Scholar
18.	G Sonpavde, GR Pond, AJ Armstrong, etal: Prognostic impact of the neutrophil-to-lymphocyte ratio in men with metastatic castration-resistant prostate cancer Clin Genitourin Cancer 12:317–324,2014 Crossref, Medline, Google Scholar
19.	S Halabi, NJ Vogelzang, SS Ou, etal: Progression-free survival as a predictor of overall survival in men with castrate-resistant prostate cancer J Clin Oncol 27:2766–2771,2009 Link, Google Scholar
20.	MR Smith, F Kabbinavar, F Saad, etal: Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer J Clin Oncol 23:2918–2925,2005 Link, Google Scholar
21.	MR Smith, F Saad, S Oudard, etal: Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: Exploratory analyses by baseline prostate-specific antigen doubling time J Clin Oncol 31:3800–3806,2013 Link, Google Scholar
22.	JS de Bono, HI Scher, RB Montgomery, etal: Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer Clin Cancer Res 14:6302–6309,2008 Crossref, Medline, Google Scholar
23.	DC Danila, M Fleisher, HI Scher: Circulating tumor cells as biomarkers in prostate cancer Clin Cancer Res 17:3903–3912,2011 Crossref, Medline, Google Scholar
24.	A Goldkorn, B Ely, DI Quinn, etal: Circulating tumor cell counts are prognostic of overall survival in SWOG S0421: A phase III trial of docetaxel with or without atrasentan for metastatic castration-resistant prostate cancer J Clin Oncol 32:1136–1142,2014 Link, Google Scholar
25.	HI Scher, G Heller, A Molina, etal: Circulating tumor cell biomarker panel as an individual-level surrogate for survival in metastatic castration-resistant prostate cancer J Clin Oncol 33:1348–1355,2015 Link, Google Scholar
26.	ES Antonarakis, C Lu, H Wang, etal: AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer N Engl J Med 371:1028–1038,2014 Crossref, Medline, Google Scholar
27.	M Crespo, G van Dalum, R Ferraldeschi, etal: Androgen receptor expression in circulating tumour cells from castration-resistant prostate cancer patients treated with novel endocrine agents Br J Cancer 112:1166–1174,2015 Crossref, Medline, Google Scholar
28.	HI Scher, J Louw, A Jendrisak, etal: Predictive biomarkers of sensitivity to androgen receptor signaling (ARS) and taxane-based chemotherapy in circulating tumor cells (CTCs) of patients (pts) with metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol 201533:suppl 7; abstr 147 Link, Google Scholar
29.	RC Chen, P Chang, RJ Vetter, etal: Recommended patient-reported core set of symptoms to measure in prostate cancer treatment trials J Natl Cancer Inst 106:dju132,2014 Crossref, Medline, Google Scholar
30.	S Halabi, NJ Vogelzang, AB Kornblith, etal: Pain predicts overall survival in men with metastatic castration-refractory prostate cancer J Clin Oncol 26:2544–2549,2008 Link, Google Scholar
31.	MJ Fisch, JW Lee, M Weiss, etal: Prospective, observational study of pain and analgesic prescribing in medical oncology outpatients with breast, colorectal, lung, or prostate cancer J Clin Oncol 30:1980–1988,2012 Link, Google Scholar
32.	KA Autio, AV Bennett, X Jia, etal: Prevalence of pain and analgesic use in men with metastatic prostate cancer using a patient-reported outcome measure J Oncol Pract 9:223–229,2013 Link, Google Scholar
33.	AJ Armstrong, E Garrett-Mayer, Y Ou Yang, etal: Prostate-specific antigen and pain surrogacy analysis in metastatic hormone-refractory prostate cancer J Clin Oncol 25:3965–3970,2007 Link, Google Scholar
34.	E Basch, AM Trentacosti, LB Burke, etal: Pain palliation measurement in cancer clinical trials: The US Food and Drug Administration perspective Cancer 120:761–767,2014 Crossref, Medline, Google Scholar
35.	RC Serlin, TR Mendoza, Y Nakamura, etal: When is cancer pain mild, moderate or severe? Grading pain severity by its interference with function Pain 61:277–284,1995 Crossref, Medline, Google Scholar
36.	E Basch, BB Reeve, SA Mitchell, etal: Development of the National Cancer Institute's patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) J Natl Cancer Inst 106:dju244,2014 Crossref, Medline, Google Scholar
37.	LH Schwartz, J Bogaerts, R Ford, etal: Evaluation of lymph nodes with RECIST 1.1 Eur J Cancer 45:261–267,2009 Crossref, Medline, Google Scholar
38.	S Halabi, WK Kelly, H Zhou, etal: The site of visceral metastases (mets) to predict overall survival (OS) in castration-resistant prostate cancer (CRPC) patients (pts): A meta analysis of five phase III trials J Clin Oncol 32:5s,2014 (abstr 5002) Link, Google Scholar
39.	H Matzkin, MS Soloway, PF Schellhammer, etal: Prognostic factors in stage D2 prostate cancer treated with a pure nonsteroidal antiandrogen Cancer 72:1286–1290,1993 Crossref, Medline, Google Scholar
40.	AJ Armstrong, R Kaboteh, MA Carducci, etal: Assessment of the bone scan index in a randomized placebo-controlled trial of tasquinimod in men with metastatic castration-resistant prostate cancer (mCRPC) Urol Oncol 32:1308–1316,2014 Crossref, Medline, Google Scholar
41.	P Sabbatini, SM Larson, A Kremer, etal: Prognostic significance of extent of disease in bone in patients with androgen-independent prostate cancer J Clin Oncol 17:948–957,1999 Link, Google Scholar
42.	MS Brown, GH Chu, HJ Kim, etal: Computer-aided quantitative bone scan assessment of prostate cancer treatment response Nucl Med Commun 33:384–394,2012 Crossref, Medline, Google Scholar
43.	GR Pond, G Sonpavde, R de Wit, etal: The prognostic importance of metastatic site in men with metastatic castration-resistant prostate cancer Eur Urol 65:3–6,2014 Crossref, Medline, Google Scholar
44.	D Robinson, EM Van Allen, YM Wu, etal: Integrative clinical genomics of advanced prostate cancer Cell 161:1215–1228,2015 [Erratum: Cell 162:454, 2015] Crossref, Medline, Google Scholar
45.	M Gerlinger, AJ Rowan, S Horswell, etal: Intratumor heterogeneity and branched evolution revealed by multiregion sequencing N Engl J Med 366:883–892,2012 Crossref, Medline, Google Scholar
46.	CE Spritzer, PD Afonso, EN Vinson, etal: Bone marrow biopsy: RNA isolation with expression profiling in men with metastatic castration-resistant prostate cancer--factors affecting diagnostic success Radiology 269:816–823,2013 Crossref, Medline, Google Scholar
47.	S Halabi, EJ Small, PW Kantoff, etal: Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer J Clin Oncol 21:1232–1237,2003 Link, Google Scholar
48.	S Halabi, CY Lin, WK Kelly, etal: Updated prognostic model for predicting overall survival in first-line chemotherapy for patients with metastatic castration-resistant prostate cancer J Clin Oncol 32:671–677,2014 Link, Google Scholar
49.	AJ Armstrong, ES Garrett-Mayer, YC Yang, etal: A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: A TAX327 study analysis Clin Cancer Res 13:6396–6403,2007 Crossref, Medline, Google Scholar
50.	O Smaletz, HI Scher, EJ Small, etal: Nomogram for overall survival of patients with progressive metastatic prostate cancer after castration J Clin Oncol 20:3972–3982,2002 Link, Google Scholar
51.	S Halabi, CY Lin, EJ Small, etal: Prognostic model predicting metastatic castration-resistant prostate cancer survival in men treated with second-line chemotherapy J Natl Cancer Inst 105:1729–1737,2013 Crossref, Medline, Google Scholar
52.	H Wakabayashi, K Nakajima, A Mizokami, etal: Bone scintigraphy as a new imaging biomarker: The relationship between bone scan index and bone metabolic markers in prostate cancer patients with bone metastases Ann Nucl Med 27:802–807,2013 Crossref, Medline, Google Scholar
53.	Food and Drug Administration: Guidance for industry: Clinical trial endpoints for the approval of cancer drugs and biologics: May 2007 http://www.fda.gov/downloads/Drugs/Guidances/ucm071590.pdf Google Scholar
54.	K Fizazi, R Jones, S Oudard, etal: Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5 J Clin Oncol 33:723–731,2015 Link, Google Scholar
55.	A Hoos, AM Eggermont, S Janetzki, etal: Improved endpoints for cancer immunotherapy trials J Natl Cancer Inst 102:1388–1397,2010 Crossref, Medline, Google Scholar
56.	MJ Morris, A Molina, EJ Small, etal: Radiographic progression-free survival as a response biomarker in metastatic castration-resistant prostate cancer: COU-AA-302 results J Clin Oncol 33:1356–1363,2015 Link, Google Scholar
57.	K Fizazi, M Carducci, M Smith, etal: Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: A randomised, double-blind study Lancet 377:813–822,2011 Crossref, Medline, Google Scholar
58.	F Saad, DM Gleason, R Murray, etalZoledronic Acid Prostate Cancer Study Group: A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma J Natl Cancer Inst 94:1458–1468,2002 Crossref, Medline, Google Scholar
59.	PG Kluetz, W Pierce, VE Maher, etal: Radium Ra 223 dichloride injection: U.S. Food and Drug Administration drug approval summary Clin Cancer Res 20:9–14,2014 Crossref, Medline, Google Scholar
60.	U.S. Department of Health and Human Services FDA Center for Drug Evaluation and Research; U.S. Department of Health and Human Services FDA Center for Biologics Evaluation and Research; U.S. Department of Health and Human Services FDA Center for Devices and Radiological Health: Guidance for industry: Patient-reported outcome measures: Use in medical product development to support labeling claims: draft guidance Health Qual Life Outcomes 4:79,2006 Crossref, Medline, Google Scholar
61.	E Basch, K Autio, CJ Ryan, etal: Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: Patient-reported outcome results of a randomised phase 3 trial Lancet Oncol 14:1193–1199,2013 Crossref, Medline, Google Scholar
62.	JD Wolchok, A Hoos, S O'Day, etal: Guidelines for the evaluation of immune therapy activity in solid tumors: Immune-related response criteria Clin Cancer Res 15:7412–7420,2009 Crossref, Medline, Google Scholar
63.	Food and Drug Administration: Guidance for Industry and FDA Staff: Qualification process for drug development tools: January 2014 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM230597.pdf Google Scholar
64.	AJ Armstrong, MA Eisenberger, S Halabi, etal: Biomarkers in the management and treatment of men with metastatic castration-resistant prostate cancer Eur Urol 61:549–559,2012 Crossref, Medline, Google Scholar
65.	HI Scher, MJ Morris, S Larson, etal: Validation and clinical utility of prostate cancer biomarkers Nat Rev Clin Oncol 10:225–234,2013 Crossref, Medline, Google Scholar
66.	DR Parkinson, RT McCormack, SM Keating, etal: Evidence of clinical utility: An unmet need in molecular diagnostics for patients with cancer Clin Cancer Res 20:1428–1444,2014 Crossref, Medline, Google Scholar
67.	CR Pound, AW Partin, MA Eisenberger, etal: Natural history of progression after PSA elevation following radical prostatectomy JAMA 281:1591–1597,1999 Crossref, Medline, Google Scholar

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Source: https://ascopubs.org/doi/10.1200/JCO.2015.64.2702

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