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. Author manuscript; available in PMC: 2022 Feb 9.
Published in final edited form as: Clin Genitourin Cancer. 2017 Apr 26;15(5):534–539. doi: 10.1016/j.clgc.2017.04.020

Prevalence of Measurable Disease in Metastatic Castration-resistant Prostate Cancer

Guru Sonpavde 1, Ankit Madan 1, Mary K Baker 1, Jori E May 1, Gurudatta Naik 1, Sejong Bae 1
PMCID: PMC8826449  NIHMSID: NIHMS1764930  PMID: 28526418

Abstract

Measurable disease was significantly more frequent in phase III trials accruing after 2000. Because of the subjective nature of prostate-specific antigen and bone scan changes and the robust association of objective measurable disease changes with survival, Response Evaluation Criteria in Solid Tumors changes should be a major end point in phase II trials to obtain a firm signal of efficacy before launching phase III trials.

Background:

Because of the low historical prevalence of measurable disease in metastatic castration-resistant prostate cancer (mCRPC), phase II trials have used prostate-specific antigen (PSA) and bone scan changes as primary end points. Frequent whole-body imaging and improved computed tomography technology currently identify measurable disease more frequently, warranting consideration of objective response as a major end point.

Patients and Methods:

Data from reported phase III trials of mCRPC were analyzed. The proportion of patients with measurable disease, setting (pre-docetaxel [D], D-based, post-D), year of starting accrual, PSA, and the requirement for symptoms were collected. The χ2 test was used to evaluate the association of variables with measurable disease rate.

Results:

Twenty phase III trials totaling 19,276 men with mCRPC were evaluable. Three trials (n = 1289) started accruing before 2000 and 17 trials (n = 17,987) accrued after 2000. The proportion of measurable disease rate for all trials was 47.5%. The measurable disease rate was significantly higher (P < .001) in trials that accrued after 2000 versus before 2000 (48.7% vs. 31.1%; P < .001), D-based (51.8%) or post-D patients (48.9%) compared with pre-D patients (38.6%) and in trials allowing symptomatic versus asymptomatic/minimally symptomatic patients (50.1% vs. 40.0%).

Conclusion:

The proportion of men with measurable disease was significantly higher in phase III trials of mCRPC that accrued after 2000, in D-based or post-D patients and in trials that allowed symptomatic patients. Because of the association of objective measurable changes with survival, Response Evaluation Criteria in Solid Tumors changes might warrant consideration as a major end point in phase II trials to obtain a firm signal of efficacy before launching phase III trials.

Keywords: Castration-resistant, Measurable tumor, Metastatic, Prostate cancer, RECIST

Introduction

The investigation of new agents for metastatic castration-resistant prostate cancer (mCRPC) is confounded by the frequent presence of nonmeasurable bone metastases and absence of objectively measurable disease. Radiographic progression-free survival has been used as an end point in recent phase II trials to provide a signal of therapeutic activity, which accounts primarily for new lesions on bone scan followed by a component of patients who show Response Evaluation Criteria in Solid Tumors (RECIST) disease progression.1,2 However, new lesions on bone scan might not always represent tumor progression. Prostate-specific antigen (PSA) response or progression has also been used as a surrogate for clinical activity, but is also plagued by poor association with clinical outcomes.

In contrast, trials of most solid tumors rely exclusively on objective changes in measurable disease by using RECIST 1.0 or 1.1 to screen the activity of new agents.3,4 We hypothesized that more frequent use of improved computed tomography (CT) technology might be increasing the proportion of men with measurable disease in more recent years and in certain subsets of more heavily pretreated or symptomatic patients. If our hypothesis is proven, measurable changes might need to be reconsidered as major end points in phase II trials of mCRPC seeking a signal of activity. Moreover, recent studies have shown the association of changes in measurable disease with survival in men receiving chemotherapy for mCRPC.5,6 To substantiate our hypothesis, we analyzed phase III trials of mCRPC to systematically quantitate the proportion of mCRPC with measurable disease.

Patients and Methods

Eligible Trials

Trial-level data from both arms of all reported randomized trials of mCRPC were eligible for analysis. Trials were required to report baseline measurable disease according to conventional criteria such as World Health Organization, RECIST 1.0, or RECIST 1.1. The overall number enrolled, the proportion of patients with measurable disease, the years of trial accrual, and year of publication were recorded. Certain eligibility criteria that might affect the proportion of patients with measurable tumors were recorded including the requirement for symptomatic disease or absence of visceral disease. In addition, the baseline key prognostic variables were recorded including PSA, pain, pre-versus post-docetaxel or docetaxel-based therapy.

Statistical Considerations

The study primarily represents a descriptive report of the proportion of patients with measurable disease overall in evaluable phase III trials. The χ2 test was used to evaluate the difference in measurable disease rate on the basis of the period of starting accrual (before the year 2000 and after 2000), setting (pre-docetaxel, docetaxel-based, post-docetaxel), PSA level, and the presence or absence of symptomatic disease. For proportion of patients with the disease, the 95% confidence intervals (CIs) were also estimated.

Results

Patient Characteristics

A total of 30 reported randomized phase III trials of mCRPC patients were identified in October 2015. Ten trials were not eligible because of absence of recording of baseline measurable disease or the use of unconventional means to report measurable disease (Figure 1).7–16 Thus, 20 randomized trials totaling 19,276 men with mCRPC were evaluable: 5775 patients from 7 trials were pre-docetaxel, 8625 patients from 8 trials were docetaxel-based, and 4876 patients from 5 trials were post-docetaxel (Table 1).1,17–35 The evaluable trials started accrual between 1993 and 2010: 3 trials started accrual before the year 2000, and the remaining 17 trials started in the year 2000 or later (8 trials from 2000–2007, and 7 trials after 2007). Eleven trials used RECIST 1.0, 5 trials used RECIST 1.1, and 4 trials used other criteria.

Figure 1. Trial Selection Process.

Figure 1

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Abbreviation: mCRPC = metastatic castrate-resistant prostate cancer.

Table 1.

Measurable Disease Rate in mCRPC Randomized Trials on the Basis of Setting in Relation to Docetaxel

Reference Years of Accrual Total n (All Arms of Trial) Treatments Patients With Measurable Tumors, n (%) Criteria Used to Measure Tumors Enrolled Asymptomatic or Minimally Symptomatic Only Trial Excluded Visceral Metastasis Median PSA (Range), ng/mL
Ryan et al 17 2009 to 2010 1088 Prednisone and abiraterone/placebo 435 (40.3) RECIST 1.0 Yes Yes 21.5 (0.3–9726.3)
Beer et al 18 2010 to 2012 1717 Placebo vs. enzalutamide 772 (45) RECIST 1.1 Yes No 49.2 (0.1–3627.0)
Nelson et al 19 2007 to 2009 594 Placebo vs. zibotentan 294 (49) RECIST 1.0 Yes No 52.8 (0.1–5172)
Pili et al 1 2007 to 2009 201 Placebo vs. tasquinimod 114 (57) RECIST 1.0 No No 24 (not reported)
Saad et al 20 2010 to 2012 1560 Prednisone and orteronel/placebo 479 (30.5) RECIST 1.1 Yes No 55.6 (18–150)
Hudes et al 21 1993 to 1995 201 Vinblastine with or without estramustine 63 (31.3) ECOG No No 166.8 (49.7–480)
Abratt et al 22 1997 to 2001 414 Hormonal therapy with or without vinorelbine 142 (34.3) WHO No No 91 (4–4119)
Tannock et al 23 2000 to 2002 1006 Prednisone and docetaxel/mitoxantrone 405 (40) WHO No No 115 (NR)
Petrylak et al 24 1999 to 2003 674 Mitoxantrone-prednisone vs. docetaxel-estramustine 196 (29.1) Study-specific No No 87 (0.1–10,820)
Tannock et al 25 2007 to 2010 1224 Docetaxel-prednisone and placebo/aflibercept 643 (52.5) RECIST No No 87.8 (0–6138)
Petrylak et al 26 2009 to 2011 1059 Docetaxel-prednisone and lenalidomide/placebo 927 (87.5) RECIST 1.1 No No 95.0 (32.1–306.0)
Araujo et al 27 2008 to 2011 1522 Docetaxel-prednisone and dasatinib/placebo 761 (50.2) mRECIST 1.0 No No 126 (0–8318)
Kelly et al 28 2005 to 2007 1050 Docetaxel-prednisone and bevacizumab/placebo 525 (50) RECIST 1.0 No No 85 (31–239)
Quinn et al 29 2006 to 2010 1038 Docetaxel-prednisone and atrasentan/placebo 482 (46.4) RECIST 1.0 No No 73.3 (23.5–228.3)
Fizazi et al 30 2008 to 2011 1052 Docetaxel and zibotentan/placebo 531 (50.5) RECIST 1.0 No No 92.1
Fizazi et al 31 2013 1099 Prednisone and orteronel/placebo 426 (38.8) RECIST 1.1 No No 128.3 (0–19,009)
Michaelson et al 32 2008 to 2010 873 Prednisone and sunitinib/placebo 494 (56.6) RECIST 1.0 No No NR
Scher et al 33 2009 to 2010 1199 Docetaxel and calcitriol/prednisone 653 (54.5) RECIST 1.1 No No 118 (0.0–19,000.0)
Sternberg et al 34 2003 to 2006 950 Prednisone and satraplatin/placebo 407 (42.9) RECIST 1.0 No No NR
de Bono et al 35 2007 to 2008 755 Prednisone and cabazitaxel/mitoxantrone 404 (53.5) RECIST 1.0 No No 135.7 (44.0–419.0)
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Abbreviations: ECOG = Eastern Cooperative Oncology Group; mRECIST = modified RECIST; RECIST = Response Evaluation Criteria in Solid Tumors; WHO = World Health Organization.

Proportion of Patients With Measurable Disease and Effect of Year of Accrual

The overall proportion of men with measurable disease was 47.5% (9153 of 19,276 patients). Among patients enrolled in trials that opened before 2000, 401 of 1289 patients enrolled in 3 pooled trials exhibited measurable tumors (31.1%; range, 29.1–34.3).21,22,24 Among patients enrolled in the trials that opened after 2000, 8752 of 17,987 patients enrolled in 17 trials exhibited measurable tumors (48.7%; range 30.5–87.5); among 8 trials starting accrual between 2000 and 2007, 3274 of 6818 exhibited measurable tumors (48%; range, 40–57) and among 9 trials starting accrual after 2007, 5478 of 11,169 exhibited measurable tumors (49.1%; range, 30.5–87.5). The difference in overall weighted measurable disease rate between patients enrolled in trials starting before 2000 versus after 2000 was significant (95% CI, 29.0–34.1 vs. 47.9–49.3; P < .001).

Measurable Tumor Rate on the Basis of Setting, PSA Level, and Eligibility Criteria

Pre-docetaxel patients exhibited measurable tumors in 2229 of 5775 patients (38.6%; range, 30.5–57; 95% CI, 37.3–39.9) of patients. Those who received docetaxel-based therapy had measurable tumors in 4470 of 8625 patients (51.8%; range, 29.1–87.5; 95% CI, 50.8–52.9) and the post-docetaxel group had measurable tumors in 2384 of 4876 patients (48.9%; range, 38.8–56.6; 95% CI, 47.5–50.3) of patients (P < .001). Four trials that restricted enrollment to asymptomatic or minimally symptomatic disease showed measurable tumors in 1980 of 4949 patients (40.0%; range, 30.5–49), and 16 trials that allowed patients with or without symptoms showed measurable tumors in 7173 of 14,327 patients (50.1%; range, 29.1–87.5; P < .001). Twelve trials with median baseline PSA < 100 ng/mL exhibited measurable tumors in 5540 of 11,671 patients (47.5%; range, 29.1–87.5), whereas among 6 trials for those with median PSA ≥ 100 ng/mL exhibited measurable tumors in 2712 of 5782 patients (46.9%; range, 31.3–54.5; P = not significant).

Discussion

This large pooled systematic analysis of 20 evaluable randomized phase III trials of 19,276 men with mCRPC showed an overall baseline measurable tumor rate of 47.5%. The overall pooled measurable disease rate in 3 trials that started accrual before 2000 versus 17 trials that started accrual after 2000 was 31.1% versus 48.7% (P < .001). A lower proportion of pre-docetaxel patients had measurable disease (38.6%) compared with docetaxel-based (51.8%) or post-docetaxel patients (48.9%; P < .001). Additionally, a significantly higher measurable tumor rate was observed in trials that enrolled patients with or without symptoms compared with trials that enrolled asymptomatic or minimally symptomatic patients (50.1% vs. 40.0%; P < .001). The rate of measurable tumors reported herein appears substantially higher than the historically observed low rates of measurable tumors.

Thus, our hypothesis appears to be correct (ie, that the proportion of men with mCRPC harboring measurable disease has increased recently), which might be ascribed to the use of better CT technology and more frequent comprehensive CT imaging of the chest, abdomen, and pelvis. However, there was no statistically significant difference in the prevalence of measurable disease on the basis of baseline median PSA level < 100 ng/mL versus ≥ 100 ng/mL.

Recent studies have shown the robust association of objective tumor response with survival in patients with mCRPC who received docetaxel-based chemotherapy.5,6 Taken together, the accumulating body of evidence supports the contention that the prevalence of objectively measurable disease is increasing in recent years and RECIST response might constitute an excellent end point to obtain a robust signal of antitumor activity of new drugs being evaluated in phase II trials.

Unlike most solid tumors, trials that evaluated new agents for mCRPC have not used measurable disease changes as the primary end point to make the go or no-go decision to initiate phase III trials.3,4 mCRPC trials have not required the presence of measurable disease, because the low proportion of patients with measurable disease has been considered a barrier to timely trial accrual and drug development. Unfortunately, PSA declines and bone scan progression are suboptimal and subjective indicators of clinical benefit and long-term outcomes.36,37 PSA and bone scan flares have been reported in multiple settings, which introduces barriers in the practice of readily using these metrics.38,39 Despite an association of bone scan progression using Prostate Cancer Working Group guidelines with overall survival (OS), surrogacy for OS has not been shown (eg, tasquinimod extended radiographic progression-free survival; mostly represented by bone scan changes, but did not prolong OS).1,40–43 Some agents can induce bone scan improvements because of a stromal effect, which might not translate to improved OS (eg, cabozantinib).44,45 Additionally, multiple phase III trials that combined docetaxel with biologic agents have not yielded increments in OS, suggesting that a more optimal intermediate objective end point warrants consideration when making the go or no-go decision after phase II trials.25–29,46 Indeed, drugs that have extended OS (abiraterone, enzalutamide, cabazitaxel) have also exhibited increases in objective response rates. The caveat is that measurable tumor changes might not be appropriate end points when evaluating some agents, such as radium-223, which specifically targets nonmeasurable bone metastases, and sipuleucel-T, which shows delayed activity and prolongs survival without early benefits.

The 47.5% (range, 29.1%−87.5%) proportion of patients with measurable tumors is respectable, albeit somewhat lower than the proportion of patients with measurable tumors in trials of other solid tumors. For example, when examining some key phase III trials of other major solid tumors not requiring baseline measurable disease, the proportion of patients with measurable disease ranged from 70% to 90%.47–49 Nevertheless, the recent prevalence of measurable disease in mCRPC patients enrolled in phase III trials after the year 2000 appears higher than historically noted in phase III trials that started before the year 2000. Indeed, studies previously reported measurable tumors in only approximately 20% of patients enrolled in phase II trials of mCRPC in the late 1980s and early 1990s.50,51

The study is limited by its retrospective design and the availability of trial-level (and not individual patient-level) data. Ten of 30 trials were not evaluable because of lack of required data for measurable disease. Although all included trials required CT scans of the abdomen and pelvis, trials allowed either CT scans or x-rays to image the chest. However, the proportion of patients who underwent CT scans of the chest as opposed to chest x-rays is unclear. Therefore, it is not possible to report differences in measurable disease rates on the basis of differences in chest imaging. The patients were derived from trial populations, which might be inherently different from patients treated in the community and not participating in a trial. However, it is possible that patients who are not participating in a trial might have poorer performance status and more advanced disease, which might be associated with an even higher prevalence of measurable disease.

Conclusion

The proportion of men with measurable disease in phase III trials of mCRPC was significantly higher in phase III trials starting accrual more recently after 2000 (48.7%) compared with those in trials that started before 2000 (31.1%). We propose that because of the increasing detection of measurable disease and association of objective measurable disease changes with survival, RECIST changes need to be considered as a key supportive or even coprimary end point in phase II trials to obtain a firm signal of efficacy before launching phase III trials.52

Clinical Practice Points.

  • The low historical prevalence of measurable disease in mCRPC has led to the use of PSA and bone scan changes to estimate disease progression in phase II trials; however, such changes are not objectively measurable and numerous phase II trials that show promising results have subsequently not been validated by phase III trials.

  • The increasing frequency of whole-body imaging and improved CT technology currently identify measurable disease more frequently, warranting consideration of objective response as a major end point.

  • In this retrospective analysis of 20 phase III trials totaling 19,276 men with mCRPC, the measurable disease rate was significantly higher in trials that accrued after 2000 versus before 2000 (48.7% vs. 31.1%; P < .001), docetaxel-based (51.8%) or post-docetaxel patients (48.9%) compared with pre-docetaxel patients (38.6%) and in trials allowing symptomatic versus asymptomatic/minimally symptomatic patients (50.1% vs. 40.0%).

  • Because of the association of objective measurable changes with survival, RECIST changes might warrant consideration as a major end point in phase II trials to obtain a firm signal of efficacy before launching phase III trials.

Acknowledgments

Disclosure

Guru Sonpavde has served as consultant for Bayer, Sanofi, Pfizer, Novartis, Eisai, Janssen, Amgen, Astrazeneca, Merck, Genentech, Argos, Agensys; and has research support to institution from Bayer, Onyx, Celgene, Boehringer-Ingelheim, Merck, Pfizer; Author for Uptodate; Speaker for Clinical Care Options.

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