TAX327 Trial Research Articles

Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART II.

The summary presented herein represents Part II of the two-part series dedicated to Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline discussing prognostic and treatment recommendations for patients with castration-resistant disease. Please refer to Part I for discussion of the management of patients with biochemical recurrence without metastatic disease after exhaustion of local treatment options as well as those with metastatic hormone-sensitive prostate cancer. The Advanced Prostate Cancer Panel created evidence- and consensus-based guideline statements to aid clinicians in the management of patients with advanced prostate cancer. Such statements are summarized in figure 1[Figure: see text] and detailed herein. The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. A research librarian conducted searches in Ovid MEDLINE (1998 to January Week 5 2019), Cochrane Central Register of Controlled Trials (through December 2018), and Cochrane Database of Systematic Reviews (2005 through February 6, 2019). An updated search was conducted prior to publication through January 20, 2020. The methodology team supplemented searches of electronic databases with the studies included in the prior AUA review and by reviewing reference lists of relevant articles. This guideline attempts to improve a clinician's ability to treat patients diagnosed with advanced prostate cancer. Continued research and publication of high-quality evidence from future trials will be essential to improve the level of care for these patients.

862P - Retrospective evaluation of neutropenic admission events in metastatic or high-risk hormone-sensitive prostate cancer (HSPC) patients having docetaxel chemotherapy upfront or for castrate-resistant prostate cancer (CRPC) in STAMPEDE

BackgroundDocetaxel (Doc) was initially licenced for CRPC (TAX327) but more recently trials showed Doc at HSPC diagnosis improved survival, shifting patterns of use. Higher neutropenic toxicity rates were reported in the HSPC trials, but it is unclear if this was due to the Doc timing or differences in case-mix. We compared sepsis rates for Doc at HSPC and CRPC using routine NHS data for men randomised in STAMPEDE in England. MethodsSTAMPEDE patient data were linked to routine NHS data (Hospital Episode Statistics: HES; Systemic Anti-Cancer Therapy: SACT). Patient note review (ref) linked to NHS data assessed admission rates by HSPC & CRPC Doc at 1 site (N=44) and were used to develop and validate algorithms for detecting sepsis events across the entire data set. Algorithms were restricted to sepsis-only & sepsis + neutropenia (S+N) (N=3645). Missing HES CRPC Doc regimens were imputed with HES (N=3645) or enhanced with SACT (N=1573). Odds ratios (OR) were calculated for risk of sepsis (OR<1 = lower risk for HSPC). ResultsSepsis rates varied by method; for most, rates at CRPC were higher than in TAX327 but similar to or higher than reported STAMPEDE HSPC data.Table862PTableHSPC Sepsis/PtsCRPC Sepsis/Pts% diffOR, 95% CIN%N%Ref2/15136/2227-140.4 (0.1 - 2.1)HESSepsis69/8348114/118310-20.9 (0.6 - 1.2)S+N134/83416148/11831331.3 (1.0 - 1.6)Imputed134/83416489/135136-200.4 (0.4 - 0.6)+ SACT41/2002160/2972011.0 (0.7 - 1.6) ConclusionsThis analysis does not support the hypothesis that HSPC Doc has a higher sepsis risk than Doc use in CRPC. Sepsis rates found using routine data were higher than in the TAX327 trial but similar to reported “real world” CRPC data. Rates varied by data-identification method used; for most, CRPC sepsis rates were higher or similar to HSPC rates & overall a little higher than the reported STAMPEDE HSPC rate. These data suggest CRPC Doc has a similar or higher sepsis rate than use in HSPC & this should be factored into discussions for men with newly-diagnosed metastatic HSPC and supports Doc use in this setting. Legal entity responsible for the studyThe STAMPEDE Trial Group. FundingUniversity of Warwick, Warwick Medical School (HM PhD studentship). DisclosureM.K.B. Parmar: Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Clovis oncology; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution), The Unit I am Director of also receives educational grants and other non- financial support from a large number of different companies: Other. P. Patel: Advisory / Consultancy: Roche/Genentech. M.R. Sydes: Honoraria (self): Lilly; Honoraria (self), Research grant / Funding (self): Sanofi; Honoraria (self): Janssen; Research grant / Funding (self): Astellas Pharma; Research grant / Funding (self): Janssen-Cilag; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Novartis; Research grant / Funding (self): Clovis Oncology. N.D. James: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy: Bayer; Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Astellas Pharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Janssen; Honoraria (self), Speaker Bureau / Expert testimony: Pierre Fabre; Speaker Bureau / Expert testimony: Ferring; Honoraria (self): Oncogenex; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Novartis. All other authors have declared no conflicts of interest.

Current era clinical outcomes of castration-resistant prostate cancer in real-life population study in Quebec, Canada.

226 Background: Prostate cancer (PCa) death is mainly due to castration-resistant PCa (CRPC) which results from disease progression despite androgen ablation therapy (ADT). Little is known about clinical outcomes and trends of real-life CRPC management in the present era, which has become very complex. Our study aimed to analyze healthcare services use, clinical outcomes and survival trends in real-life management of CRPC in Quebec, Canada. Methods: The study cohort consisted of 7,123 patients which shown evidence of CRPC from January/2001 to July/2013, selected from the public healthcare insurance programs the Régie de l’Assurance Maladie du Québec (RAMQ) databases. Survival was evaluated by Kaplan-Maier and the difference in survival between pre-/post-docetaxel (Doc) (2002-2005 vs 2008-2011) era by log-rank test. The association between Doc exposure and survival was evaluated by Cox proportional hazards model adjusted for several co-variables. Results: Chemotherapy was offered to 17% of patients, while 45% were kept on maximal androgen blockade (MAB) alone, or offered Abiraterone (3%). Androgen targeted therapies (MAB or Abiraterone) were the treatment of choice for the elderly population (mean age 78.8 and 78 ±7, respectively) while chemotherapy was offered to younger patients (mean age 72 ±7.3). Survival rates at 1 and 2 years after the initiation of chemotherapy were 52% and 26% in post-Doc era vs 46% and 17% in the pre-Doc period. In patients receiving first line chemotherapy only, hospitalization due to PCa was a poor prognostic predictor (HR: 2.0; 95%CI: 1.5-2.6), as expected. In addition among patients without previous hospitalization the risk of death was higher in the pre- vs post-Doc era (HR: 1.7 CI: 1.003-2.851). Conclusions: Patient age seems to be a strong determinant in CRPC therapy selection. In patients without serious complications leading to hospitalization, survival was greatly improved in the post-Doc era. Our data also supports that patients older than those in the TAX327 trial (72 vs 68) may equally benefit from chemotherapy. This is encouraging as we hope to observe comparable results for new approved therapies for CRPC.

Clinical outcome (CO) evaluation of very old (≥ 80 years) castration resistant prostate cancer (CRPC) patients (pts) treated with docetaxel (DOC): Preliminary results of an Italian multicenter retrospective study (DELPHI study).

5050 Background: Since prostate cancer is mainly diagnosed in pts over 65 yrs of age, castration resistance is usually observed in older pts. In the case of very old pts (≥ 80 years), fear of high toxicity degree limit chemotherapy use due to both pts frailty and several comorbidities occurrence. Moreover, if treated these pts usually receive an adapted chemotherapy, often with a weekly schedule, which in TAX327 trial failed to show survival advantage compared to mitoxantrone. The present retrospective study is aimed to assess CO in this very elderly CRPC population. Methods: In this multicentric retrospective study, after Ethical Committee approval, we have reviewed the clinical records of all ≥ 80 yrs CRPC pts from participating institutions, treated with DOC in clinical practice, recording the pre and post-DOC clinical history, the DOC treatment details and outcomes. Results: To date we collected a consecutive series of 81 pts from 17 Italian hospitals. The median age was 82 yrs (range 80-90). The median baseline PSA was 107 ng/ml (range 3-1597); 81% of the pts had bone metastases, while nodal, lung and liver metastases were observed in 37%, 6%, and 6% of the pts, respectively. Median Cumulative Illness Rating Scale score was 3 (range 0-11), median Activity Daily Living index score was 0 (range 0-5), median Instrumental Activities of Daily Living score was 0 (range 0-5). The DOC was administered on 3-week or weekly schedule basis (41%/59%). A PSA reduction &gt; 50% and an objective response were observed in 74% and 11% of the pts, respectively. Grade 3-4 toxicities were: neutropenia (11%) , fatigue (8%), diarrhea (1%), renal (2%), and febrile neutropenia (1%). The median PFS and OS were 7 mos and 22 mos, while the 1-year PFS and OS rates were 17.3% and 43.9%, respectively. Conclusions: This data suggests that DOC treatment, both on 3-week or weekly schedule, is able to produce good survival outcomes, comparable to pivotal trials (18 mos), also in highly selected very older (≥ 80 yrs) CRPC pts.

Ability of C-reactive protein to complement multiple prognostic classifiers in men with metastatic castration resistant prostate cancer receiving docetaxel-based chemotherapy

What's known on the subject? and What does the study add? Serum C-reactive protein (C-reactive protein) is emerging as a potential novel prognostic factor in metastatic castration-resistant prostate cancer (mCRPC). In the present study, a prospective trial was investigated retrospectively and a significant prognostic impact for C-reactive protein that was independent of multiple published prognostic models was identified in men receiving docetaxel-based chemotherapy for mCRPC. Prospective validation is warranted. • Given the recent emergence of C-reactive protein levels as a novel prognostic factor in men with metastatic castration-resistant prostate cancer (mCRPC), we sought to evaluate the independent prognostic ability of C-reactive protein in the context of published prognostic nomograms, risk grouping and disease state models in men receiving docetaxel-based chemotherapy for mCRPC. • A large randomized phase II trial (CS-205) of mCRPC patients who received docetaxel-prednisone + AT-101 (Bcl-2 inhibitor) or docetaxel-prednisone + placebo was analyzed retrospectively (n= 220). • Overall survival (OS), progression-free survival (PFS) and measures of discriminatory ability were assessed in a hypothesis-generating analysis using Cox regression and concordance probabilities. • Patients from both treatment groups were combined for this analysis because no significant differences in outcomes were observed. • Because some factors used in nomograms were not collected or defined differently, risk was estimated based on slightly modified versions of nomograms. • C-reactive protein was independently prognostic for OS and PFS (P ≤ 0.002) after adjusting for all modeled risk estimates and classifiers. • C-reactive protein showed a concordance probability of 0.65 for both OS and PFS. • A 10-factor modified prognostic model based on the TAX327 trial had the greatest observed discrimination ability for OS and PFS (concordance probability = 0.623 and 0.603, respectively) among the modified nomograms or classifiers. • Adding the TAX327 model risk estimates to C-reactive protein did not substantially increase discrimination ability over C-reactive protein alone. • Current prognostic classifications provide modest discrimination of outcomes in mCRPC receiving docetaxel-based chemotherapy, highlighting the need for improved risk-based models. • Baseline C-reactive protein appears to be an useful, independent prognostic factor and prospective external validation is warranted.

The unfolding treatment landscape for men with castration-resistant prostate cancer

Castration-resistant prostate cancer (CRPC) is a fatal disease in virtually all patients. Docetaxel chemotherapy became the standard front-line agent based on the results of the TAX327 trial in 2004, with a survival advantage of 3 months achieved over mitoxantrone. Over the past few years, an improved understanding of the molecular biology of castration-resistance has resulted in expansion of the treatment armamentarium for advanced prostate cancer with the emergence of novel androgen receptor-directed therapies, cytotoxic chemotherapies, as well as immunotherapies. Four different agents have very recently gained approval by the U.S. Food and Drug Administration for the treatment of CRPC and this review will summarize the development, mechanism of action, and safety and efficacy of these agents as demonstrated in preclinical as well as clinical studies.

Evaluating the Value of Number of Cycles of Docetaxel and Prednisone in Men With Metastatic Castration-Resistant Prostate Cancer

Background The optimal number of 3-wk docetaxel plus prednisone (DP) cycles for metastatic castration-resistant prostate cancer (mCRPC) is unclear. Objective A retrospective analysis of two clinical trials was performed to evaluate the association of the number of cycles with overall survival (OS). Design, setting, and participants An exploratory analysis compared outcomes of 332 men who received DP in the TAX-327 trial, which stipulated up to 10 cycles, and 220 men who received DP in CS-205, a randomized phase 2 trial comparing DP plus AT-101 (bcl-2 inhibitor) versus DP plus placebo, which allowed up to 17 cycles. Measurements Patients who completed 10 cycles of DP without progression in both trials were included. Men in both arms of CS-205 were combined for analysis, as no significant differences in outcomes were observed. OS was estimated from the date of cycle 10 docetaxel infusion. Results and limitations The number of men receiving 10 cycles was similar ( p = 0.26) in the two trials (166 [50.0%] in TAX-327 vs 99 [45.0%] in CS-205; the latter group received a median of five additional cycles). Six- and 12-mo estimated survival after cycle 10 was 92.2% (95% confidence interval [CI], 86.9–95.4%) and 74.6% (CI, 67.2–80.5%) in TAX-327, compared with 92.8% (CI, 85.5–96.5) and 63.4% (CI, 51.8–72.9%) in CS-205. Subanalyses suggested that <10 cycles may have a negative impact and prostate-specific antigen (PSA) declines at cycle 10 may carry a favorable impact. The significance of continued PSA declines up to 17 cycles is unclear. Limitations of a retrospective analysis apply. Conclusions A survival benefit was not detected with >10 cycles of DP in men with mCRPC in this retrospective hypothesis-generating analysis.

Impact of docetaxel‐based chemotherapy on quality of life of patients with castration‐resistant prostate cancer: results from a prospective phase II randomized trial

What's known on the subject? and What does the study add? Data on quality of life during docetaxel treatment in castration resistant prostate cancer was mainly provided by SWOG and TAX327 trials. In the TAX327 trial biochemical response and pain predicted survival, whereas quality of life outcomes did not. In the present study, there were no statistically significant changes in the quality of life scales during treatment except in the case of patients receiving docetaxel and estramustine, who experienced a significant decrease in pain. Our data seem to suggest that patients with a better baseline quality of life (and consequently with fewer symptoms) are more likely to achieve a biochemical response. • To assess quality of life (QoL) outcomes and pain changes in patients affected by castration-resistant prostate cancer enrolled in a phase II randomized trial of 3-week docetaxel (DOC)-based chemotherapy. • To provide further data to clarify the conflicting published data concerning the impact of DOC on the patients' QoL. • QoL outcomes were assessed using the European Organisation for the Research and Treatment of Cancer QLQ-C30 questionnaire. • Pain changes were evaluated by means of the Brief Pain Inventory at baseline and after every two DOC courses. • The patients completing at least two questionnaires (at baseline and before the third course) were considered evaluable. • In all, 59 patients were evaluable. • Asymptomatic patients and responders had a better baseline QoL than symptomatic patients and non-responders. • There were no statistically significant changes in the QLQ-C30 scales during treatment except in the case of patients receiving DOC and estramustine, who experienced a significant decrease in pain. • There was a progressive improvement in the mean intensity and interference scores of the Brief Pain Inventory. • Our data confirm that QoL is generally maintained during chemotherapy. • There is a substantial reduction in pain. • Our results also suggest that baseline QoL may predict treatment response.

Ability of serum alkaline phosphatase (ALP) changes to complement PSA changes and predict survival in men with metastatic castration-resistant prostate cancer (mCRPC) receiving docetaxel and prednisone (DP).

e15019 Background: PSA decline ≥30% and ≥50% within 90 days of starting chemotherapy are suboptimal surrogates for overall survival (OS) and only capture a proportion of total benefit. Changes in ALP were shown to complement PSA changes as prognostic factors for overall survival [OS] in men treated with chemotherapy in the TAX327 trial dataset. This analysis was performed to independently validate these findings in a different dataset. Methods: 221 men recruited to a randomized phase II trial of DP+AT-101 (bcl-2 inhibitor) versus DP+placebo were studied. No significant differences in outcomes were observed; hence, both arms were combined for analysis. Changes in ALP and PSA prior to day 90 were measured and evaluated for prognostic ability to predict OS from day 90 using the Kaplan-Meir method and Cox proportional hazards regression. For inclusion, patients were required to have bony metastases at baseline, ALP ≥120 u/L and survival beyond day 90. ALP normalization was defined as an ALP of <120 and PSA response was defined as decline ≥30% from baseline within 90 days of randomization. Results: 100 men were eligible for analysis h ALP≥120 and 45 had normalization of ALP by day 90. OS from day 90 was significantly improved (HR: 0.38, 95% CI: 0.21-0.68) among those with normalization (1-year OS: 71.5%, 95% CI: 55.3-82.7) compared with those not having normalization (47.3%, 95% CI: 33.1-60.2). ALP normalization was independent of PSA response as a prognostic factor. 1-year OS for men with ALP normalization and with/without PSA-response was 76.9% / 62.5%, and for men without ALP normalization and with/without PSA-response was 56.6% / 30.0%. 29 men had increased ALP at day 90 from baseline and these men had significantly worse survival (9.7 months vs. 17.4 months) even after adjusting for PSA progression (hazard ratio:2.43; 95% CI: 1.48-4.00). Conclusions: ALP changes on DP based therapy complement PSA changes as prognostic factors associated with OS. Although not a surrogate for OS, ALP changes may be useful in estimating prognosis and facilitating treatment decisions in the setting of PSA flare or lack of PSA response to docetaxel.

The association between radiographic response and overall survival in men with metastatic castration‐resistant prostate cancer receiving chemotherapy

In men with metastatic castration-resistant prostate cancer (CRPC), the association of measurable tumor responses with overall survival (OS) is unknown. The authors retrospectively evaluated the TAX327 phase 3 trial to study this relation. Eligible patients for this analysis included those with World Health Organization (WHO)-defined measurable metastatic disease randomized to receive either docetaxel or mitoxantrone. OS was estimated by using the Kaplan-Meier method, and the prognostic relation of WHO-defined radiologic response with OS was performed by using Cox proportional hazards regression. Landmark analyses evaluated survival from baseline and at 2, 3, 4, and 6 months after baseline. Four hundred twelve patients enrolled on the TAX327 trial had measurable tumors. Thirty-seven patients exhibited a complete or partial objective response (CR/PR, 9.0%), 116 had stable disease (SD, 28.2%), 99 had progressive disease (PD, 24%) and 160 (38.8%) did not have a after-baseline objective assessment. Partial responders demonstrated longer median OS (29.0 months) than patients with SD (22.1 months) or those with PD (10.8 months) or those who were not assessed (12.7 months). These results remained after landmark analysis. The authors found a significant association between ≥ 30% prostate-specific antigen (PSA) declines and radiologic response, with ≥ 30% PSA declines occurring in all patients with CR/PR, 79.8% of patients with SD, and 34.4% with PD. Radiologic response remained a significant but modest post-treatment prognostic factor for OS after adjusting for treatment, pain response, and ≥ 30% PSA decline (P = .009). In men with metastatic CRPC and measurable disease receiving chemotherapy, objective tumor response was prognostic for OS and appeared to complement PSA assessment.

Association between radiographic response and overall survival in men with metastatic castration-resistant prostate cancer receiving chemotherapy.

118 Background: In men with metastatic castration resistant prostate cancer (CRPC),the association of measurable tumor responses with overall survival (OS) is unknown. We retrospectively evaluated the TAX327 phase III trial to study this relationship. Methods: Eligible patients for this analysis included those with WHO-defined measurable metastatic disease randomized to receive either docetaxel or mitoxantrone. OS was estimated using the Kaplan-Meier method and the prognostic relationship of WHO-defined radiologic response with OS was performed using Cox proportional hazards regression. Landmark analyses evaluated survival from baseline and 2, 3, 4 and 6 months after baseline. Results: Four hundred and twelve patients enrolled on the TAX327 trial had measurable tumors. Thirty-seven patients exhibited a complete or partial objective response (CR/PR, 9.0%), 116 had stable disease (SD, 28.2%), 99 had progressive disease (PD,24%) and 160 (38.8%) did not have a post-baseline objective assessment. Partial responders demonstrated longer median OS (29.0 months) than patients with SD (22.1 months), or those with PD (10.8 months) or those who were not assessed (12.7 months). These results remained after landmark analysis. We found a significant association between ≥30% PSA declines and radiologic response, with ≥30% PSA declines occurring in all patients with CR/PR, 79.8% of patients with SD and 34.4% with PD. Radiologic response remained a significant but modest post-treatment prognostic factor for OS after adjusting for treatment, pain-response and ≥30% PSA-decline (p=0.009). Conclusions: In men with metastatic CRPC and measurable disease receiving chemotherapy, objective tumor response was prognostic for OS, and appears to complement PSA assessment. [Table: see text]

Serum alkaline phosphatase changes predict survival independent of PSA changes in men with castration-resistant prostate cancer and bone metastasis receiving chemotherapy

ObjectivesThe association of a change in serum alkaline phosphatase (ALP) with overall survival OS in men with metastatic castration-resistant prostate cancer (CRPC) receiving chemotherapy is unknown. We evaluated the association of changes in ALP within 90 days with OS in men with CRPC and bone metastases treated with docetaxel or mitoxantrone in the TAX327 trial. Materials and methodsEligible patients included those with bony metastatic disease, baseline ALP ≥ 120 u/L (upper limit of normal) and ≥2 post-therapy measurements of ALP available. Survival was estimated using the Kaplan-Meier method and prognostic potential of change in ALP was evaluated using Cox proportional hazards regression. Surrogacy was calculated by the Likelihood Reduction Factor. Results601 patients met the eligibility criteria. By day 90, 159 patients had ALP normalization (<120 u/L) and 442 patients did not normalize. Normalization of ALP remained prognostic for OS after adjusting for PSA decline ≥ 30% by day 90 (HR 0.79, 95% CI = 0.65–0.97, P = 0.022). Increase in ALP remained prognostic for OS when adjusting for PSA increase ≥ 50% by day 90 (HR 1.69, 95% CI = 1.33–2.14, P < 0.001). ALP changes did not meet criteria for surrogacy for OS. ConclusionsFor men with CRPC, bone metastasis and high baseline ALP receiving docetaxel or mitoxantrone chemotherapy, normalization of ALP by day 90 was predictive of better survival independent of ≥30% PSA declines. An increase in ALP by day 90 was also predictive of poor survival independent of ≥50% PSA increase. Given the ready availability of ALP, the validation of our data is warranted.

Use of changes in serum alkaline phosphatase to predict survival independent of PSA changes in men with castration-resistant prostate cancer and bone metastasis receiving chemotherapy: A retrospective analysis of the TAX327 trial.

4637 Background: Whilebaseline serum alkaline phosphatase (ALP) appears to be prognostic for overall survival (OS) in men with metastatic castration-resistant prostate cancer (CRPC), the associatio...

The impact of docetaxel (D) in an older population of patients with advanced prostate cancer (PC): A simulation study using TAX327 and SEER Medicare data

e16074 Background: The survival benefit of D in treatment of hormone refractory PC (HRPC) has been established in the TAX327 trial, but it is unclear how this benefit would translate in a heterogeneous population. This study sought to simulate the survival impact of D in a population of older pts with M1 PC on androgen deprivation therapy (ADT). Methods: A combination of TAX327 trial data and SEER-Medicare (SM) data were used. In pts age 69+ and randomized to D (every 3 weeks, D3P) or mitoxantrone (M), trial data showed a survival benefit for D. Accordingly, SM pts age 69+ diagnosed with M1 PC between 1994 and 2002 and receiving only ADT were selected. Graphical plots and statistical tests were used to find best-fitting parametric survival functions for D3P, M, and SM pts. The survival benefit for D was imposed on unadjusted and covariate-adjusted SM survival curves. The simulated benefit was assessed at 12 mos and 24 mos post-diagnosis of M1 PC in SM pts. Results: There were 326 TAX327 trial pts (D3P = 159, M = 167) used in the analysis. Median survival was 15.7 mos (12.6 - 19) in the M arm and 18.9 mos [17 - 21.8] in the D3P arm (p = 0.03). There were 3,515 SM pts, based on inclusion criteria. Median survival benefit of D was 3.2 mos based on Kaplan-Meier estimates and 2.4 mos using parametric curves in the TAX327 69+ group. Following covariate-adjustment in the SM sample, at 12 mos post-diagnosis, the median survival in mos was 61.7 (CI 36.3 - 87) in the ADT group and 62 (CI 37.6 - 87.1) in the simulated ADT+D group (i.e., 0.3 mos simulated benefit of D). A 0.8 mos simulated benefit was found if D was initiated 24 mos post diagnosis (in pts more likely to have HRPC). Conclusions: The survival benefit of docetaxel from the TAX327 trial is attenuated in a heterogeneous SEER-Medicare sample, and the simulated survival benefit is larger among patients who are more likely to have hormone refractory prostate cancer. [Table: see text]

Prostate-Specific Antigen and Pain Surrogacy Analysis in Metastatic Hormone-Refractory Prostate Cancer

It is currently unclear if early prostate-specific antigen (PSA) or pain improvements are adequate surrogates for overall survival in men with metastatic hormone-refractory prostate cancer (HRPC). Here we examined various degrees of PSA decline and pain response as surrogates for the survival benefit observed in the TAX327 trial. In the TAX327 trial, 1,006 men with HRPC were randomly assigned to receive docetaxel in two schedules, or mitoxantrone, each with prednisone: 989 men provided data on 3-month PSA decline. Surrogacy was examined for post-treatment changes in PSA and pain response using Cox proportional hazards models to calculate the proportion of treatment effect (PTE) explained by each potential surrogate. A > or = 30% PSA decline within 3 months of treatment initiation provides the highest degree of surrogacy, with a PTE of 0.66 (95% CI, 0.23 to 1.0), and was associated with a hazard ratio (HR) of 0.50 (95% CI, 0.43 to 0.58) for overall survival after adjusting for treatment effect. Introduction of a > or = 30% PSA decline is predictive of survival regardless of treatment arm. Other changes in PSA or PSA kinetics, PSA normalization, and pain responses were highly prognostic but weaker surrogates for survival. In the TAX327 trial, a PSA decline of > or = 30% within 3 months of chemotherapy initiation had the highest degree of surrogacy for overall survival, confirming data from the Southwest Oncology Group 9916 trial. However, given the wide CIs around the estimate of this moderate surrogate effect, overall survival should remain the preferred end point for phase III trials of cytotoxic agents in HRPC.

Achieving Treatment Goals for Hormone-Refractory Prostate Cancer with Chemotherapy

The belief that hormone-refractory prostate cancer (HRPC) is a chemotherapy-resistant disease has been effectively refuted by the results of two recent randomized phase III trials. The TAX327 trial compared weekly docetaxel, every-3-weeks (Q3W) docetaxel, and Q3W mitoxantrone plus prednisone in 1,006 patients with HRPC, and results demonstrated that survival was significantly longer with a docetaxel-based regimen than with mitoxantrone. That trial demonstrated that only Q3W docetaxel was significantly superior to mitoxantrone with respect to overall survival. Quality of life was also superior in the docetaxel groups. In the Southwest Oncology Group (SWOG) 9916 trial, 674 men with progressive HRPC were randomized to 3-week cycles of docetaxel plus estramustine or mitoxantrone plus prednisone. Overall and disease-free survival times were significantly longer in the docetaxel arm. Collectively, the results of these trials demonstrate that survival can be significantly improved with chemotherapy in patients with HRPC to an extent that is comparable with the survival benefits seen in other cancers considered sensitive to chemotherapy such as breast cancer. Among various research tasks in HRPC is the definition of potential surrogate end points for survival, which will facilitate the conduct of pivotal trials. Prostate-specific antigen (PSA) response rate and changes in PSA constructs (i.e., PSA doubling time and PSA velocity) are promising potential surrogate end points for future trials and are being actively evaluated at the present time. Until there is clear demonstration of a surrogate role for these alternative end points, survival remains the appropriate end point for phase III trials in HRPC. There is a need for safe and effective second- and third-line regimens for patients progressing after docetaxel, and these patients should enter clinical trials designed for this population. Mitoxantrone, vinorelbine, the platinum analogue satraplatin, and epothilone are among compounds that require careful testing in this setting. The addition of targeted therapies, such as the endothelin receptor antagonist, atrasentan, and angiogenesis inhibitors, such as thalidomide and bevacizumab, to docetaxel-based therapy is being evaluated. High-dose calcitriol may also be an effective addition to docetaxel. The extensive effort devoted to the evaluation of chemotherapy and other systemic modalities of treatment of HRPC is likely to yield additional clinical benefit for patients, making HRPC a more manageable, less lethal, and less debilitating disease.

Chemotherapy for advanced prostate cancer: Results of new clinical trials and future studies

Our understanding of the role of chemotherapy for advanced prostate cancer has improved considerably in 2004 with the publication of two large randomized phase III trials and the approval by the US Food and Drug Administration of docetaxel and prednisone for metastatic hormone-refractory disease. Although treatment is still considered palliative in nature, studies of chemotherapy for metastatic hormone-refractory prostate cancer (HRPC) have demonstrated improved overall survival compared with older regimens as well as clinically significant improvements in important endpoints, such as quality of life and time to progression. In particular, docetaxel has emerged as first-line therapy on an every-3-week schedule for metastatic HRPC, replacing mitoxantrone, as recently reported in the TAX327 trial. Docetaxel and estramustine combinations have the disadvantage of significant cardiovascular and gastrointestinal toxicity, and further use of estramustine is likely unwarranted as first-line therapy. Future trials examining novel biologic agents and combination therapies should use single-agent docetaxel as the reference standard. The role of chemotherapy for advanced disease in the neoadjuvant or adjuvant setting, in biochemically (PSA) relapsed patients, and as second-line therapy for relapsed disease, remains a subject of active clinical investigation.