Development of risk groups in metastatic castration-resistant prostate cancer (mCRPC) to facilitate the identification of active chemotherapy regimens

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5137-5137
Author(s):  
A. J. Armstrong ◽  
S. Halabi ◽  
I. F. Tannock ◽  
D. J. George ◽  
R. DeWit ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Risk Factors ◽  
Predictive Factors ◽  
Predictive Accuracy ◽  
Risk Groups ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Disease States ◽  
Phase Iii Trials ◽  
Chemotherapy Initiation

5137 Background: Our aim was to develop and validate clinically applicable predictive factors for a >30% PSA decline 3 months following chemotherapy initiation, and to assess the performance of a risk-group based classification in predicting PSA declines and overall survival (OS) in men receiving chemotherapy for mCRPC. Methods: In TAX327, 1006 men with mCRPC were randomized to receive docetaxel (D) in two schedules, or mitoxantrone (M), each with prednisone: 989 provided data on PSA decline at 3 months. Predictive factors for a >30% 3-month decline in PSA levels were identified using multivariate logistic regression in D treated men (n = 656) and validated in M treated men (n = 333). Risk factors were combined to form risk groups to predict PSA declines, OS, tumor, and pain responses. Prostate Cancer Working Group (PCWG2) disease states were evaluated for these outcomes in docetaxel treated men. Results: In multivariate analysis, four independent risk factors predicted for absence of >30% decline in 3-month PSA: significant baseline pain (OR 0.63 p = 0.02), visceral metastases (OR 0.66, p = 0.03), anemia (hemoglobin <13 g/dl, OR 0.72 p = 0.07), and bone scan progression at baseline (OR 0.60 p = 0.009). Predictive accuracy was moderate with a concordance index (c-index) of 0.61. Risk groups (good, intermediate, poor) were developed with median OS of 25.7 (95% CI 23.3–28.6), 18.7 (17.3–19.7), and 12.8 (11.5–14.6) months, respectively (p < 0.0001), and >30% PSA decline in 78, 66, and 58 percent of men (p < 0.001). In the validation M cohort, similar trends for PSA declines and OS were noted across risk groups (OS 22.5, 16.0, 11.8 mo, p < 0.001). PCWG2 subtypes (node only, bone metastatic, and visceral disease), were also highly prognostic and predictive but did not predict OS as well as the TAX327 risk groups (c-index 0.56). Conclusions: Risk groups have been identified and internally validated that predict PSA decline and OS in men with mCRPC. This classification may facilitate evaluation of new regimens of systemic therapy that warrant definitive testing in comparison to docetaxel and prednisone in phase III trials. Prospective validation of these risk groups is needed. [Table: see text]

scholarly journals Inferences About Drug Safety in Phase III Trials in Oncology: Examples From Advanced Prostate Cancer

2020 ◽  
Author(s):  
Joshua Z Drago ◽  
Mithat Gönen ◽  
Gita Thanarajasingam ◽  
Chana A Sacks ◽  
Michael J Morris ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Drug Safety ◽  
Advanced Prostate Cancer ◽  
Patient Characteristics ◽  
Similar Efficacy ◽  
Phase Iii ◽  
Statistical Uncertainty ◽  
Cancer Disease ◽  
Disease States ◽  
Phase Iii Trials

Abstract Background Safety is a central consideration when choosing between multiple medications with similar efficacy. We aimed to evaluate whether adverse event (AE) profiles of 3 such drugs in advanced prostate cancer could be distinguished based on published literature. Methods We assessed consistency in AE reporting, AE risk in placebo arms, and methodology used for risk estimates and quantification of statistical uncertainty in randomized placebo-controlled phase III trials of apalutamide, enzalutamide, and darolutamide in advanced prostate cancer. Results Seven included clinical trials enrolled a total of 9215 participants (range = 1051-1715 per trial) across 3 prostate cancer disease states. Within disease states, baseline patient characteristics appeared similar between trials. Of 54 distinct AE types in total, only 3 (fatigue, hypertension, and seizure) were reported by all 7 trials. Absolute risks of AEs in the placebo arms differed systematically and more than twofold between trials, which was associated with visit frequency and resulted in different degrees of uncertainty in AE profiles between trials. No trial used inferential methodology to quantify statistical uncertainty in AE risks, but 6 of 7 trials drew overall conclusions. Two trials concluded that there was no elevated AE risk because of the intervention, including the trial of darolutamide, which had the greatest statistical uncertainty. Conclusions Rigorous comparison of drug safety was precluded by heterogeneity in AE reporting, variation in AE risks in the placebo arms, and lack of inferential statistical methodology, underscoring considerable opportunities to improve how AE data are collected, analyzed, and interpreted in oncology trials.

scholarly journals Clinical Development of PARP Inhibitors in Treating Metastatic Castration-Resistant Prostate Cancer

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 860 ◽  
Author(s):  
Jacob J. Adashek ◽  
Rohit K. Jain ◽  
Jingsong Zhang
Keyword(s):  
Prostate Cancer ◽  
Unmet Need ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Phase Ii Studies ◽  
Phase Iii Trials ◽  
Signaling Inhibitors

The approval of upfront abiraterone for castration-sensitive prostate cancer and the approval of enzalutamide and apalutamide for non-metastatic castration-resistant prostate cancer have led to early utilization of potent androgen receptor (AR) signaling inhibitors in treating advanced prostate cancer. There is an unmet need to develop novel therapies beyond targeting AR signaling for metastatic castration-resistant prostate cancer (mCRPC). Poly (ADP-ribose) polymerase inhibitors (PARPi) belong to a class of targeted agents being developed for the treatment of homologous recombination repair (HRR) deficient tumors. Olaparib, rucaparib, niraparib, veliparib, and talazoparib were evaluated in early phase trials as a monotherapy for HRR-deficient mCRPC. Among them, olaparib and rucaparib have breakthrough designations for BRCA1/2-mutated mCRPC. Phase II studies also reported clinical activity of the PARPi and abiraterone combination and the PARPi checkpoint inhibitor combination in HRR-intact mCRPC. Ongoing phase III trials are testing these combinations as frontline or later line treatments for mCRPC. This review summarizes the critical clinical data as well as ongoing clinical trials for developing PARPi in treating mCRPC.

State-of-the-Art Management for the Patient with Castration-Resistant Prostate Cancer in 2012

2012 ◽  
pp. 289-291 ◽  
Author(s):  
Oliver Sartor
Keyword(s):  
Prostate Cancer ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Optimal Sequence ◽  
Molecular Stratification ◽  
Castration Resistant ◽  
Radium 223 ◽  
Phase Iii Trials

Overview: Much progress has been made in metastatic castration-resistant prostate cancer (CRPC), and multiple new U.S. Food and Drug Administration (FDA)-approved survival-prolonging drugs are now available. In 2004, docetaxel/prednisone was the first therapy shown to prolong survival. In 2010 and 2011, sipuleucel-T, cabazitaxel/prednisone, and abiraterone/prednisone were FDA approved. Two new agents, radium-223 and MDV-3100, have recently reported large phase III trials prolonging overall survival and will be submitted for regulatory approval in 2012. One can now begin to ask, is there an optimal sequence for therapies in metastatic CRPC? Despite the recent progress, there is much we do not know and virtually no information on this important question. We know that abiraterone/prednisone and cabazitaxel/prednisone are appropriate choices for a patient after receiving docetaxel, but we do not know what, if anything, represents the optimal sequence for abiraterone and cabazitaxel. In fact we do not understand how one therapy may affect the response to a subsequent therapy. We are also aware that the pre- and postdocetaxel spaces represent regulatory rather than biologic divisions. In addition, despite the proven role of docetaxel/prednisone, many patients with CRPC are not considered to be suitable for chemotherapy, and worldwide many never receive any form of chemotherapy. What is the optimal management for these patients? Taken together it is reasonable to assess patient preferences, prior therapies and response/tolerance to prior therapies, burden of disease, comorbidities, current symptoms, drug toxicities, out-of-pocket costs, etc., in clinical decision making. Given the many factors we do not know, it is hard to be dogmatic in approaching the therapeutic options for the patient with CRPC. We will likely soon move beyond the current sequencing paradigm and begin to assess new combinations in a systematic and rational fashion. Perhaps one day, in the not too distant future, we will develop molecular “stratification systems” to better guide therapeutic choices in CRPC.

scholarly journals Updated Prognostic Model for Predicting Overall Survival in First-Line Chemotherapy for Patients With Metastatic Castration-Resistant Prostate Cancer

2014 ◽  
Vol 32 (7) ◽  
pp. 671-677 ◽  
Author(s):  
Susan Halabi ◽  
Chen-Yen Lin ◽  
W. Kevin Kelly ◽  
Karim S. Fizazi ◽  
Judd W. Moul ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prognostic Model ◽  
Risk Groups ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Phase Iii Trial ◽  
Castration Resistant ◽  
Validation Set ◽  
Line Chemotherapy

Purpose Prognostic models for overall survival (OS) for patients with metastatic castration-resistant prostate cancer (mCRPC) are dated and do not reflect significant advances in treatment options available for these patients. This work developed and validated an updated prognostic model to predict OS in patients receiving first-line chemotherapy. Methods Data from a phase III trial of 1,050 patients with mCRPC were used (Cancer and Leukemia Group B CALGB-90401 [Alliance]). The data were randomly split into training and testing sets. A separate phase III trial served as an independent validation set. Adaptive least absolute shrinkage and selection operator selected eight factors prognostic for OS. A predictive score was computed from the regression coefficients and used to classify patients into low- and high-risk groups. The model was assessed for its predictive accuracy using the time-dependent area under the curve (tAUC). Results The model included Eastern Cooperative Oncology Group performance status, disease site, lactate dehydrogenase, opioid analgesic use, albumin, hemoglobin, prostate-specific antigen, and alkaline phosphatase. Median OS values in the high- and low-risk groups, respectively, in the testing set were 17 and 30 months (hazard ratio [HR], 2.2; P < .001); in the validation set they were 14 and 26 months (HR, 2.9; P < .001). The tAUCs were 0.73 (95% CI, 0.70 to 0.73) and 0.76 (95% CI, 0.72 to 0.76) in the testing and validation sets, respectively. Conclusion An updated prognostic model for OS in patients with mCRPC receiving first-line chemotherapy was developed and validated on an external set. This model can be used to predict OS, as well as to better select patients to participate in trials on the basis of their prognosis.

Identification of a predictive factor of metastatic castration-resistant prostate cancer patients’ response to alternative antiandrogen therapy with flutamide.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 321-321
Author(s):  
Masato Yasui ◽  
Shuko Yoneyama ◽  
Koichi Uemura ◽  
Takashi Kawahara ◽  
Yusuke Hattori ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Risk Factors ◽  
Hormone Therapy ◽  
Predictive Factors ◽  
Hormonal Therapy ◽  
Bone Scan ◽  
Second Line ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
N Stage

321 Background: Recently, new androgen pathway inhibitors, abiraterone and enzalutamide, are demonstrated to improve overall survival for metastatic castration-resistant prostate cancer (mCRPC). In Japan, alternative antiandrogen (AA) as second-line hormonal therapy for mCRPC that relapses after initial hormone therapy have been commonly used before new androgen pathway inhibitors. In this study, we attempted to identify the predictive factors for efficacy of AA as second-line hormone therapy. Methods: We identified consecutive 65 mCRPC patients treated with AA as second-line hormonal therapy. All patients were treated with maximum androgen blockade (MAB) initially and evaluated antiandrogen withdrawal syndrome after relapse. We analyzed the correlations between progression-free survival (PFS) of AA and clinicopathological characteristics, including patients’ age, initial PSA levels, PSA levels at flutamide induction, Gleason scores, T stage, N stage, extent of disease (EOD) classifications on bone scan, and the previous duration of prostate cancer sensitivity to MAB. Results: The median duration of prostate cancer sensitivity to MAB was 11.3 months (range: 1.5-53.0 months). In multivariate analysis, four significant risk factors for poor PFS were identified; initial PSA levels ( > 263 ng/mL vs ≤ 263; HR 0.53, p = 0.038), N stage (1 vs 0; HR 3.00, p = 0.001), EOD classifications (3-4 vs 1-2; HR 2.50, p = 0.007), and the previous duration of prostate cancer sensitivity to MAB ( < 12 months vs ≥ 12; HR 2.16, p = 0.026). We stratified the patients into two cohorts with low risk (0-2 risk factor present) and high risk (3-4 risk factors present). We found a significant difference in PFS among risk groups (median PFS 7.3 months vs 1.5, p < 0.000). Conclusions: Initial PSA, N stage, EOD classifications on bone scan, and the previous duration of prostate cancer sensitivity to MAB were the significant predictive factors for efficacy of AA as second-line hormone therapy in patients with mCRPC. These findings might support that decision-making of when to start the new AR pathway inhibitors.

Nonhormone Therapy for Metastatic Castration-Resistant Prostate Cancer: Chemotherapy, Bone-Targeted Treatments, and Others

2013 ◽  
pp. e161-e165
Author(s):  
Karim Fizazi
Keyword(s):  
Prostate Cancer ◽  
Kinase Inhibitors ◽  
Time Frame ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
New Agents ◽  
Castration Resistant ◽  
Radium 223 ◽  
Targeted Treatments ◽  
Phase Iii Trials

There is no doubt that more therapeutic progress has been achieved during the last 3 years for patients with metastatic castration-resistant prostate cancer (mCRPC) than during the previous 30 years. During this limited time frame, not only have six compounds (sipuleucel-T, cabazitaxel, denosumab, abiraterone, radium-223, and enzalutamide, listed in chronologic order) yielded positive results in phase III trials, we have also learned that their mechanisms of action are different, making it quite likely that part of their anticancer activity may be incremental. Most of these agents have already been approved. Further progress may well soon complete this recently enlarged armamentarium, with important trials testing new agents derived from existing families of compounds (new endocrine therapies, new immunotherapies, etc.) and exploring the activity of new families of agents (tyrosine kinase inhibitors such as cabozantinib, inhibitors of chaperone proteins like OGX-O11 and OGX-427). The availability of these agents creates a new major challenge for those who conduct clinical research in mCRPC. Will we be able to personalize therapy based on the biology of the individual's tumor, as we are already doing in other neoplasms?

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