The development of risk groups in men with metastatic castration-resistant prostate cancer based on risk factors for PSA decline and survival

84 Background: Loss of retinoblastoma tumor suppressor (RB) function has been shown to lead to CRPC and is strongly associated with poor outcome. RB functions as a transcriptional repressor; as such, loss of RB causes de-repression of pro-tumorigenic gene networks, including deregulation of the androgen receptor (AR) locus, excessive AR production, and castration-resistant (ligand independent) AR activity that can bypass hormone therapy. Our hypothesis is that leveraging RB status can direct treatment decisions. The primary objective of the trial (NCT02218606) was to determine the radiographic progression free survival (rPFS) of AA/prednisone (AAP) with and without CBZ in mCRPC patients (pts) that have progressed on primary androgen deprivation therapy and no prior AR directed therapy or chemotherapy. Methods: This is a multicenter non-comparative randomized phase 2 trial. Pts were randomized 1:1 to AAP with crossover to CBZ upon AAP failure (Arm 1), or the combination of AAP + CBZ (Arm 2). Randomization was stratified by the CALGB 90401 prognostic risk groups. The primary endpoint was rPFS (time from randomization to radiographic progression or death, whichever occurs first). Arms were analyzed separately. Results: Between October 2014 and March 2019, 93 pts were accrued; 81 were randomized. Median age was 68 years and ECOG performance status was 0 or 1. Endpoints are shown in Table. Therapies were well tolerated. Conclusions: Results of AAP + CBZ (Arm 2) in chemotherapy naïve pts suggest that men may derive benefit from the earlier use of CBZ with acceptable toxicity, supporting further study of this combination in mCRPC pts. Circulating Tumor Cells are being analyzed for changes in RB/AR expression. Managed by: Prostate Cancer Clinical Trials Consortium; Funding: Sanofi US; Support: Prostate Cancer Foundation. Clinical trial information: NCT02218606. [Table: see text]

Download Full-text

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

Journal of Clinical Oncology ◽

10.1200/jco.2013.52.3696 ◽

2014 ◽

Vol 32 (7) ◽

pp. 671-677 ◽

Cited By ~ 247

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.

Download Full-text

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

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.5137 ◽

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]

Download Full-text

Analysis of time to castration-resistant prostate cancer (CRPC) after initiating primary androgen depletion therapy (PADT) of prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e15106 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e15106-e15106

Author(s):

Hideyuki Akaza ◽

Shiro Hinotsu ◽

Keyword(s):

Prostate Cancer ◽

Clinical Trials ◽

High Risk ◽

Risk Groups ◽

Rank Test ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Psa Progression ◽

Lh Rh ◽

Androgen Depletion

e15106 Background: Recent clinical trials for developing new drugs for castration resistant prostate cancer (CRPC) have been done for the patients who are surgically or medically castrated, with castration level of testosterone. Although patients who received combined androgen blockade (CAB) with anti-androgen must have shown PSA progression after discontinuing the anti-androgen prior to study enrollment, such patients are analyzed together with patients with castration monotherapy. Methods: We analyzed the time to CRPC among the patients with primary androgen depletion therapy (PADT); LH-RH agonist or CAB (LH-RH agonist + anti-androgen) who have registered to the J-CaP study and were followed up for >10 years. Time to CRPC was defined as PSA progression or other disease progression. Patients were stratified into three risk groups using JCAPRA score (JCO 2009; 26: 4309). In addition to the time to CRPC, overall survival length (OS) after initiating PADT was analyzed. Results: Time to CRPC was significantly longer in the CAB group than monotherapy group in intermediate and high risk groups (Table). In addition, in the intermediate and high risk groups, OS was significantly longer for the patients with CAB (Log-rank test). Conclusions: The significant differences of the time to CRPC and OS will influence to the outcome of clinical trials of CRPC. It is important to take the type of ADT in to consideration when we analyze the results of clinical study of CRPC. [Table: see text]

Download Full-text

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

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.2_suppl.321 ◽

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.

Download Full-text