scholarly journals Impact of Precision Medicine in Diverse Cancers: A Meta-Analysis of Phase II Clinical Trials

2015 ◽  
Vol 33 (32) ◽  
pp. 3817-3825 ◽  
Author(s):  
Maria Schwaederle ◽  
Melissa Zhao ◽  
J. Jack Lee ◽  
Alexander M. Eggermont ◽  
Richard L. Schilsky ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Phase Ii ◽  
Meta Analysis ◽  
Single Agent ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Cytotoxic Agents ◽  
Pubmed Search ◽  
Personalized Approach ◽  
The Impact

Purpose The impact of a personalized cancer treatment strategy (ie, matching patients with drugs based on specific biomarkers) is still a matter of debate. Methods We reviewed phase II single-agent studies (570 studies; 32,149 patients) published between January 1, 2010, and December 31, 2012 (PubMed search). Response rate (RR), progression-free survival (PFS), and overall survival (OS) were compared for arms that used a personalized strategy versus those that did not. Results Multivariable analysis (both weighted multiple linear regression and random effects meta-regression) demonstrated that the personalized approach, compared with a nonpersonalized approach, consistently and independently correlated with higher median RR (31% v 10.5%, respectively; P < .001) and prolonged median PFS (5.9 v 2.7 months, respectively; P < .001) and OS (13.7 v 8.9 months, respectively; P < .001). Nonpersonalized targeted arms had poorer outcomes compared with either personalized targeted therapy or cytotoxics, with median RR of 4%, 30%, and 11.9%, respectively; median PFS of 2.6, 6.9, and 3.3 months, respectively (all P < .001); and median OS of 8.7, 15.9, and 9.4 months, respectively (all P < .05). Personalized arms using a genomic biomarker had higher median RR and prolonged median PFS and OS (all P ≤ .05) compared with personalized arms using a protein biomarker. A personalized strategy was associated with a lower treatment-related death rate than a nonpersonalized strategy (median, 1.5% v 2.3%, respectively; P < .001). Conclusion Comprehensive analysis of phase II, single-agent arms revealed that, across malignancies, a personalized strategy was an independent predictor of better outcomes and fewer toxic deaths. In addition, nonpersonalized targeted therapies were associated with significantly poorer outcomes than cytotoxic agents, which in turn were worse than personalized targeted therapy.

Meta-analysis of outcomes of VEGF and EGFR targeted biologic therapy in relapsed metastatic colorectal cancer (mCRC).

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 534-534 ◽  
Author(s):  
David Chan ◽  
Eva Segelov ◽  
Jeremy David Shapiro ◽  
Timothy Jay Price ◽  
Christos Stelios Karapetis ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Kinase Inhibitors ◽  
Biologic Therapy ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Biologic Agents ◽  
First Line ◽  
Grade 3 ◽  
Line Setting ◽  
The Impact

534 Background: Biologic therapies used in treatment of mCRC are expensive and there is debate about their value. We examined the impact of biologic therapy on overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade 3/4 toxicity for patients beyond first-line treatment. Methods: MEDLINE, EMBASE, and Cochrane libraries were searched for randomized studies in relapsed mCRC comparing treatment containing targeted therapy to the same treatment without targeted therapy. Biologic agents were classed as: EGFR-inhibitors (EGFR-I), VEGF antibody/trap and VEGFR tyrosine kinase inhibitors (TKI). Only KRAS wild-type patients were included for EGFR-I analysis. Results were aggregated according to standard meta-analytic techniques. Results: 10 studies evaluating 5,847 patients were identified. Considering subgroups and lines, OS and PFS benefit was demonstrated in all groups across all lines except for OS in 2nd line EGFR-I use (which may be due to subsequent crossover). A benefit to ORR was seen with EGFR-I 2nd line (Pooled ORR benefit +24%, Odds Ratio (OR) 4.44, 95% CI 3.20-6.18), EGFR-I 3rd line and beyond (Pooled ORR benefit +16%), VEGF antibody/trap (Pooled ORR benefit +7.2%, OR 2.00, 95% CI 1.57-2.54) and VEGFR TKI (Pooled ORR benefit +1.9%, OR 2.05, 95% CI 1.27-3.30). The risk of grade 3/4 toxicity was greater with the addition of all targeted agents. Conclusions: The use of VEGF and EGFR targeted biologic agents beyond first-line setting in mCRC results in a benefit to OS, PFS and ORR for all agents except for OS benefit with second-line EGFR-I. This benefit comes at the cost of increased toxicity. [Table: see text]

scholarly journals Durvalumab in frail and elder patients with stage four NSCLC: Study protocol of the randomized phase II DURATION trial

2019 ◽  
Author(s):  
Jonas Kuon ◽  
Adriane Hommertgen ◽  
Johannes Krisam ◽  
Felix Lasitschka ◽  
Albrecht Stenzinger ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Phase Ii ◽  
Single Agent ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Open Label ◽  
Randomized Phase Ii ◽  
Effect Of Pd ◽  
The Impact ◽  
Single Agent Chemotherapy

Abstract Background Elderly patients represent a major fraction of non-small cell lung cancer (NSCLC) patients in routine clinical practice, yet are underrepresented in clinical trials. In particular, data regarding efficacy and safety in frail or elderly patients with respect to immunotherapy is lacking. Importantly, immunosenescence in elderly patients might interfere with activities of immune-modulating drugs such as PD-1/PD-L1 inhibitors. Thus, there is an urgent need to assess safety and efficacy of such inhibitors in this group. Methods/design In this prospective, open label, treatment stratified, and randomized phase II study, 200 patients with stage IV NSCLC amenable at least to single-agent chemotherapy. Eligible patients must be 70 years or older and/or “frail” (Charlson Comorbidity Index >1), or have a restricted performance score (ECOG >1). Patients are stratified according to modified Cancer and Age Research Group (CARG) Score: ”fit” patients are allocated to combination chemotherapy (carboplatin/ nab -paclitaxel), “less fit” patients receive single-agent chemotherapy (gemcitabine or vinorelbine). After allocation to strata, patients are randomized 1:1 to receive either 4 cycles of chemotherapy or 2 cycles of chemotherapy followed by 2 cycles of durvalumab and subsequent maintenance treatment with durvalumab every 4 weeks. The primary endpoint is the rate of treatment related grade III/IV adverse events (CTCAE V4.03). As secondary endpoints, progression-free survival according to RECIST 1.1, response rate, overall survival, descriptive subgroup analyses according to PD-L1 expression, and quality of life are addressed. Geriatric screening assessments and functional tests will be performed to complete the phenotyping of a potential “frail” and “elderly” patient cohort (G8-questionnaire, Timed up & go test, 6MWT). The trial is accompanied by a biomaterial repository (FFPE-tissue, Blood samples) to explore potential biomarkers. Discussion The DURATION trial will prospectively investigate the safety and tolerability of anti-PD-L1 treatment with durvalumab after chemotherapy in elderly and frail patients and thereby provide new insights into the effect of PD-L1 blockade and the impact of immunosenescence in this cohort of patients.

Targeted Therapy for Metastatic Renal Cell Carcinoma

2006 ◽  
Vol 24 (35) ◽  
pp. 5601-5608 ◽  
Author(s):  
Robert J. Motzer ◽  
Ronald M. Bukowski
Keyword(s):  
Renal Cell Carcinoma ◽  
Targeted Therapy ◽  
Cell Carcinoma ◽  
Phase Ii ◽  
Renal Cell ◽  
Progression Free Survival ◽  
Targeted Agents ◽  
Cell Renal Cell Carcinoma ◽  
Phase Ii And Iii ◽  
The Impact

The discovery of a relationship for the VHL tumor suppressor gene, hypoxia inducible factor-1 alpha, and vascular endothelial growth factor in the growth of clear-cell renal cell carcinoma (RCC) has identified a pathway for novel targeted therapy. This study evaluated the impact of these agents on metastatic RCC (mRCC), and highlights recent phase II and III trials. A systematic review examined the clinical data for novel targeted agents in mRCC, with a focus on randomized phase II and III trials of the novel targeted agents sunitinib, temsirolimus, sorafenib, and bevacizumab. Several agents, including the small-molecule targeted inhibitors sunitinib, temsirolimus, sorafenib, and the monoclonal antibody bevacizumab, have demonstrated antitumor activity in randomized trials. Superior activity was found with sunitinib and temsirolimus versus cytokines in first-line therapy. Improved progression-free survival was reported with sorafenib and bevacizumab given second-line compared with placebo. Targeted therapies show promising activity in this disease, and they have been changing patient management. Sunitinib and sorafenib were recently approved by the US Food and Drug Administration for treatment of mRCC, These drugs are currently included in clinical practice.

The impact of increasing karyotypic complexity and evolution on survival in CLL patients treated with ibrutinib.

Blood ◽  
2021 ◽  
Author(s):  
Adam S Kittai ◽  
Cecelia R Miller ◽  
Daniel Goldstein ◽  
Ying Huang ◽  
Lynne V. Abruzzo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clonal Evolution ◽  
Single Agent ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Continuous Variable ◽  
Lymphocytic Leukemia ◽  
Karyotypic Analysis ◽  
Cytogenetic Abnormalities ◽  
The Impact

Complex karyotype defined as ≥3 cytogenetic abnormalities is prognostic of survival in patients treated with ibrutinib or venetoclax in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL). Recent studies re-evaluating this dichotomous variable have shown that higher numbers of cytogenetic abnormalities (i.e. ≥5) have a worse overall survival in patients treated with chemoimmunotherapy. We sought to determine if increasing karyotypic complexity, treated as a continuous variable, was prognostic of survival for patients treated with ibrutinib for CLL. We conducted a retrospective analysis of all patients with CLL treated with single-agent ibrutinib or in combination with an anti-CD20 antibody at our institution. We included 456 patients with both treatment-naïve (TN) and RR disease. Median number of prior therapies was 2 (range 0-13), 30% of patients had del(17p), and 75% were IGHV unmutated. 50% had ≥3 cytogenetic abnormalities including 30% with ≥5. In a multivariable analysis, increasing karyotypic complexity was an independent predictor of shorter progression-free survival (HR 1.07 (95% CI 1.04-1.10), p&lt;0.0001) and overall survival (HR 1.09 (95% CI 1.05-1.12), p&lt;0.0001). Furthermore, we found that presence of clonal evolution determined by cytogenetic analysis at progression was prognostic of subsequent survival (p=0.02). This solidifies karyotypic complexity as an important prognostic factor for CLL patients treated with ibrutinib. Further research should consider sequential karyotypic analysis as a determination of risk of progression and death in patients with CLL.

scholarly journals Cabozantinib As Salvage Therapy for Patients With Tyrosine Kinase Inhibitor–Refractory Differentiated Thyroid Cancer: Results of a Multicenter Phase II International Thyroid Oncology Group Trial

2017 ◽  
Vol 35 (29) ◽  
pp. 3315-3321 ◽  
Author(s):  
Maria E. Cabanillas ◽  
Jonas A. de Souza ◽  
Susan Geyer ◽  
Lori J. Wirth ◽  
Michael E. Menefee ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapy ◽  
Phase Ii ◽  
Differentiated Thyroid Cancer ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Multikinase Inhibitor

Purpose Sorafenib and lenvatinib are oral multikinase inhibitors targeting vascular endothelial growth factor receptor (VEGFR) and approved for radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). However, there are no approved second- or third-line therapies. MET is implicated in resistance to VEGFR inhibitors. Cabozantinib is an oral multikinase inhibitor targeting MET in addition to VEGFR and is approved for medullary thyroid cancer. In a phase I study of cabozantinib, five of eight patients with DTC previously treated with a VEGFR-targeted therapy had an objective response to cabozantinib. Patients and Methods Patients with RAI-refractory disease with Response Evaluation Criteria in Solid Tumor (RECIST) measurable disease and evidence of progression on prior VEGFR-targeted therapy were enrolled in this single-arm phase II study. The cabozantinib starting dose was 60 mg/day orally but could be escalated to 80 mg if the patient did not experience a response. Patients underwent tumor assessment according to RECIST v1.1 every 8 weeks. In this study, if at least five of 25 response-evaluable patients had an objective response, cabozantinib would be considered a promising agent in this patient population. Results Twenty-five patients were enrolled. The median age was 64 years, and 64% of patients were men. Twenty-one patients had received only one prior VEGFR-targeted therapy (sorafenib, pazopanib, or cediranib), and four patients had received two such therapies. The most common treatment-related adverse events were fatigue, weight loss, diarrhea, palmar-plantar erythrodysesthesia, and hypertension. One drug-related death was noted. Of the 25 patients, 10 (40%) had a partial response, 13 (52%) had stable disease, and two (8%) had nonevaluable disease. The median progression-free survival and overall survival were 12.7 months and 34.7 months, respectively. Conclusion Cabozantinib demonstrated clinically significant, durable objective response activity in patients with RAI-refractory DTC who experienced disease progression while taking prior VEGFR-targeted therapy.

scholarly journals Treatment with Antiangiogenic Drugs in Multiple Lines in Patients with Metastatic Colorectal Cancer: Meta-Analysis of Randomized Trials

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
R.-D. Hofheinz ◽  
U. Ronellenfitsch ◽  
S. Kubicka ◽  
A. Falcone ◽  
I. Burkholder ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Optimal Sequence ◽  
Primary Endpoints ◽  
Disease Stabilization ◽  
Antiangiogenic Drugs ◽  
The Impact

Background. In metastatic colorectal cancer (mCRC), continuing antiangiogenic drugs beyond progression might provide clinical benefit. We synthesized the available evidence in a meta-analysis.Patients and Methods. We conducted a meta-analysis of studies investigating the use of antiangiogenic drugs beyond progression. Eligible studies were randomized phase II/III trials. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints were the impact of continuing antiangiogenic drugs (i) in subgroups, (ii) in different types of compounds targeting the VEGF-axis (monoclonal antibodies versus tyrosine kinase inhibitors), and (iii) on remission rates and prevention of progression.Results. Eight studies (3,668 patients) were included. Continuing antiangiogenic treatment beyond progression significantly improved PFS (HR 0.64; 95%-CI, 0.55–0.75) and OS (HR 0.83; 95%-CI, 0.76–0.89). PFS was significantly improved in all subgroups with comparable HR. OS was improved in all subgroups stratified by age, gender, and ECOG status. The rate of patients achieving at least stable disease was improved with an OR of 2.25 (95%-CI, 1.41–3.58).Conclusions. This analysis shows a significant PFS and OS benefit as well as a benefit regarding disease stabilization when using antiangiogenic drugs beyond progression in mCRC. Future studies should focus on the optimal sequence of administering antiangiogenic drugs.

scholarly journals CTIM-15. PRELIMINARY RESULTS OF A PHASE II STUDY OF NIVOLUMAB WITH HYPOFRACTIONATED RE-RADIATION AND BEVACIZUMAB FOR RECURRENT MGMT METHYLATED GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii36-ii36
Author(s):  
Christian Grommes ◽  
Minesh Mehta ◽  
Alexandra Miller ◽  
Mariza Daras ◽  
Anna Piotrowski ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Disease Recurrence ◽  
Primary Objective ◽  
Significant Finding ◽  
Trial Treatment

Abstract Standard of standard of care for glioblastoma (GBM) remains unsatisfactory with universal disease recurrence and a median survival of &lt; 2 years. Immune checkpoint inhibitors (ICI) have shown limited single-agent activity in GBM thus far. GBMs with methylated MGMT promoter and no baseline corticosteroid dependence may be most likely to derive benefit from ICI. The combination of ICIs with radiation has shown promising activity in other human cancers. Combining nivolumab and re-RT/bevacizumab in GBM may augment ICI activity through immunogenic effects of radiation, may reduce the risk of radiation necrosis by addition of bevacizumab at the time of radiation, and may reduce the need for corticosteroids. In this multicenter phase II study, nivolumab is combined with re-irradiation and optional concurrent bevacizumab followed by nivolumab in patients with first recurrence of IDH-wildtype and MGMT methylated glioblastoma. Primary objective is to improve 1-year overall survival (OS) from 33 (based on EORTC 26101) to 50%. Nine-three patients are required to show a significant finding with an α of 0.05 and 81% power. Thirteen of 93 patient (14%) have been enrolled with a median age of 59 (range 42–71) with a median KPS of 90 (range 70–90). Treatment has been tolerated well without any grade ≥ 4 toxicities and only one grade 3 (amylase elevation). The most common adverse events were pruritus and hypothyroidism in 3/13 (23%). The median progression-free survival (PFS) is 7 months with a 6months PFS of 55.6%. The 12months OS is 66.7%. Patients with recurrent MGMT methylated, IDH-wildtype glioblastoma tolerate trial treatment with acceptable toxicities. Clinical efficacy in the first patients enrolled shows a promising effect. Enrollment is ongoing.

scholarly journals Phase II Trial of Cetuximab With or Without Paclitaxel in Patients With Advanced Urothelial Tract Carcinoma

2012 ◽  
Vol 30 (28) ◽  
pp. 3545-3551 ◽  
Author(s):  
Yu-Ning Wong ◽  
Samuel Litwin ◽  
David Vaughn ◽  
Seth Cohen ◽  
Elizabeth R. Plimack ◽  
...  
Keyword(s):  
Phase Ii ◽  
Urothelial Cancer ◽  
Single Agent ◽  
Progression Free Survival ◽  
Salvage Chemotherapy ◽  
Free Survival ◽  
Metastatic Urothelial Cancer ◽  
Metastatic Setting ◽  
Previously Treated ◽  
Grade 3

Purpose The benefit of salvage chemotherapy is modest in metastatic urothelial cancer. We conducted a randomized, noncomparative phase II study to measure the efficacy of cetuximab with or without paclitaxel in patients with previously treated urothelial cancer. Patients and Methods Patients with metastatic urothelial cancer who received one line of chemotherapy in the perioperative or metastatic setting were randomly assigned to 4-week cycles of cetuximab 250 mg/m2 with or without paclitaxel 80 mg/m2 per week. We used early progression as an indicator of futility. Either arm would close if seven of the initial 15 patients in that arm progressed at the first disease evaluation at 8 weeks. Results We enrolled 39 evaluable patients. The single-agent cetuximab arm closed after nine of the first 11 patients progressed by 8 weeks. The combination arm completed the full accrual of 28 patients, of whom 22 patients (78.5%) had visceral disease. Twelve of 28 patients had progression-free survival greater than 16 weeks. The overall response rate was 25% (95% CI, 11% to 45%; three complete responses and four partial responses). The median progression-free survival was 16.4 weeks (95% CI, 12 to 25.1 weeks), and the median overall survival was 42 weeks (95% CI, 30.4 to 78 weeks). Treatment-related grade 3 and 4 adverse events that occurred in at least two patients were rash (six cases), fatigue (five cases), and low magnesium (three cases). Conclusion Although it had limited activity as a single agent, cetuximab appears to augment the antitumor activity of paclitaxel in previously treated urothelial cancers. The cetuximab and paclitaxel combination merits additional study to establish its role in the treatment of urothelial cancers.

scholarly journals Phase II trial of the IDO pathway inhibitor indoximod plus pembrolizumab for the treatment of patients with advanced melanoma

2021 ◽  
Vol 9 (6) ◽  
pp. e002057
Author(s):  
Yousef Zakharia ◽  
Robert R McWilliams ◽  
Olivier Rixe ◽  
Joseph Drabick ◽  
Montaser F Shaheen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Complete Response ◽  
Advanced Melanoma ◽  
Free Survival ◽  
Programmed Death ◽  
Evaluable Population

BackgroundThe indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma.MethodsPatients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label.ResultsBetween July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator’s choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P).The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P).ConclusionIn this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.

Validation of the decipher genomic classifier (GC) in SAKK 09/10: A phase III randomized trial of dose-escalated salvage radiotherapy (SRT) after radical prostatectomy (RP).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5010-5010
Author(s):  
Alan Dal Pra ◽  
Pirus Ghadjar ◽  
Stefanie Hayoz ◽  
Daniel Eidelberg Spratt ◽  
Vinnie YT Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Controlled Trial ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Risk Groups ◽  
Phase Iii ◽  
Clinical Progression ◽  
Clinical Value ◽  
Prognostic Utility ◽  
The Impact

5010 Background: GC has been shown to independently prognosticate outcomes in prostate cancer. Herein, we validate the GC in a European randomized phase III trial of dose escalated SRT after RP. Methods: SAKK 09/10 (NCT01272050) randomized 350 patients with biochemical recurrence after RP to 64Gy vs 70Gy. No patients received androgen deprivation therapy (ADT) or pelvic nodal radiotherapy. A pre-specified statistical plan was developed to assess the impact of the GC on clinical outcomes. RP samples were centrally reviewed for the highest-grade tumor and those passing quality control (QC) were run on a clinical-grade whole-transcriptome assay to obtain the GC score (0 to 1; < 0.45, 0.45-0.6, > 0.6 for low-, intermediate-, and high, respectively). The primary aim of this study was to validate the GC for the prediction of freedom from biochemical progression (FFBP) using Cox multivariable analysis (MVA) adjusting for age, T-category, Gleason score, persistent PSA after RP, PSA at randomization, and randomization arm. The secondary aims were to evaluate the association of GC with clinical progression-free survival (CPFS) and use of salvage ADT. Results: Of 233 patients with tissue available, 226 passed QC and were included for analysis. The final GC cohort was a representative sample of the overall cohort, with a median follow-up of 6.3 years (IQR 6.0-7.2). GC score (continuous per 0.1 unit, score 0-1) was independently associated with FFBP (HR 1.14 [95% CI 1.03-1.25], p = 0.009). Higher GC scores were independently associated with CPFS, use of salvage ADT, and rapid biochemical failure ( < 18 months after SRT). High- vs. low/intermediate-GC showed a HR of 2.22 ([95% CI 1.37-3.58], p = 0.001) for FFBP, 2.29 ([95% CI 1.32-3.98], p = 0.003) for CPFS, and 2.99 ([95% CI 1.50-5.95], p = 0.002) for use of salvage ADT. Patients with high-GC had 5-year FFBP of 45% [95% CI 32-59] vs 71% [95% CI 64-78] in low-intermediate GC. Similar estimates for GC risk groups were observed in the 64Gy vs 70Gy in GC high (5-year FFBP of 51% [95% CI 32-70] vs 39% [95% CI 20-59]) and in low-intermediate GC (75% [95% CI 65-84] vs 69% [95% CI 59-78]). Conclusions: This study represents the first contemporary randomized controlled trial in patients with recurrent prostate cancer treated with early SRT without ADT that has validated the prognostic utility of the GC. Independent of standard clinicopathologic variables and radiotherapy dose, patients with a high-GC were more than twice as likely than a lower GC score to experience biochemical and clinical progression and receive salvage ADT. This data confirms the clinical value of Decipher GC for tailoring treatment in the postoperative salvage setting.

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