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      Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer

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          Abstract

          Background

          In the SPARTAN study, compared with placebo, apalutamide added to ongoing androgen deprivation therapy significantly prolonged metastasis-free survival (MFS) and time to symptomatic progression in patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC). Overall survival (OS) results at the first interim analysis (IA1) were immature, with 104 of 427 (24%) events required for planned final OS analysis. Here, we report the results of a second pre-specified interim analysis (IA2).

          Methods

          One thousand two hundred and seven patients with nmCRPC were randomized 2 : 1 to apalutamide (240 mg daily) or placebo. The primary end point of the study was MFS. Subsequent therapy for metastatic CRPC was permitted. When the primary end point was met, the study was unblinded. Patients receiving placebo who had not yet developed metastases were offered open-label apalutamide. At IA2, pre-specified analysis of OS was undertaken, using a group-sequential testing procedure with O’Brien–Fleming-type alpha spending function. Safety and second progression-free survival (PFS2) were assessed.

          Results

          Median follow-up was 41 months. With 285 (67% of required) OS events, apalutamide was associated with an improved OS compared with placebo (HR 0.75; 95% CI 0.59–0.96; P = 0.0197), although the P-value did not cross the pre-specified O’Brien–Fleming boundary of 0.0121. Apalutamide improved PFS2 (HR 0.55; 95% CI 0.45–0.68). At IA2, 69% of placebo-treated and 40% of apalutamide-treated patients had received subsequent life-prolonging therapy for metastatic CRPC. No new safety signals were observed.

          Conclusion

          In patients with nmCRPC, apalutamide was associated with a 25% reduction in risk of death compared with placebo. This OS benefit was observed despite crossover of placebo-treated patients and higher rates of subsequent life-prolonging therapy for the placebo group.

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          Most cited references6

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          Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer.

          To describe the natural history of nonmetastatic prostate cancer and rising prostate-specific antigen (PSA) despite androgen deprivation therapy. The 201 patients in this report were the placebo control group from an aborted randomized controlled trial to evaluate the effects of zoledronic acid on time to first bone metastasis in men with prostate cancer, no bone metastases, and rising PSA despite androgen deprivation therapy. Relationships between baseline covariates and clinical outcomes were assessed by Cox proportional hazard analyses. Covariates in the model were baseline PSA, Gleason sum, history of bilateral orchiectomies, regional lymph node metastases at diagnosis, prior prostatectomy, time from androgen deprivation therapy to random assignment, time from diagnosis to random assignment, and PSA velocity. At 2 years, 33% of patients had developed bone metastases. Median bone metastasis-free survival was 30 months. Median time to first bone metastases and overall survival were not reached. Baseline PSA level greater than 10 ng/mL (relative risk, 3.18; 95% CI, 1.74 to 5.80; P < .001) and PSA velocity (4.34 for each 0.01 increase in PSA velocity; 95% CI, 2.30 to 8.21; P < .001) independently predicted shorter time to first bone metastasis. Baseline PSA and PSA velocity also independently predicted overall survival and metastasis-free survival. Other covariates did not consistently predict clinical outcomes. Men with nonmetastatic prostate cancer and rising PSA despite androgen deprivation therapy have a relatively indolent natural history. Baseline PSA and PSA velocity independently predict time to first bone metastasis and survival.
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            Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time.

            Denosumab, an anti-RANK ligand monoclonal antibody, significantly increases bone metastasis-free survival (BMFS; hazard ratio [HR], 0.85; P = .028) and delays time to first bone metastasis in men with nonmetastatic castration-resistant prostate cancer (CRPC) and baseline prostate-specific antigen (PSA) ≥ 8.0 ng/mL and/or PSA doubling time (PSADT) ≤ 10.0 months. To identify men at greatest risk for bone metastasis or death, we evaluated relationships between PSA and PSADT with BMFS in the placebo group and the efficacy and safety of denosumab in men with PSADT ≤ 10, ≤ 6, and ≤ 4 months. A total of 1,432 men with nonmetastatic CRPC were randomly assigned 1:1 to monthly subcutaneous denosumab 120 mg or placebo. Enrollment began February 2006; primary analysis cutoff was July 2010, when approximately 660 men were anticipated to have developed bone metastases or died. In the placebo group, shorter BMFS was observed as PSADT decreased below 8 months. In analyses by shorter baseline PSADT, denosumab consistently increased BMFS by a median of 6.0, 7.2, and 7.5 months among men with PSADT ≤ 10 (HR, 0.84; P = .042), ≤ 6 (HR, 0.77; P = .006), and ≤ 4 months (HR, 0.71; P = .004), respectively. Denosumab also consistently increased time to bone metastasis by PSADT subset. No difference in survival was observed between treatment groups for the overall study population or PSADT subsets. Patients with shorter PSADT are at greater risk for bone metastasis or death. Denosumab consistently improves BMFS in men with shorter PSADT and seems to have the greatest treatment effects in men at high risk for progression.
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              Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant nonmetastatic prostate cancer.

              The natural history of castration-resistant nonmetastatic prostate cancer is poorly defined. The authors used data from 331 subjects in the placebo group of a randomized controlled trial to evaluate the relations of disease and host characteristics with time to first bone metastases in men with prostate cancer, rising prostate-specific antigen (PSA) despite androgen deprivation therapy, and no radiographic evidence of metastases. Relations between baseline covariates and clinical outcomes were assessed by Cox proportional hazard analyses. Covariates in the model were age, body mass index, prior prostatectomy, prior orchiectomy, Gleason score, performance status, PSA, urinary N-telopeptide, bone alkaline phosphatase, albumin, lactate dehydrogenase, and hemoglobin. At 2 years, 46% of subjects had developed bone metastases, and 20% had died. Median bone metastasis-free survival was 25 months. In multivariate analyses, baseline PSA ≥ 13.1 ng/mL was associated with shorter overall survival (relative risk [RR], 2.34; 95% confidence interval [CI], 1.71-3.21; P < .0001), time to first bone metastasis (RR, 1.98; 95% CI, 1.43-2.74; P < .0001), and bone metastasis-free survival (RR, 1.98; 95% CI, 1.45-2.70; P < .0001). PSA velocity was significantly associated with overall and bone metastasis-free survival. Other covariates were not consistently associated with clinical outcomes. In men with progressive castration-resistant prostate cancer and no detectable metastases, baseline PSA was significantly associated with time to first bone metastasis, bone metastasis-free survival, and overall survival. Other disease and host characteristics, including body mass index and bone turnover markers, were not consistently associated with clinical outcomes. 2010 American Cancer Society.
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                Author and article information

                Journal
                Ann Oncol
                Ann. Oncol
                annonc
                Annals of Oncology
                Oxford University Press
                0923-7534
                1569-8041
                November 2019
                27 September 2019
                27 September 2019
                : 30
                : 11 , Therapy in breast cancer patients treated in the aTTom trial
                : 1813-1820
                Affiliations
                [1 ] Helen Diller Family Comprehensive Cancer Center, University of California San Francisco , San Francisco, CA, USA
                [2 ] Centre Hospitalier de l'Université de Montréal, Université de Montréal, Montréal , QC, Canada
                [3 ] Guy’s, King’s and St. Thomas’ Hospitals , London
                [4 ] Sarah Cannon Research Institute , London, UK
                [5 ] Georges Pompidou Hospital, University René Descartes , Paris, France
                [6 ] University of Duisburg-Essen , Essen
                [7 ] Ruprecht-Karls University Heidelberg , Heidelberg, Germany
                [8 ] VA Portland Health Care System , Portland
                [9 ] Knight Cancer Institute, Oregon Health & Science University , Portland, OR, USA
                [10 ] Spanish National Cancer Research Centre (CNIO) , Madrid
                [11 ] Hospitales Universitarios Virgen de la Victoria y Regional, Institute of Biomedical Research in Málaga (IBIMA) , Málaga, Spain
                [12 ] Centre for Personalized Nanomedicine, University of Queensland , Brisbane, Australia
                [13 ] St. Mary’s Hospital of Catholic University , Seoul, South Korea
                [14 ] Yokohama City University Medical Center , Yokohama, Japan
                [15 ] Janssen Research & Development , Beerse, Belgium
                [16 ] Janssen Research & Development , Spring House, PA
                [17 ] Janssen Research & Development , San Diego, CA
                [18 ] Janssen Research & Development , Los Angeles, CA
                [19 ] Massachusetts General Hospital Cancer Center , Boston, MA
                [20 ] Harvard Medical School , Boston, MA, USA
                Author notes
                Correspondence to: Dr Eric J. Small, Department of Medicine/Division of Hematology/Oncology, UCSF Helen Diller Family Comprehensive Cancer Center, 1450 3rd Street, San Francisco, CA 94158, USA. Tel: +1-415-353-7095; E-mail: Eric.Small@ 123456ucsf.edu
                Article
                mdz397
                10.1093/annonc/mdz397
                6927320
                31560066
                39116e10-2a7d-456b-b633-2b89a497e9c4
                © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                Page count
                Pages: 1820
                Funding
                Funded by: Janssen Research & Development 10.13039/100005205
                Funded by: Janssen Global Services
                Funded by: LLC
                Categories
                Original Articles
                Urogenital Tumors

                Oncology & Radiotherapy
                apalutamide,non-metastatic castration-resistant prostate cancer,overall survival,subsequent therapy

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