Matthew R Smith

Massachusetts General Hospital, Boston, Massachusetts, United States

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Publications (196)1928.61 Total impact

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    ABSTRACT: Enzalutamide is an androgen receptor inhibitor with a demonstrated overall survival benefit in metastatic castration-resistant prostate cancer. A phase 2 study of enzalutamide monotherapy in patients with hormone-naïve prostate cancer (HNPC) showed a high response rate for the prespecified primary endpoint (ie, prostate-specific antigen [PSA] response at week 25), regardless of metastases at baseline, and favorable tolerability. To determine the long-term efficacy and safety of enzalutamide monotherapy at 1 and 2 yr. Open-label, single-arm study in patients with HNPC and noncastrate testosterone (≥230 ng/dl). Oral enzalutamide 160mg/d until disease progression or unacceptable toxicity. PSA response (≥80% decline from baseline) assessed at 1 yr (49 wk) and 2 yr (97 wk). The median (range) age was 73 (48-86) yr and 26 patients (39%) presented with metastases at study entry. Of 67 patients enrolled, 45 (67%) remained on enzalutamide at week 97. For patients remaining on therapy, the PSA response rate at week 97 was 100% (95% confidence interval 92-100%). Of 26 patients with metastases at baseline, 13 (50%) had a complete and four (15.4%) had a partial response as best overall tumor response up to 97 wk on treatment. There was overall maintenance of total-body bone mineral density (BMD) and moderate changes in lean and fat body mass at 49 and 97 wk. The most common adverse events were gynecomastia, nipple pain, fatigue, and hot flushes. The study limitations include lack of a control group and of endocrine, glycemic, and lipid data at 97 wk. Long-term enzalutamide monotherapy in men with noncastrate HNPC is associated with large sustained reductions in PSA, signals indicating a favorable tumor response, and favorable safety/tolerability profile, with relatively small negative effects on total-body BMD. In this long-term follow-up of the efficacy and safety of enzalutamide monotherapy in patients with hormone-naïve prostate cancer, enzalutamide maintained long-term reductions in prostate-specific antigen, with a minimal impact on total-body bone mineral density. NCT01302041. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
    European Urology 02/2015; 65. DOI:10.1016/j.eururo.2015.01.027 · 12.48 Impact Factor
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    ABSTRACT: Background Abiraterone acetate (an androgen biosynthesis inhibitor) plus prednisone is approved for treating patients with metastatic castration-resistant prostate cancer (mCRPC). Study COU-AA-302 evaluated abiraterone acetate plus prednisone versus prednisone alone in mildly symptomatic or asymptomatic patients with progressive mCRPC without prior chemotherapy. Objective Report the prespecified third interim analysis (IA) of efficacy and safety outcomes in study COU-AA-302. Design, setting, and participants Study COU-AA-302, a double-blind placebo-controlled study, enrolled patients with mCRPC from April 2009 to June 2010. A total of 1088 patients were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1). Intervention Patients were randomised 1:1 to abiraterone 1000 mg plus prednisone 5 mg twice daily by mouth versus prednisone. Outcome measurements and statistical analysis Co–primary end points were radiographic progression-free survival (rPFS) and overall survival (OS). Median times to event outcomes were estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived using the Cox model, and treatment comparison used the log-rank test. The O’Brien-Fleming Lan-DeMets α-spending function was used for OS. Adverse events were summarised descriptively. Results and limitations With a median follow-up duration of 27.1 mo, improvement in rPFS was statistically significant with abiraterone treatment versus prednisone (median: 16.5 vs 8.2 mo; HR: 0.52 [95% CI, 0.45–0.61]; p < 0.0001). Abiraterone improved OS (median: 35.3 vs 30.1 mo; HR: 0.79 [95% CI, 0.66–0.95]; p = 0.0151) but did not reach the prespecified statistical efficacy boundary (α-level: 0.0035). A post hoc multivariate analysis for OS using known prognostic factors supported the primary results (HR: 0.74 [95% CI, 0.61–0.89]; p = 0.0017), and all clinically relevant secondary end points and patient-reported outcomes improved. While the post hoc nature of the long-term safety analysis is a limitation, the safety profile with longer treatment exposure was consistent with prior reports. Conclusions The updated IA of study COU-AA-302 in patients with mCRPC without prior chemotherapy confirms that abiraterone delays disease progression, pain, and functional deterioration and has clinical benefit with a favourable safety profile, including in patients treated for ≥24 mo. Trial registration Study COU-AA-302, ClinicalTrials.gov number, NCT00887198. Patient summary The updated results of this ongoing study showed that disease progression was delayed in patients with advanced prostate cancer who were treated with abiraterone acetate and prednisone, and there was a continued trend in prolongation of life compared with patients treated with prednisone alone. Treatment with abiraterone acetate and prednisone was well tolerated by patients who were treated for >2 yr.
    European Urology 11/2014; 66(5). DOI:10.1016/j.eururo.2014.02.056 · 10.48 Impact Factor
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    ABSTRACT: Background We retrospectively evaluated the prognostic impact of neutrophil-lymphocyte ratio (NLR) as a marker for inflammatory and immune state in men with progressive metastatic castration resistant prostate cancer (mCRPC) following docetaxel. Methods The SUN-1120 phase III trial comparing prednisone combined with sunitinib (n=584) or placebo (n=289) for mCRPC following docetaxel-based chemotherapy was evaluated. The arms were combined for analysis, since no difference was observed in the primary endpoint of overall survival (OS). A logarithmic transformation was applied to non-normal factors. The Kaplan-Meier method was used for OS estimation. To identify an optimal prognostic model for survival, we used a Cox proportional hazards regression method with forward stepwise selection, stratifying for ECOG PS, progression type (PSA or radiographic) and treatment group. Patients were categorized into risk groups. Results Complete data was evaluable in 784 men for construction of a prognostic model. The factors used in the model that remained individually significant for OS in multivariable analysis were: log-LDH (HR 2.86 [95% CI=2.29, 3.56], P<0.001), hemoglobin (0.80 [0.74, 0.85], P<0.001), >1 organ involved by metastatic disease (1.49 [1.21, 1.84], P<0.001), log-alkaline phosphatase (1.13 [0.99, 1.28], P=0.074), log-number of prior cycles of docetaxel (0.84 [0.71, 0.98], P=0.031), progression on docetaxel (1.35 [1.00, 1.81], P=0.049), log-PSA (1.06 [1.00, 1.12], P=0.075) and log-NLR (1.55 [1.32, 1.83], P<0.001). NLR increased the c-statistic of the prognostic model from 0.703 to 0.715. Conclusion High NLR may be associated with an independent poor prognostic impact in post-docetaxel patients with mCRPC. These data warrant external validation.
    Clinical Genitourinary Cancer 10/2014; 12(5). DOI:10.1016/j.clgc.2014.03.005 · 1.69 Impact Factor
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    ABSTRACT: Purpose Cabozantinib (XL184), an oral inhibitor of multiple receptor tyrosine kinases such as MET and VEGFR2, was evaluated in a phase II nonrandomized expansion study in castration-resistant prostate cancer (CRPC). Patients and Methods Patients received open-label cabozantinib at daily starting doses of 100 mg or 40 mg until disease progression or unacceptable toxicity. The primary end point was bone scan response, defined as >= 30% reduction in bone scan lesion area. Other efficacy end points included overall survival, pain, analgesic use, and biomarkers. Results One hundred forty-four patients sequentially enrolled in either a 100-mg (n = 93) or 40-mg (n = 51) study cohort. Ninety-one patients (63%) had a bone scan response, often by week 6. Treatment resulted in clinically meaningful pain relief (57% of patients) and reduction or discontinuation of narcotic analgesics (55% of patients), as well as improvements in measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Improvements in each of these outcomes were observed in both cohorts: bone scan response in 73% and 45%, respectively; reductions in measurable soft tissue disease in 80% and 79%, respectively. Median overall survival was 10.8 months for the entire population. Most common grade 3 or 4 adverse events were fatigue (22%) and hypertension (14%). Fewer dose reductions because of toxicity were required in the 40-mg group. Conclusion The evidence suggests that cabozantinib has clinically meaningful activity in CRPC. Cabozantinib resulted in improvements in bone scans, pain, analgesic use, measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Taken together, these phase II observations warrant further development of cabozantinib in prostate cancer.
    Journal of Clinical Oncology 09/2014; DOI:10.1200/JCO.2013.54.5954 · 17.88 Impact Factor
  • Matthew R Smith, Susan Halabi, Eric J Small
    Journal of Clinical Oncology 09/2014; DOI:10.1200/JCO.2014.57.3808 · 17.88 Impact Factor
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    ABSTRACT: Abiraterone acetate, an androgen biosynthesis inhibitor, prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) in the pre- and post-chemotherapy setting as demonstrated by the pivotal phase III studies COU-AA-301 and COU-AA-302. We performed population pharmacokinetic analyses to estimate pharmacokinetic parameters after oral administration of 1,000 mg/day of abiraterone acetate in patients with mCRPC, with or without prior chemotherapy, and after a single 1,000 mg dose in healthy volunteers. The study objectives were to determine consistency between patient populations and to characterize factors that may influence abiraterone pharmacokinetics.
    Clinical Pharmacokinetics 09/2014; DOI:10.1007/s40262-014-0178-6 · 5.49 Impact Factor
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    ABSTRACT: Androgen deprivation therapy (ADT) may increase diabetes risk. As benefits of primary ADT (PADT) for localized PCa are controversial, and most PCa survivors are of advanced age with comorbidities, it is important to determine if PADT increases diabetes risk and what are the susceptibility factors. We conducted a retrospective cohort study of 12,191 men diagnosed with incident localized PCa during 1995-2008, aged 35-100 years, and without diabetes or receipt of prostatectomy or radiation one year after diagnosis. Patients were enrolled in one of three managed health plans and followed through 2010. PADT was defined as ADT within 1 year after diagnosis. Incident diabetes was ascertained using inpatient and outpatient diagnosis codes, diabetes medications, and hemoglobin A1c values. We estimated PADT-associated diabetes risk using Cox-proportional hazards models in both conventional and propensity score analyses. 1,203 (9.9%) patients developed diabetes during follow-up (median 4.8 years) with incidence rates of 2.5 and 1.6 events per 100 person-years in the PADT and non-PADT group, respectively. PADT was associated with a 1.61-fold increased diabetes risk (95% C.I. =1.38-1.88). Number-needed-to-harm was 29. The association was stronger in men ≤70 years than in older men (HR=2.25 versus 1.40, p-value for interaction=0.008). PADT may increase diabetes risk by 60% and should be used with caution when managing localized PCa. Because of the consistent association between ADT and greater diabetes risk across disease states, we recommend routine screening and lifestyle interventions to reduce diabetes risk in men receiving ADT. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
    Annals of Epidemiology 09/2014; 24(9):682. DOI:10.1016/j.annepidem.2014.06.009 · 2.15 Impact Factor
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    ABSTRACT: Context Androgen-deprivation therapy (ADT) is a key component of treatment for aggressive and advanced prostate cancer, but it has also been associated with adverse effects on bone, metabolic, cardiovascular, sexual, and cognitive health as well as body composition. Objective To review the current literature on the adverse effects of ADT and strategies for ameliorating harm from ADT. Evidence acquisition The Medline database (through PubMed) was searched from inception to August 1, 2013, for studies documenting the side effects of ADT and for randomized and prospective trials of interventions to mitigate those side effects. Evidence synthesis Adverse effects of ADT include decreases in bone mineral density; metabolic changes such as weight gain, decreased muscle mass, and increased insulin resistance; decreased libido and sexual dysfunction; hot flashes; gynecomastia; reduced testicle size; anemia; and fatigue. Several observational studies suggest an increased risk of diabetes and cardiovascular events, although most published studies report that ADT is not linked to greater cardiovascular mortality. Randomized trials have found value in treatments for some adverse effects including bone loss (bisphosphonates, denosumab, selective estrogen receptor modulators), markers of metabolic syndrome (exercise, diet, metformin), gynecomastia (tamoxifen, prophylactic radiation), muscle loss (resistance and aerobic exercise), and hot flashes (venlafaxine, medroxyprogesterone, cyproterone acetate, gabapentin). Conclusions ADT is often a necessary component of the treatment of aggressive prostate cancer, yet it has known harms that can impair health and quality of life. Clinicians should be aware of interventions that can help mitigate these adverse effects. Patient summary Androgen deprivation therapy is a critical component of the management of aggressive and advanced prostate cancer, but it causes adverse effects including bone loss, metabolic changes, gynecomastia, muscle loss, hot flashes, and possibly increased cardiovascular events. Clinicians should be aware of interventions that can help mitigate these adverse effects.
    European Urology 08/2014; DOI:10.1016/j.eururo.2014.07.010 · 12.48 Impact Factor
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    ABSTRACT: Context: Myostatin is a negative regulator of muscle growth. Androgen deprivation (ADT) is associated with muscle loss and increased body fat and currently available therapies have limited efficacy to treat this complication. The anti-myostatin peptibody (AMG 745/Mu-S) markedly attenuated muscle loss and decreased fat accumulation in orchiectomized mice. Objective: The objective was to evaluate safety, pharmacokinetics (PK) and muscle efficacy of AMG 745 in men undergoing ADT for non-metastatic prostate cancer. Methods: This was a randomized, blinded, placebo-controlled multiple dose phase 1 study of AMG 745 given for 28 days. The endpoint of percent change from baseline in lean body mass (LBM) as assessed by dual x-ray absorptiometry (DXA) was pre-specified. Results: Rates of adverse events (AMG 745 versus placebo) were: diarrhea (13% versus 9%), fatigue (13% versus 4%), contusion (10% versus 0%), and injection site bruising (6% versus 4%). Exposure increased linearly from 0.3 mg/kg to 3 mg/kg. AMG 745 significantly increased LBM in the 3 mg/kg versus placebo groups on Day 29 by 2.2% (± 0.8% standard error [SE]), p = 0.008; in exploratory fat mass analysis, a decrease - 2.5% (± 1.0% SE), p = 0.021 was observed. Pharmacodynamic changes in muscle and fat were maintained at follow-up, 1 month after Day 29. Conclusion: Four weekly SC doses of AMG 745 were well tolerated and were associated with increased LBM and decreased fat in the men receiving ADT for non-metastatic prostate cancer. Results support further investigation of AMG 745 in clinical settings with muscle loss and atrophy.
    Journal of Clinical Endocrinology &amp Metabolism 06/2014; 99(10):jc20141271. DOI:10.1210/jc.2014-1271 · 6.31 Impact Factor
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    ABSTRACT: The androgen receptor inhibitor enzalutamide is approved for the treatment of metastatic castration-resistant prostate cancer that has progressed on docetaxel. Our aim was to assess the activity and safety of enzalutamide monotherapy in men with hormone-naive prostate cancer. This trial is an ongoing open-label, single-arm, phase 2 study, done across 12 European sites. Men aged over 18 years, with hormone-naive prostate cancer for whom hormone therapy was indicated, and who had non-castration levels of testosterone and prostate-specific antigen (PSA) of 2 ng/mL or greater at screening, and an Eastern Cooperative Oncology Group score of 0, received oral enzalutamide 160 mg/day. The primary outcome was the proportion of patients with an 80% or greater decline in PSA at week 25. All analyses included all patients who had received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT01302041. 67 men were enrolled into the study. 62 patients (92·5%, 95% CI 86·2-98·8) had a decline in PSA of 80% or greater at week 25. The most commonly reported treatment-emergent adverse events up to week 25 were gynaecomastia (n=24), fatigue (n=23), nipple pain (n=13), and hot flush (n=12), all of which were of mild to moderate severity. Nine patients had a treatment-emergent adverse event of grade 3 or higher, most of which were reported in one patient each, except for pneumonia (grade 3, two patients) and hypertension (grade 3, four patients). Five patients reported serious adverse events, none of which were deemed to be treatment related. Our findings suggest that enzalutamide monotherapy in men with hormone-naive prostate cancer of varying severity provides a level of disease suppression, and was generally well tolerated. These findings provide a rationale for further investigation of clinical response and outcomes with enzalutamide in non-castrate men with prostate cancer. Astellas Pharma Inc, Medivation Inc.
    The Lancet Oncology 04/2014; DOI:10.1016/S1470-2045(14)70129-9 · 25.12 Impact Factor
  • The Journal of Urology 04/2014; 191(4):e810. DOI:10.1016/j.juro.2014.02.2210 · 3.75 Impact Factor
  • The Journal of Urology 04/2014; 191(4):e764. DOI:10.1016/j.juro.2014.02.2100 · 3.75 Impact Factor
  • The Journal of Urology 04/2014; 191(4):e920. DOI:10.1016/j.juro.2014.02.2484 · 3.75 Impact Factor
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    ABSTRACT: Primary androgen-deprivation therapy (PADT) is often used to treat clinically localized prostate cancer, but its effects on cause-specific and overall mortality have not been established. Given the widespread use of PADT and the potential risks of serious adverse effects, accurate mortality data are needed to inform treatment decisions. We conducted a retrospective cohort study using comprehensive utilization and cancer registry data from three integrated health plans. All men were newly diagnosed with clinically localized prostate cancer. Men who were diagnosed between 1995 and 2008, were not treated with curative intent therapy, and received follow-up through December 2010 were included in the study (n = 15,170). We examined all-cause and prostate cancer-specific mortality as our main outcomes. We used Cox proportional hazards models with and without propensity score analysis. Overall, PADT was associated with neither a risk of all-cause mortality (hazard ratio [HR], 1.04; 95% CI, 0.97 to 1.11) nor prostate-cancer-specific mortality (HR, 1.03; 95% CI, 0.89 to 1.19) after adjusting for all sociodemographic and clinical characteristics. PADT was associated with decreased risk of all-cause mortality but not prostate-cancer-specific mortality. PADT was associated with decreased risk of all-cause mortality only among the subgroup of men with a high risk of cancer progression (HR, 0.88; 95% CI, 0.78 to 0.97). We found no mortality benefit from PADT compared with no PADT for most men with clinically localized prostate cancer who did not receive curative intent therapy. Men with higher-risk disease may derive a small clinical benefit from PADT. Our study provides the best available contemporary evidence on the lack of survival benefit from PADT for most men with clinically localized prostate cancer.
    Journal of Clinical Oncology 03/2014; 32(13). DOI:10.1200/JCO.2013.52.5782 · 17.88 Impact Factor
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    ABSTRACT: Zoledronic acid decreases the risk for skeletal-related events (SREs) in men with castration-resistant prostate cancer and bone metastases but its role earlier in the natural history of the disease is unknown. This phase III study evaluated the efficacy and safety of earlier treatment with zoledronic acid in men with castration-sensitive metastatic prostate cancer. Men with castration-sensitive prostate cancer and bone metastases whose androgen-deprivation therapy was initiated within 6 months of study entry were randomly assigned in a blinded 1:1 ratio to receive zoledronic acid (4 mg intravenously every 4 weeks) or a placebo. After their disease progressed to castration-resistant status, all patients received open-label treatment with zoledronic acid. The primary end point was time to first SRE, defined as radiation to bone, clinical fracture, spinal cord compression, surgery to bone, or death as a result of prostate cancer. Target accrual was 680 patients. Primary analysis was planned after 470 SREs. The study was discontinued prematurely (645 patients; 299 SREs) after the corporate supporter withdrew study drug supply. Early zoledronic acid was not associated with increased time to first SRE. The median time to first SRE was 31.9 months in the zoledronic acid group (95% CI, 24.2 to 40.3) and 29.8 months in the placebo group (95% CI, 25.3 to 37.2; hazard ratio, 0.97; 95% CI, 0 to 1.17; one-sided stratified log-rank P = .39). Overall survival was similar between the groups (hazard ratio, 0.88; 95% CI, 0.70 to 1.12; P = .29). Rates of adverse events were similar between the groups. In men with castration-sensitive prostate cancer and bone metastases, early treatment with zoledronic acid was not associated with lower risk for SREs.
    Journal of Clinical Oncology 03/2014; 32(11). DOI:10.1200/JCO.2013.51.6500 · 17.88 Impact Factor
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    ABSTRACT: Pain negatively affects quality of life for cancer patients. Preliminary data in metastatic castration-resistant prostate cancer (mCRPC) suggested a benefit of the oral tyrosine kinase inhibitor cabozantinib to pain palliation. Prospective evaluation of cabozantinib's benefits on pain and narcotic use in mCRPC. This was a nonrandomized expansion (NRE) cohort (n=144) of a phase 2 randomized discontinuation trial in docetaxel-refractory mCRPC patients. Pain and interference of symptoms with sleep and general activity were electronically self-reported daily for 7-d intervals at baseline and regularly scheduled throughout the study. Mean per-patient scores were calculated for each interval. Narcotic use was recorded daily during the same intervals. Open-label cabozantinib (100mg or 40mg). The following stringent response definition was used: clinically meaningful pain reduction (≥30% improvement in mean scores from baseline) confirmed at a later interval without concomitant increases in narcotics. Only patients with moderate or severe baseline pain were analyzed. Sixty-five patients with moderate or severe baseline pain were evaluable. Of these, 27 (42%) experienced pain palliation according to the stringent response definition. Thirty-seven patients (57%) had clinically meaningful pain relief at two consecutive intervals, reported ≥6 wk apart in the majority. Forty-four patients (68%) had palliation at one or more intervals; 36 (55%) decreased narcotics use during one or more intervals. Clinically meaningful pain reduction was associated with significant (p ≤ 0.001) improvements in sleep quality and general activity. A limitation of this study was its open-label design. Cabozantinib demonstrated clinically meaningful pain palliation, reduced or eliminated patients' narcotic use, and improved patient functioning, thus meriting prospective validation in phase 3 studies. We evaluated the potential of cabozantinib to improve symptoms in patients with metastatic prostate cancer that no longer responds to standard therapies. We saw a promising reduction in pain and reduced need for narcotic painkillers. Larger, well-controlled trials are necessary to confirm these findings.
    European Urology 02/2014; DOI:10.1016/j.eururo.2014.02.013 · 10.48 Impact Factor
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    ABSTRACT: Background: In a randomized controlled trial of men with castration-resistant prostate cancer (CRPC) and bone metastases, denosumab was superior to zoledronic acid (ZA) for reducing skeletal-related events (SRE, defined as pathological fracture, surgery or radiation to bone [including the use of radioisotopes], or spinal cord compression) (Fizazi, et al. Lancet 2011;377:813-822.). Recently, the composite endpoint of symptomatic skeletal event (SSE, defined as symptomatic fracture, surgery or radiation to bone, or spinal cord compression) was introduced as an alternative term/clinical trial endpoint to describe skeletal morbidity. Methods: Men with CRPC, ≥ 1 bone metastasis, and no prior IV bisphosphonate use received either SC denosumab 120 mg or IV ZA 4 mg (adjusted for creatinine clearance) in a blinded fashion every 4 weeks. Oral calcium and vitamin D supplements were recommended. SSEs included pathologic fractures considered symptomatic by the investigator, spinal cord compression and surgery and radiation to bone. Results: As previously reported, fewer men who received denosumab than ZA had confirmed first SREs, and experienced multiple SREs (Table). Similarly, fewer patients in the denosumab group than the ZA group had confirmed first SSE and multiple SSEs. The median (95% CI) estimate of time to first SSE (superiority analysis) for denosumab was not reached (28.8 mo, not estimable), and for ZA it was 24.2 (20.7, 30.2) mo (HR = 0.78 (0.66, 0.93) P = 0.01). Conclusions: Denosumab reduced the risk of skeletal events in men with CRPC regardless of endpoint definition as SRE or SSE. The risk of developing SSEs was reduced by up to 22% when comparing denosumab with ZA.
    2014 Genitourinary Cancers Symposium, J Clin Oncol 32, 2014 (suppl 4; abstr 35); 02/2014
  • Matthew R Smith
    JAMA The Journal of the American Medical Association 12/2013; 310(21):2313. DOI:10.1001/jama.2013.281599 · 29.98 Impact Factor
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    ABSTRACT: To investigate the association of radiographic progression defined by Prostate Cancer Working Group (PCWG)-2 guidelines and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC) PATIENTS AND METHODS: Two trials that employed PCWG-2 guidelines to define progression were analyzed: a randomized phase II trial (n=221) comparing first-line docetaxel-prednisone (DP) plus AT-101 or placebo, and a phase III trial (n=873) comparing prednisone plus sunitinib (SP) or placebo (PP) following docetaxel-based chemotherapy. Cox proportional hazards regression models were used to estimate the association of radiographic progression with OS. Landmark analyses compared progressing patients with those who had not progressed. Sub-analyses compared patients removed from trial for progression vs. other reasons. An increased risk of death was seen for radiographic progression at landmark times from 6 to 12 months with docetaxel-based therapy (HR>1.7 at all time points). An increased risk of death was also seen with post-docetaxel prednisone alone or with sunitinib for progression at landmark times from 2 to 8 months (HR >2.7 at all time points). Kendall's τ was 0.50 (p<0.001) in the setting of docetaxel-based therapy and 0.34 (p<0.001) in the post-docetaxel setting for association between radiographic progression and death amongst patients with both events. Removal from study due to radiographic progression was associated with a significantly lower OS compared to removal for other reasons in both trials. Limitations of a retrospective analysis apply and there was no central radiology review. Radiographic progression by PCWG-2 criteria was significantly associated with OS in mCRPC patients receiving first-line docetaxel-based chemotherapy or post-docetaxel therapy. With external validation as a surrogate endpoint in trials showing survival benefits, the use of rPFS may expedite drug development in mCRPC, which has been hampered by the lack of intermediate endpoints.
    BJU International 12/2013; 114(6B). DOI:10.1111/bju.12589 · 3.13 Impact Factor
  • Richard J Lee, Matthew R Smith
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    ABSTRACT: Treatment with cabozantinib, an inhibitor of MET and VEGFR2 signaling, has demonstrated clinical benefit in early trials in men with metastatic prostate cancer. Preclinical evidence suggests that cabozantinib can kill cancer cell seeds while disrupting angiogenesis and stromal cells in the metastatic soil.
    Clinical Cancer Research 11/2013; 20(3). DOI:10.1158/1078-0432.CCR-13-2636 · 8.19 Impact Factor

Publication Stats

10k Citations
1,928.61 Total Impact Points

Institutions

  • 1999–2015
    • Massachusetts General Hospital
      • • Department of Radiation Oncology
      • • Department of Psychiatry
      Boston, Massachusetts, United States
  • 2006–2014
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2001–2013
    • Harvard Medical School
      • • Department of Medicine
      • • Department of Health Care Policy
      Boston, Massachusetts, United States
  • 2004–2010
    • University of California, San Francisco
      • Department of Urology
      San Francisco, California, United States
    • Cornell University
      • Department of Medicine
      Итак, New York, United States
  • 2007–2009
    • Pennsylvania State University
      • Department of Medicine
      University Park, Maryland, United States
  • 2005
    • University of Waterloo
      Ватерлоо, Ontario, Canada
  • 2004–2005
    • Dana-Farber Cancer Institute
      • • Department of Medical Oncology
      • • Lank Center for Genitourinary Oncology
      Dana, NC, United States