Mary Beth Todd

Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer

Background Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration‐resistant prostate cancer. We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen‐deprivation therapy in patients with newly diagnosed, metastatic, castration‐sensitive prostate cancer. Methods In this double‐blind, placebo‐controlled, phase 3 trial, we randomly assigned 1199 patients to receive either androgen‐deprivation therapy plus abiraterone acetate (1000 mg daily, given once daily as four 250‐mg tablets) plus prednisone (5 mg daily) (the abiraterone group) or androgen‐deprivation therapy plus dual placebos (the placebo group). The two primary end points were overall survival and radiographic progression‐free survival. Results After a median follow‐up of 30.4 months at a planned interim analysis (after 406 patients had died), the median overall survival was significantly longer in the abiraterone group than in the placebo group (not reached vs. 34.7 months) (hazard ratio for death, 0.62; 95% confidence interval [CI], 0.51 to 0.76; P<0.001). The median length of radiographic progression‐free survival was 33.0 months in the abiraterone group and 14.8 months in the placebo group (hazard ratio for disease progression or death, 0.47; 95% CI, 0.39 to 0.55; P<0.001). Significantly better outcomes in all secondary end points were observed in the abiraterone group, including the time until pain progression, next subsequent therapy for prostate cancer, initiation of chemotherapy, and prostate‐specific antigen progression (P<0.001 for all comparisons), along with next symptomatic skeletal events (P=0.009). These findings led to the unanimous recommendation by the independent data and safety monitoring committee that the trial be unblinded and crossover be allowed for patients in the placebo group to receive abiraterone. Rates of grade 3 hypertension and hypokalemia were higher in the abiraterone group. Conclusions The addition of abiraterone acetate and prednisone to androgen‐deprivation therapy significantly increased overall survival and radiographic progression‐free survival in men with newly diagnosed, metastatic, castration‐sensitive prostate cancer. (Funded by Janssen Research and Development; LATITUDE ClinicalTrials.gov number, NCT01715285.)

Phase II trial of antiepidermal growth factor receptor antibody C225 in patients with advanced renal cell carcinoma.

Fifty-five patients with metastatic renal cell carcinoma (RCC) were treated on a multicenter, single-arm Phase II trial. Patients received single-agent Cetuximab (C225) administered by intravenous infusion at a loading dose of 400 or 500 mg/m2 followed by weekly maintenance doses at 250 mg/m2. None of the patients treated with C225 achieved either a complete or partial response. The median time to progression was 57 days. The most frequently reported grade 3 or 4 toxicity treatment-related adverse events were acne (17%) and rash or dry skin (4%). The lack of clinical response or suggestion of prolonging time to progression compared to historical data with interferon-alfa supports no further study of single-agent C225 in patients with metastatic RCC.

Phase I Trial of Weekly Docetaxel With Concurrent Three-Dimensional Conformal Radiation Therapy in the Treatment of Unfavorable Localized Adenocarcinoma of the Prostate

PURPOSE A phase I trial was conducted to determine the maximally tolerated dose (MTD) of concurrent weekly docetaxel and three-dimensional conformal radiation therapy (3-D CRT) in unfavorable localized adenocarcinoma of the prostate. PATIENTS AND METHODS Patients with unfavorable localized adenocarcinoma of the prostate underwent daily 3-D CRT to a total dose of 70.2 Gy at 1.8 Gy/fraction and concurrent docetaxel given once a week for 8 to 9 weeks. The initial weekly docetaxel dose level was 5 mg/m(2) and the docetaxel doses were escalated as follows: 8, 12, 16, 20, and 25 mg/m(2). RESULTS Between January 2000 and August 2002, 22 men completed the chemoradiation therapy protocol. The dose-limiting toxicity was grade 3 diarrhea, which occurred in the first two patients treated at the 25 mg/m(2) docetaxel dose level. The MTD of weekly docetaxel was determined to be 20 mg/m(2). The overall incidence of grade 2 diarrhea and grade 2 dysuria was 36% and 23%, respectively. Seven (32%) and 15 (68%) patients did not experience any diarrhea or dysuria, respectively. No neutropenia or thrombocytopenia was observed. One patient required intermittent urinary catheterization 10 months postcompletion of therapy, which resolved without any surgical intervention. Seventeen patients remain in prostate-specific antigen remission. At a median follow-up interval of 8 months (range, 2 to 27 months), all patients are alive. CONCLUSION Concurrent weekly docetaxel in conjunction with 3-D CRT is well tolerated with acceptable toxicity. The MTD of weekly docetaxel was determined to be 20 mg/m(2) with concurrent 3-D CRT.

Prevalence of Prostate Cancer Clinical States and Mortality in the United States: Estimates Using a Dynamic Progression Model

Objective To identify patient populations most in need of treatment across the prostate cancer disease continuum, we developed a novel dynamic transition model based on risk of disease progression and mortality. Design and Outcome Measurements We modeled the flow of patient populations through eight prostate cancer clinical states (PCCS) that are characterized by the status of the primary tumor, presence of metastases, prior and current treatment, and testosterone levels. Simulations used published US incidence rates for each year from 1990. Progression and mortality rates were derived from published clinical trials, meta-analyses, and observational studies. Model outputs included the incidence, prevalence, and mortality for each PCCS. The impact of novel treatments was modeled in three distinct scenarios: metastatic castration-resistant prostate cancer (mCRPC), non-metastatic CRPC (nmCRPC), or both. Results and Limitations The model estimated the prevalence of prostate cancer as 2,219,280 in the US in 2009 and 3,072,480 in 2020, and incidence of mCRPC as 36,100 and 42,970, respectively. All-cause mortality in prostate cancer was estimated at 168,290 in 2009 and 219,360 in 2020, with 20.5% and 19.5% of these deaths, respectively, occurring in men with mCRPC. The majority (86%) of incidence flow into mCRPC states was from the nmCRPC clinical state. In the scenario with novel interventions for nmCRPC states, the progression to mCRPC is reduced, thus decreasing mCRPC incidence by 12% in 2020, with a sustained decline in mCRPC mortality. A limitation of the model is that it does not estimate prostate cancer—specific mortality. Conclusion The model informs clinical trial design for prostate cancer by quantifying outcomes in PCCS, and demonstrates the impact of an effective therapy applied in an earlier clinical state of nmCRPC on the incidence of mCRPC morbidity and subsequent mortality.

Effect of Docetaxel in Patients With Hormone-Dependent Prostate-Specific Antigen Progression After Local Therapy for Prostate Cancer

PURPOSE To evaluate docetaxel in the treatment of patients with early-stage prostate cancer with prostate-specific antigen (PSA) progression after local therapy without androgen ablation therapy. PATIENTS AND METHODS Twenty-five patients with adenocarcinoma of the prostate with PSA progression despite local therapy were treated with 70 mg/m2 docetaxel every 21 days. Treatment was planned for eight cycles. Patients were followed up for effects on PSA, testosterone, and toxicity. RESULTS Twenty-three of 25 patients completed at least one full cycle of therapy. Ten (43%) of 23 patients demonstrated a decrease in PSA by > or = 50% for at least 4 weeks. The nadir decrease in PSA occurred beyond 150 days of therapy in most patients. Therapy was well tolerated. Grade 4 neutropenia with fever occurred in only six cycles (4.5%). Two patients required 25% dose reductions, both occurring with cycle 6, secondary to increased transaminases in one patient, and grade 3 lacrimation in the other patient. Two patients were removed after the first cycle of therapy due to toxicity (deep venous thrombosis, chest palpitations). Mean testosterone levels were not reduced in 17 patients assessed before and during therapy (P = .12). CONCLUSION This study demonstrated the activity of docetaxel alone, without androgen ablation, in patients with PSA progression after completion of local therapy. Treatment with docetaxel in this population with early disease progression was well tolerated, biochemically active, and was not androgen ablative. Accrual to national phase III studies in early disease is now critical and should be strongly encouraged to determine the ability of early chemotherapy to improve survival.

Antineoplastic Effects of Partially HLA-Matched Irradiated Blood Mononuclear Cells in Patients With Renal Cell Carcinoma

PURPOSE Vaccines, cytokines, and other biologic-based therapies are being developed as antineoplastic agents. Many of these agents are designed to induce an autologous immune response directed against the malignancy. In contrast, hematopoietic stem-cell transplantation is being developed as a form of allogeneic immunotherapy. This study tests the tolerance and antineoplastic activity of sequential infusions of partially HLA-matched allogeneic blood mononuclear cells (obtained from relatives) when administered outside of the context of a hematopoietic stem-cell transplantation. The cells are irradiated to prevent graft-versus-host disease. PATIENTS AND METHODS Fifteen patients with relapsed or refractory malignancies for which no standard therapy was available were enrolled onto a clinical trial designed to assess the tolerability and antineoplastic effects of irradiated partially HLA-matched blood mononuclear cells obtained from relatives. RESULTS There was disease regression in three patients with metastatic renal cell carcinoma during treatment. There was disease progression in six patients with metastatic renal cell carcinoma and two patients with metastatic melanoma during treatment. There was no change in disease state in several other patients. CONCLUSION Irradiated allogeneic blood mononuclear cells administered outside the context of hematopoietic stem-cell transplantation may induce disease responses in patients with relapsed or refractory malignancies. Transfusion of irradiated allogeneic blood mononuclear cells should be developed further as a novel therapeutic antineoplastic approach.

Treatment evolution for metastatic castration‐resistant prostate cancer with recent introduction of novel agents: retrospective analysis of real‐world data

Despite increasing drug treatment options for metastatic castration‐resistant prostate cancer (mCRPC) patients, real‐world treatment data are lacking. We conducted retrospective analyses of commercial claims and electronic medical record (EMR) databases to understand how treatment patterns for mCRPC have changed in a US‐based real‐world population. Truven Health Analytics MarketScan® (2000–2013) and EMR (2004–2013) databases were used to identify patients with an index prostate cancer diagnosis (ICD‐9 codes 185X or 233.4X) and prescription claims for an mCRPC drug (mitoxantrone, estramustine, docetaxel, sipuleucel‐T, cabazitaxel, abiraterone acetate, enzalutamide, or radium‐223). Regimen analyses for first line of therapy (LOT1), second line of therapy, and beyond were performed among cohorts based on year of first mCRPC drug usage. mCRPC drug usage and treatment duration were compared across cohorts and age groups within each cohort. The commercial claims cohort yielded 3437 evaluable patients. Most men (91%) commencing mCRPC treatment had docetaxel as LOT1 in 2010; this number had declined to 15% in 2013. In 2013, 67% and 9% of patients used abiraterone acetate and enzalutamide, respectively, as LOT1. Among both commercial claims and EMR cohorts, treatment pattern changes were most pronounced in men aged >80 years, and median treatment duration for some mCRPC drugs was shorter than expected based on available clinical trial information. These results demonstrate a shift in mCRPC treatments during the past 5 years, with greater use of newer noncytotoxic treatments than docetaxel. These real‐world data aid in understanding the changing role of chemotherapy in the management of mCRPC.

Subsequent Chemotherapy and Treatment Patterns After Abiraterone Acetate in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302

Background Treatment patterns for metastatic castration-resistant prostate cancer (mCRPC) have changed substantially in the last few years. In trial COU-AA-302 (chemotherapy-naïve men with mCRPC), abiraterone acetate plus prednisone (AA) significantly improved radiographic progression-free survival and overall survival (OS) when compared to placebo plus prednisone (P). Objective This post hoc analysis investigated clinical responses to docetaxel as first subsequent therapy (FST) among patients who progressed following protocol-specified treatment with AA, and characterized subsequent treatment patterns among older (≥75 yr) and younger (<75 yr) patient subgroups. Design, setting, and participants Data were collected at the final OS analysis (96% of expected death events). Subsequent therapy data were prospectively collected, while response and discontinuation data were collected retrospectively following discontinuation of the study drug. Intervention At the discretion of the investigator, 67% (365/546) of patients from the AA arm received subsequent treatment with one or more agents approved for mCRPC. Outcome measurements and statistical analysis Efficacy analysis was performed for patients for whom baseline and at least one post-baseline prostate-specific antigen (PSA) values were available. Results and limitations Baseline and at least one post-baseline PSA values were available for 100 AA patients who received docetaxel as FST. While acknowledging the limitations of post hoc analyses, 40% (40/100) of these patients had an unconfirmed ≥50% PSA decline with first subsequent docetaxel therapy, and 27% (27/100) had a confirmed ≥50% PSA decline. The median docetaxel treatment duration among these 100 patients was 4.2 mo. Docetaxel was the most common FST among older and younger patients from each treatment arm. However, 43% (79/185) of older patients who progressed on AA received no subsequent therapy for mCRPC, compared with 17% (60/361) of younger patients. Conclusions Patients with mCRPC who progress with AA treatment may still derive benefit from subsequent docetaxel therapy. These data support further assessment of treatment patterns following AA treatment for mCRPC, particularly among older patients. Trial registration ClinicalTrials.gov NCT00887198. Patient summary Treatment patterns for advanced prostate cancer have changed substantially in the last few years. This additional analysis provides evidence of clinical benefit for subsequent chemotherapy in men with advanced prostate cancer whose disease progressed after treatment with abiraterone acetate. Older patients were less likely to be treated with subsequent therapy.

Does Gleason score at initial diagnosis predict efficacy of abiraterone acetate therapy in patients with metastatic castration-resistant prostate cancer? An analysis of abiraterone acetate phase III trials

BACKGROUND The usefulness of Gleason score (<8 or ≥8) at initial diagnosis as a predictive marker of response to abiraterone acetate (AA) plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) was explored retrospectively. PATIENTS AND METHODS Initial diagnosis Gleason score was obtained in 1048 of 1195 (COU-AA-301, post-docetaxel) and 996 of 1088 (COU-AA-302, chemotherapy-naïve) patients treated with AA 1 g plus prednisone 5 mg twice daily by mouth or placebo plus prednisone. Efficacy end points included radiographic progression-free survival (rPFS) and overall survival (OS). Distributions and medians were estimated by Kaplan-Meier method and hazard ratio (HR) and 95% confidence interval (CI) by Cox model. RESULTS Baseline characteristics were similar across studies and treatment groups. Regardless of Gleason score, AA treatment significantly improved rPFS in post-docetaxel [Gleason score <8: median, 6.4 versus 5.5 months (HR = 0.70; 95% CI 0.56-0.86), P = 0.0009 and Gleason score ≥8: median, 5.6 versus 2.9 months (HR = 0.58; 95% CI 0.48-0.72), P < 0.0001] and chemotherapy-naïve patients [Gleason score <8: median, 16.5 versus 8.2 months (HR = 0.50; 95% CI 0.40-0.62), P < 0.0001 and Gleason score ≥8: median, 13.8 versus 8.2 months (HR = 0.61; 95% CI 0.49-0.76), P < 0.0001]. Clinical benefit of AA treatment was also observed for OS, prostate-specific antigen (PSA) response, objective response and time to PSA progression across studies and Gleason score subgroups. CONCLUSION OS and rPFS trends demonstrate AA treatment benefit in patients with pre- or post-chemotherapy mCRPC regardless of Gleason score at initial diagnosis. The initial diagnostic Gleason score in patients with mCRPC should not be considered in the decision to treat with AA, as tumour metastases may no longer reflect the histology at the time of diagnosis. CLINICAL TRIALS NUMBER COU-AA-301 (NCT00638690); COU-AA-302 (NCT00887198).

Synthesis of tissue factor messenger RNA and procoagulant activity in breast cancer cells in response to serum stimulation.

The procoagulant activity observed in many types of tissue and cultured cells is due to tissue factor, a 30 kd transmembrane protein. The mRNA for tissue factor is a 2.2-kb species, which in some non-cancer cells can be up-regulated or induced by cytokines or by serum stimulation. In this study, induction of procoagulant activity in cancer cells was evaluated using the breast cancer cell line, MCF-7, and an adriamycin resistant subline, AdrRMCF-7, which has increased tumorigenicity in nude mice compared to the parental cell line. Procoagulant activity was factor VIIa dependent and was inhibited by an anti-tissue factor antibody. MCF-7 cells had minimal tissue factor activity, while AdrRMCF-7 cells had an 10-fold increase compared to the parental line. This increase was not observed in MCF-7 cells transfected with the multi-drug resistant gene, which is associated with adriamycin resistance. Serum stimulation of quiescent MCF-7 cells increased tissue factor activity 5-fold over baseline level, but did not increase activity in cells grown in serum-replete medium. Tissue factor activity of AdrRMCF-7 quiescent cells and AdrMCF-7 cells grown in serum-replete medium was enhanced 2-fold by serum stimulation. The predominant tissue factor mRNA species in MCF-7 cells was a 3.2 to 3.4-kb band, which increased in response to serum stimulation of cells grown in serum-replete medium. The mature 2.2-kb tissue factor mRNA band was detected in quiescent MCF-7 cells within six hours of serum stimulation and remained present 24 hours after stimulation. Synthesis of the 2.2-kb tissue factor mRNA species in MCF-7 and AdrRMCF-7 cells correlated with appearance of procoagulant activity. Thus, while procoagulant activity correlates with the level of the 2.2-kb tissue factor mRNA species in these cancer cells, there are inherent differences in tissue factor activity, antigen, and mRNA levels, as well as in regulation of its synthesis between these cells.