Chemotherapy for the initial treatment of metastatic prostate adenocarcinoma and neuroendocrine carcinoma at diagnosis: real world application and impact in the SEER database (2004 -2018).

Background: Randomized controlled phase III trials have reported significant improvements in disease response and survival with the addition of chemotherapy to androgen deprivation therapy for men presenting with metastatic prostate cancer. We examined the implementation of such knowledge and its impact within the Surveillance, Epidemiology, and End Results (SEER) database. Method: The administration of chemotherapy for men with an initial presentation of metastatic prostate cancer from 2004 to 2018 in the SEER database and its association with survival outcomes was examined. Kaplan-Meier estimates were applied to compare survival curves. Cox proportion hazard survival models were used to analyze the association of chemotherapy and other variables with both cancer- specific and overall survival. Result: A total of 727,804 patients were identified with 99.9% presenting with adenocarcinoma and 0.1% with neuroendocrine histopathology. Chemotherapy as initial treatment for men with de novo distant metastatic adenocarcinoma increased from 5.8% during 2004-2013 to 21.4% during 2014-2018. Chemotherapy was associated with a poorer prognosis during 2004-2013 but was associated with improved cancer-specific (hazard ratio (HR) = 0.85, 95% confidence interval (CI): 0.78-0.93, p=0.0004) and overall survival (HR= 0.78, 95% CI: 0.71-0.85, p < 0.0001) during 2014-2018. The improved prognosis during 2014-2018 was observed in patients with visceral or bone metastasis and most impactful for patients aged 71-80 years. These findings were confirmed by subsequent propensity score matching analyses. Furthermore, chemotherapy was consistently provided to 54% of patients with neuroendocrine carcinoma at diagnosis from 2004 to 2018. Treatment was associated with improved cancer-specific survival (HR= 0.62, 95% CI: 0.45-0.87, p=0.0055) and overall survival (HR= 0.69, 95% CI: 0.51-0. 94, p=0.0176) during 2014-2018 but not significant in earlier years. Conclusion: Chemotherapy at initial diagnosis was increasingly employed in men with metastatic adenocarcinoma after 2014 and consistent with the evolution of National Comprehensive Cancer Network (NCCN) guidelines. Benefits for chemotherapy are suggested after 2014 in the treatment of men with metastatic adenocarcinoma. The use of chemotherapy for neuroendocrine carcinoma at diagnosis has remained stable, and outcomes have improved in more recent years. Further development and optimization of chemotherapy continues to evolve for men with de novo diagnosis of metastatic prostate cancer.

Cancer and Leukemia Group B 90203 (Alliance): Radical Prostatectomy With or Without Neoadjuvant Chemohormonal Therapy in Localized, High-Risk Prostate Cancer.

PURPOSE: Radical prostatectomy (RP) alone is often inadequate in curing men with clinically localized, high-risk prostate cancer (PC). We hypothesized that chemohormonal therapy (CHT) with androgen-deprivation therapy plus docetaxel before RP would improve biochemical progression-free survival (BPFS) over RP alone. PATIENTS AND METHODS: Men with clinically localized, high-risk PC were assigned to RP alone or neoadjuvant CHT with androgen deprivation plus docetaxel (75 mg/m2 body surface area every 3 weeks for 6 cycles) and RP. The primary end point was 3-year BPFS. Biochemical failure was defined as a serum prostate-specific antigen level > 0.2 ng/mL that increased on 2 consecutive occasions that were at least 3 months apart. Secondary end points included 5-year BPFS, overall BPFS, local recurrence, metastasis-free survival (MFS), PC-specific mortality, and overall survival (OS). RESULTS: In total, 788 men were randomly assigned. Median follow-up time was 6.1 years. The overall rates of grade 3 and 4 adverse events during chemotherapy were 26% and 19%, respectively. No difference was seen in 3-year BPFS between neoadjuvant CHT plus RP and RP alone (0.89 v 0.84, respectively; 95% CI for the difference, -0.01 to 0.11; P = .11). Neoadjuvant CHT was associated with improved overall BPFS (hazard ratio [HR], 0.69; 95% CI, 0.48 to 0.99), improved MFS (HR, 0.70; 95% CI, 0.51 to 0.95), and improved OS (HR, 0.61; 95% CI, 0.40 to 0.94) compared with RP alone. CONCLUSION: The primary study end point, 3-year BPFS, was not met. Although some improvement was seen in secondary end points, any potential benefit must be weighed against toxicity. Our data do not support the routine use of neoadjuvant CHT and RP in patients with clinically localized, high-risk PC at this time.

Effects of a lifestyle intervention on body composition in prostate cancer patients on androgen deprivation therapy.

Background: Exercise and dietary (EX+D) interventions could represent an optimal treatment for attenuating or reversing adverse effects of androgen deprivation therapy (ADT) in prostate cancer (PCa) patients. The Individualized Diet and Exercise Adherence-Pilot (IDEA-P) trial compared the effects of an EX+D intervention relative to standard-of-care (SC) treatment among PCa patients undergoing ADT. The present study evaluated the effects of the EX+D intervention on body composition (BC) obtained via dual-energy X-ray absorptiometry (DXA) in a subsample of IDEA-P patients. A secondary objective was to explore the association of adiposity and lean mass with mobility performance and strength. Methods: Complete DXA data were acquired from a subsample of 22 PCa patients (EX+D: n = 13; SC: n = 9) at baseline and 3 month follow-up. Intention-to-treat analysis included data from 30 participants (M age = 66.28; SD = 7.79) with baseline DXA assessments. Results: Intention-to-treat analysis revealed EX+D resulted in significant improvements in fat mass (P = 0.022), per cent fat mass (P = 0.028), trunk fat mass (P = 0.017), fat mass/lean mass (P = 0.040), and per cent lean mass (P = 0.026) vs. SC. EX+D also resulted in more favourable changes in appendicular lean mass/body mass (d = 0.59). Select BC outcomes were also significantly correlated with mobility performance and strength (P < 0.05) at 3 month follow-up. Conclusions: Findings suggest the EX+D intervention resulted in superior preservation of lean tissue and improvement in adiposity relative to SC treatment. Results underscore the utility of implementing EX+D interventions for preserving muscle mass and reducing adiposity in PCa patients undergoing ADT.

Phase II, Multicenter, Randomized Trial of Docetaxel plus Prednisone with or Without Cediranib in Men with Chemotherapy-Naive Metastatic Castrate-Resistant Prostate Cancer.

LESSONS LEARNED: The negative results are consistent with the negative results of large phase III trials in which docetaxel plus antiangiogenic agents were used in patients with metastatic castrate-resistant prostate cancer (mCRPC).The negative data underscore that, despite a sound biological rationale and supportive early-phase clinical results, adding antiangiogenic agents to docetaxel for mCRPC is a great challenge. BACKGROUND: Inhibition of vascular endothelial growth factor (VEGF) signaling abrogates tumor-induced angiogenesis to constrain tumor growth, and can be exploited therapeutically by using cediranib, an oral tyrosine kinase inhibitor of VEGF receptor signaling. Our preliminary phase I trial data showed that adding cediranib to docetaxel plus prednisone (DP) was safe and feasible, with early evidence for efficacy in patients with metastatic castrate-resistant prostate cancer (mCRPC). METHODS: This multicenter phase II trial assessed whether adding cediranib to DP improves efficacy of DP in patients with mCRPC. Chemotherapy-naive patients with mCRPC were randomly assigned to receive either docetaxel (75 mg/m2 intravenously every 3 weeks) with prednisone (5 mg twice daily) plus cediranib (30 mg once daily; the DP+C arm) or DP only (the DP arm). The primary endpoint was to compare 6-month progression-free survival (PFS) rate between the two arms. Secondary endpoints included 6-month overall survival (OS), objective tumor and prostate-specific antigen (PSA) response rates, biomarkers, and adverse events. RESULTS: The 6-month PFS rate in a total of 58 patients was only numerically higher in the DP+C arm (61%) compared with the DP arm (57%). Similarly, the 6-month OS rate, objective tumor and PSA response rates, and biomarkers were not significantly different between the two arms. Increased baseline levels of interleukin 6 (IL-6), however, were significantly associated with increased risk of progression. Neutropenia was the only grade 4 toxicity (38% in the DP+C arm vs. 18% in the DP arm). CONCLUSION: Combining cediranib with docetaxel + prednisone failed to demonstrate superior efficacy, compared with docetaxel + prednisone, and added toxicity. Our data do not support pursuing the combination further in patients with mCRPC.

Characterization of a KLK2-FGFR2 fusion gene in two cases of metastatic prostate cancer.

BACKGROUND: The fibroblast growth factor receptor (FGFR) signaling pathway is activated in multiple tumor types through gene amplifications, single base substitutions, or gene fusions. Multiple small molecule kinase inhibitors targeting FGFR are currently being evaluated in clinical trials for patients with FGFR chromosomal translocations. Patients with novel gene fusions involving FGFR may represent candidates for kinase inhibitors. METHODS: A targeted RNA-sequencing assay identified a KLK2-FGFR2 fusion gene in two patients with metastatic prostate cancer. NIH3T3 cells were transduced to express the KLK2-FGFR2 fusion. Migration assays, Western blots, and drug sensitivity assays were performed to functionally characterize the fusion. RESULTS: Expression of the KLK2-FGFR2 fusion protein in NIH3T3 cells induced a profound morphological change promoting enhanced migration and activation of downstream proteins in FGFR signaling pathways. The KLK2-FGFR2 fusion protein was determined to be highly sensitive to the selective FGFR inhibitors AZD-4547, BGJ398, JNJ-42756943, the irreversible inhibitor TAS-120, and the non-selective inhibitor Ponatinib. The KLK2-FGFR2 fusion did not exhibit sensitivity to the non-selective inhibitor Dovitinib. CONCLUSIONS: Importantly, the KLK2-FGFR2 fusion represents a novel target for precision therapies and should be screened for in men with prostate cancer.

Effects of a Group-Mediated Exercise and Dietary Intervention in the Treatment of Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: Results From the IDEA-P Trial.

Background: Although androgen-deprivation therapy (ADT) is the foundation of treatment for prostate cancer, the physiological impacts of ADT result in functional decline and enhanced risk of chronic disease and metabolic syndrome. Purpose: The Individualized Diet and Exercise Adherence Pilot Trial (IDEA-P) is a single-blind, randomized, pilot trial comparing the effects of a group-mediated, cognitive-behavioral (GMCB) exercise and dietary intervention (EX+D) with those of a standard-of-care (SC) control during the treatment of prostate cancer patients undergoing ADT. Methods: A total of 32 prostate cancer patients (M age = 66.28, SD = 7.79) undergoing ADT were randomly assigned to the 12-week EX+D intervention (n = 16) or control (n = 16). The primary outcome in IDEA-P was change in mobility performance with secondary outcomes including body composition and muscular strength. Blinded assessment of outcomes were obtained at baseline and at 2- and 3-month follow-ups. Results: Favorable adherence and retention rates were observed, and no serious intervention-related adverse events were documented. Intent-to-treat ANCOVA controlling for baseline value and ADT duration demonstrated that EX+D resulted in significantly greater improvements in mobility performance (p < .02), muscular strength (p < .01), body fat percentage (p < .05), and fat mass (p < .03) at 3-month follow-up, relative to control. Conclusion: Findings from the IDEA-P trial suggest that a GMCB-based EX+D intervention resulted in significant, clinically meaningful improvements in mobility performance, muscular strength, and body composition, relative to controls. Collectively, these results suggest that the EX+D was a safe and well-tolerated intervention for prostate cancer patients on ADT. The utility of implementing this approach in the treatment of prostate cancer patients on ADT should be evaluated in future large-scale efficacy trials. Clinical Trial information: NCT02050906.

Analytic validation and real-time clinical application of an amplicon-based targeted gene panel for advanced cancer.

Multiplex somatic testing has emerged as a strategy to test patients with advanced cancer. We demonstrate our analytic validation approach for a gene hotspot panel and real-time prospective clinical application for any cancer type. The TruSight Tumor 26 assay amplifies 85 somatic hotspot regions across 26 genes. Using cell line and tumor mixes, we observed that 100% of the 14,715 targeted bases had at least 1000x raw coverage. We determined the sensitivity (100%, 95% CI: 96-100%), positive predictive value (100%, 95% CI: 96-100%), reproducibility (100% concordance), and limit of detection (3% variant allele frequency at 1000x read depth) of this assay to detect single nucleotide variants and small insertions and deletions. Next, we applied the assay prospectively in a clinical tumor sequencing study to evaluate 174 patients with metastatic or advanced cancer, including frozen tumors, formalin-fixed tumors, and enriched peripheral blood mononuclear cells in hematologic cancers. We reported one or more somatic mutations in 89 (53%) of the sequenced tumors (167 passing quality filters). Forty-three of these patients (26%) had mutations that would enable eligibility for targeted therapies. This study demonstrates the validity and feasibility of applying TruSight Tumor 26 for pan-cancer testing using multiple specimen types.

Validation of the Association of RECIST Changes With Survival in Men With Metastatic Castration-Resistant Prostate Cancer Treated on SWOG Study S0421.

BACKGROUND: Phase 2 trials evaluating new agents for metastatic castration-resistant prostate cancer (mCRPC) have relied on bone scan and prostate-specific antigen changes to assess activity. Given the increasing detection of measurable disease, Response Evaluation Criteria in Solid Tumors (RECIST) changes warrant consideration to evaluate activity. We validated the association of RECIST 1.0 changes with survival in men with mCRPC receiving docetaxel. PATIENTS AND METHODS: Data for men with measurable disease from the Southwest Oncology Group (SWOG) S0421, a phase 3 trial in men with mCRPC receiving docetaxel and prednisone plus placebo or atrasentan, were used. Cox proportional hazards regression was used to evaluate the association of RECIST 1.0 outcomes within 120 days, ie, unconfirmed partial response (uPR), stable disease, and progressive disease (PD), with overall survival (OS) from day 120, adjusted for prognostic factors. RESULTS: Overall, 326 men were evaluable for landmark analysis, of whom 23 had PD, 230 stable disease, and 73 uPR. OS beyond day 120 was significantly different (P = .004) among these subgroups, with median (95% confidence interval) OS of 7.1 (3.5-8.8), 13.4 (11.4-15.6), and 16.3 (10.0-19.6) months for those with PD, stable disease, and uPR, respectively. In a multivariable model, the hazard ratio (95% confidence interval) for patients with PD was 2.47 (1.42-4.29) compared to patients with an uPR (P = .002). CONCLUSION: The association of RECIST 1.0 changes with OS in men with mCRPC receiving docetaxel was validated. Given limitations of bone scan and prostate-specific antigen alterations, improvements in objective RECIST 1.0 changes should be reported in phase 2 trials before launching phase 3 trials.

The Raf Kinase Inhibitor Sorafenib Inhibits JAK-STAT Signal Transduction in Human Immune Cells.

Sorafenib is an oral multikinase inhibitor that was originally developed as a Raf kinase inhibitor. We hypothesized that sorafenib would also have inhibitory effects on cytokine signaling pathways in immune cells. PBMCs from normal donors were treated with varying concentrations of sorafenib and stimulated with IFN-α or IL-2. Phosphorylation of STAT1 and STAT5 was measured by flow cytometry and confirmed by immunoblot analysis. Changes in IFN-α- and IL-2-stimulated gene expression were measured by quantitative PCR, and changes in cytokine production were evaluated by ELISA. Cryopreserved PBMCs were obtained from cancer patients before and after receiving 400 mg sorafenib twice daily. Patient PBMCs were thawed, stimulated with IL-2 or IFN-α, and evaluated for phosphorylation of STAT1 and STAT5. Pretreatment of PBMCs with 10 µM sorafenib decreased STAT1 and STAT5 phosphorylation after treatment with IFN-α or IL-2. This inhibitory effect was observed in PBMCs from healthy donors over a range of concentrations of sorafenib (5-20 µM), IL-2 (2-24 nM), and IFN-α (10(1)-10(6) U/ml). This effect was observed in immune cell subsets, including T cells, B cells, NK cells, regulatory T cells, and myeloid-derived suppressor cells. Pretreatment with sorafenib also inhibited PBMC expression of IFN-α- and IL-2-regulated genes and inhibited NK cell production of IFN-γ, RANTES, MIP1-α, and MIG in response to IFN-α stimulation. PBMCs from patients receiving sorafenib therapy showed decreased responsiveness to IL-2 and IFN-α treatment. Sorafenib is a Raf kinase inhibitor that could have off-target effects on cytokine-induced signal transduction in immune effector cells.

Real-time scintigraphic assessment of intravenous radium-223 administration for quality control.

Radium-223 ((223)Ra) dichloride is an approved intravenous radiotherapy for patients with osseous metastases from castration-resistant prostate cancer (CRPC). In addition to the therapeutic alpha radiation, there is additional (223)Ra radiation generated which produces photons that can be imaged with conventional gamma cameras. No studies have evaluated real-time and quality imaging during intravenous (223)Ra administration to verify systemic circulation and exclude (223)Ra extravasation at the injection site. A retrospective review was performed for fifteen (223)Ra administrations for CRPC patients which were imaged using a large field of view portable gamma camera (LFOVPGC) for the purposes of quality control and patient safety. Dynamic imaging of the chest was performed before, during, and after the (223)Ra administration to verify systemic circulation, per institutional clinical protocol. Before and after (223)Ra administration, a static image was obtained of the intravenous access site. Dynamic imaging of the chest confirmed systemic administration early during the 1-minute injection period for all patients. There were no cases of focal (223)Ra extravasation at the site of intravenous access. These results verify that systemic (223)Ra administrations can be quantified with real-time imaging using an LFOVPGC. This simple approach can confirm and quantify systemic circulation of (223)Ra early during injection and exclude focal extravasation for the purposes of quality control.

Circulating tumor cell telomerase activity as a prognostic marker for overall survival in SWOG 0421: a phase III metastatic castration resistant prostate cancer trial.

Circulating tumor cells (CTC) are promising biomarkers in metastatic castration resistant prostate cancer (mCRPC), and telomerase activity (TA) is a recognized cancer marker. Therefore, we hypothesized that CTC TA may be prognostic of overall survival (OS) in mCRPC. To test this, we used a novel Parylene-C slot microfilter to measure live CTC TA in S0421, a phase III SWOG-led therapeutic trial. Blood samples underwent CTC capture and TA measurement by microfilter, as well as parallel enumeration by CellSearch (Janssen/J&J). Cox regression was used to assess baseline (pre-treatment) TA versus OS, and recursive partitioning was used to explore potential prognostic subgroups and to generate Kaplan-Meier (KM) OS curves. Samples were obtained from 263 patients and generated 215 TA measures. In patients with baseline CTC count ≥5 (47% of patients), higher CTC TA was associated with hazard ratio 1.14 (p = 0.001) for OS after adjusting for other clinical covariates including CTC counts and serum PSA at study entry. Recursive partitioning identified new candidate risk groups with KM OS curve separation based on CTC counts and TA. Notably, in men with an intermediate range baseline CTC count (6-54 CTCs/7.5 ml), low versus high CTC TA was associated with median survival of 19 versus 12 months, respectively (p = 0.009). Baseline telomerase activity from CTCs live-captured on a new slot microfilter is the first CTC-derived candidate biomarker prognostic of OS in a large patient subgroup in a prospective clinical trial. CTC telomerase activity thus merits further study and validation as a step towards molecular CTC-based precision cancer management.

Circulating tumor cell counts are prognostic of overall survival in SWOG S0421: a phase III trial of docetaxel with or without atrasentan for metastatic castration-resistant prostate cancer.

PURPOSE: Circulating tumor cell (CTC) enumeration has not been prospectively validated in standard first-line docetaxel treatment for metastatic castration-resistant prostate cancer. We assessed the prognostic value of CTCs for overall survival (OS) and disease response in S0421, a phase III trial of docetaxel plus prednisone with or without atrasentan. PATIENTS AND METHODS: CTCs were enumerated at baseline (day 0) and before cycle two (day 21) using CellSearch. Baseline counts and changes in counts from day 0 to 21 were evaluated for association with OS, prostate-specific antigen (PSA), and RECIST response using Cox regression as well as receiver operator characteristic (ROC) curves, integrated discrimination improvement (IDI) analysis, and regression trees. RESULTS: Median day-0 CTC count was five cells per 7.5 mL, and CTCs < versus ≥ five per 7.5 mL were significantly associated with baseline PSA, bone pain, liver disease, hemoglobin, alkaline phosphatase, and subsequent PSA and RECIST response. Median OS was 26 months for < five versus 13 months for ≥ five CTCs per 7.5 mL at day 0 (hazard ratio [HR], 2.74 [adjusting for covariates]). ROC curves had higher areas under the curve for day-0 CTCs than for PSA, and IDI analysis showed that adding day-0 CTCs to baseline PSA and other covariates increased predictive accuracy for survival by 8% to 10%. Regression trees yielded new prognostic subgroups, and rising CTC count from day 0 to 21 was associated with shorter OS (HR, 2.55). CONCLUSION: These data validate the prognostic utility of CTC enumeration in a large docetaxel-based prospective cohort. Baseline CTC counts were prognostic, and rising CTCs at 3 weeks heralded significantly worse OS, potentially serving as an early metric to help redirect and optimize therapy in this clinical setting.

Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: results of CALGB 90202 (alliance).

PURPOSE: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: In men with castration-sensitive prostate cancer and bone metastases, early treatment with zoledronic acid was not associated with lower risk for SREs.

The effect of prior androgen synthesis inhibition on outcomes of subsequent therapy with docetaxel in patients with metastatic castrate-resistant prostate cancer: results from a retrospective analysis of a randomized phase 3 clinical trial (CALGB 90401) (Alliance).

BACKGROUND: Preliminary data suggest a potential decreased benefit of docetaxel in patients with metastatic, castration-resistant prostate cancer (mCRPC) who previously received abiraterone acetate, a novel androgen synthesis inhibitor (ASI). Cancer and Leukemia Group B (CALGB) trial 90401 (Alliance), a phase 3 trial in patients with mCRPC who received docetaxel-based chemotherapy, offered the opportunity to evaluate effect of prior ketoconazole, an earlier generation ASI, on clinical outcomes after docetaxel. METHODS: In CALGB trial 90401, 1050 men with chemotherapy-naive mCRPC were randomized to receive treatment with docetaxel and prednisone that included either bevacizumab or placebo. In total, 1005 men (96%) had data available regarding prior ketoconazole therapy. The observed effects of prior ketoconazole on overall survival (OS), progression-free survival (PFS), prostate-specific antigen (PSA) decline, and the objective response rate (ORR) were assessed using proportional hazards and Poisson regression methods adjusted for validated prognostic factors and treatment arm. RESULTS: Baseline characteristics between patients who did (N=277) and did not (N=728) receive prior ketoconazole therapy were similar. There were no statistically significant differences between patients who did and those who did not receive prior ketoconazole therapy with respect to OS (median OS, 21.1 months vs 22.3 months, respectively; stratified log-rank P=.635), PFS (median PFS, 8.1 months vs 8.6 months, respectively; stratified log-rank P=.342), the proportion achieving a decline ≥ 50% in PSA (61% vs 66%, respectively; relative risk, 1.09; adjusted P=.129), or ORR (39% vs 43%, respectively; relative risk, 1.11; adjusted P=.366). CONCLUSIONS: As measured by OS, PFS, PSA, and the ORR, there was no evidence that prior treatment with ketoconazole had an impact on the clinical outcomes of patients with mCRPC who received subsequent docetaxel-based therapy. The current results highlight the need for prospective studies to assess for potential cross-resistance with novel ASIs and to define the optimal sequence of therapy in mCRPC.

Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial.

BACKGROUND: The endothelin pathway has a role in bone metastases, which are characteristic of advanced prostate cancer. Atrasentan, an endothelin receptor antagonist, has shown activity in prostate cancer. We therefore assessed its effect on survival in patients with castration-resistant prostate cancer with bone metastases. METHODS: In a double-blind phase 3 trial, men with metastatic castration-resistant prostate cancer, stratified for progression type (prostate-specific antigen or radiological), baseline pain, extraskeletal metastases, and bisphosphonate use, were randomly assigned in a 1:1 ratio to docetaxel (75 mg/m(2) every 21 days, intravenously) with atrasentan (10 mg/day, orally) or placebo for up to 12 cycles and treated until disease progression or unacceptable toxicity. Patients who did not progress on treatment were permitted to continue atrasentan or placebo for up to 52 weeks. Coprimary endpoints were progression-free survival (PFS) and overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00134056. FINDINGS: 498 patients were randomly assigned to the atrasentan group and 496 to the placebo group. The trial was halted early for futility in April, 2011, after a planned interim analysis. Median PFS was 9·2 months (95% CI 8·5-9·9) in the atrasentan group and 9·1 months (8·4-10·2) in the placebo group (hazard ratio 1·02, 0·89-1·16; p=0·81). Median overall survival was 17·8 months (16·4-19·8) in the atrasentan group versus 17·6 months (16·4-20·1) in the placebo group (1·04, 0·90-1·19; p=0·64). 278 (57%) of 492 patients in the atrasentan group had grade 3 and greater toxicity compared with 294 (60%) of 486 in the placebo group (p=0·22). Three deaths in the atrasentan group and seven in the placebo group were judged to be possibly or probably due to protocol treatment. INTERPRETATION: Atrasentan, when added to docetaxel, does not improve overall survival or PFS in men with castration-resistant prostate cancer and bone metastases; therefore, single-agent docetaxel should remain as one of the standard treatments. FUNDED: National Cancer Institute, Sanofi-Aventis, and Abbott Laboratories.

A phase I study of prolonged infusion of triapine in combination with fixed dose rate gemcitabine in patients with advanced solid tumors.

PURPOSE: Prolonged exposure of cancer cells to triapine, an inhibitor of ribonucleotide reductase, followed by gemcitabine enhances gemcitabine activity in vitro. Fixed-dose-rate gemcitabine (FDR-G) has improved efficacy compared to standard-dose. We conducted a phase I trial to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of prolonged triapine infusion followed by FDR-G. EXPERIMENTAL DESIGN: Triapine was given as a 24-hour infusion, immediately followed by FDR-G (1000 mg/m(2) over 100-minute). Initially, this combination was administered days 1 and 8 of a 21-day cycle (Arm A, triapine starting dose 120 mg); but because of myelosuppression, it was changed to days 1 and 15 of a 28-day cycle (Arm B, starting dose of triapine 75 mg). Triapine steady-state concentrations (Css) and circulating ribonucleotide reductase M2-subunit (RRM2) were measured. RESULTS: Thirty-six patients were enrolled. The MTD was determined to be triapine 90 mg (24-hour infusion) immediately followed by gemcitabine 1000 mg/m(2) (100-minute infusion), every 2 weeks of a 4-week cycle. DLTs included grade 4 thrombocytopenia, leukopenia and neutropenia. The treatment was well tolerated with fatigue, nausea/vomiting, fever, transaminitis, and cytopenias being the most common toxicities. Among 30 evaluable patients, 1 had a partial response and 15 had stable disease. Triapine PK was similar, although more variable, compared to previous studies using doses normalized to body-surface-area. Steady decline in circulating levels of RRM2 may correlate with outcome. CONCLUSIONS: This combination was well tolerated and showed evidence of preliminary activity in this heavily pretreated patient population, including prior gemcitabine failure.

Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401.

PURPOSE: A randomized, placebo-controlled study based on preclinical and clinical data that supports the potential role of vascular endothelial growth factor in prostate cancer was performed to evaluate the addition of bevacizumab to standard docetaxel and prednisone therapy in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Patients with chemotherapy-naive progressive mCRPC with Eastern Cooperative Oncology Group performance status ≤ 2 and adequate bone marrow, hepatic, and renal function were randomly assigned to receive docetaxel 75 mg/m(2) intravenously (IV) over 1 hour for 21 days plus prednisone 5 mg orally twice per day (DP) with either bevacizumab 15 mg/kg IV every 3 weeks (DP + B) or placebo. The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), 50% decline in prostate-specific antigen, objective response (OR), and toxicity. RESULTS: In total, 1,050 patients were randomly assigned. The median OS for patients given DP + B was 22.6 months compared with 21.5 months for patients treated with DP (hazard ratio, 0.91; 95% CI, 0.78 to 1.05; stratified log-rank P = .181). The median PFS time was superior in the DP + B arm (9.9 v 7.5 months, stratified log-rank P < .001) as was the proportion of patients with OR (49.4% v 35.5%; P = .0013). Grade 3 or greater treatment-related toxicity was more common with DP + B (75.4% v 56.2%; P ≤ .001), as was the number of treatment-related deaths (4.0% v 1.2%; P = .005). CONCLUSION: Despite an improvement in PFS and OR, the addition of bevacizumab to docetaxel and prednisone did not improve OS in men with mCRPC and was associated with greater toxicity.

Efficacy of peripheral androgen blockade in prostate cancer patients with biochemical failure after definitive local therapy: results of Cancer and Leukemia Group B (CALGB) 9782.

BACKGROUND: The treatment for prostate cancer patients with biochemical failure after local therapy remains controversial. Peripheral androgen blockade using a combination of a 5-alpha reductase inhibitor and an antiandrogen may allow control of the prostate-specific antigen (PSA). Because testosterone levels are not suppressed, this approach may be associated with less morbidity than conventional gonadal androgen suppression. METHODS: All patients had undergone previous definitive local therapy and had evidence of a rising PSA >1ng/mL, with no evidence of recurrent disease. Patients received both finasteride, 5 mg orally per day, and flutamide, 250 mg orally 3× a day. Patients were followed for a PSA response and quality of life assessment. RESULTS: Ninety-nine of 101 accrued patients were eligible. A ≥80% PSA decline was seen in 96 (96%) patients. The median time to PSA progression was 85 months. With a median follow-up of 10 years, the median survival time had not been reached, and the 5-year overall survival rate was 87%. Toxicity was mild, with 18 patients stopping for toxicity; 15 had diarrhea, 4 had gynecomastia, and 3 had transaminase elevation. Baseline Functional Assessment of Cancer Therapy Prostate Module and Treatment Outcome Index scores decreased by 5 points each at 6 months after enrollment. CONCLUSIONS: The use of the finasteride/flutamide combination is feasible, and results in PSA declines of ≥80% in 96% of patients with serologic progression after definitive local therapy. There were no unexpected toxicities, and the change in quality of life was mild. Further evaluation of this or a similar regimen in a controlled clinical trial is warranted.

A phase 1 study of KOS-862 (Epothilone D) co-administered with carboplatin (Paraplatin®) in patients with advanced solid tumors.

PURPOSE: To determine the maximally tolerated dose (MTD) and pharmacokinetics of carboplatin plus KOS-862 (Epothilone D) a novel cytotoxic macrolide capable of causing mitotic arrest, in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: Patients who have progressed on standard regimens were treated at four different levels of KOS-862(mg/m(2))/Carboplatin(AUC): 50/5,75/5, 75/6 and 100/6 in a "3 + 3" phase I study study design to determine MTD. Patients received KOS-862 on Days 1 and 8, and carboplatin on day 1, of 3-week cycles. Pharmacokinetics of KOS-862 and Carboplatin were studied. RESULTS: Twenty-seven patients enrolled in the study. At the top dose level, 2 out of the 9 patients experienced Dose Limiting Toxicity. (grade 3 peripheral motor neuropathy in both patients) Twenty-seven patients had sufficient plasma data points for pharmacokinetic analysis Both the parent drug, KOS-862, and the major inactive metabolite Seco-D KOS-862 (KOS-1965) were quantified in plasma. Kinetics of KOS-862 were the same as seen in monotherapy studies using the same route and time of administration. Two patients had tumor response after study treatment. Ten of 20 evaluable patients had stable disease after 2 cycles of study treatment. The MTD in the present study was KOS-862 100 mg/m(2) + carboplatin AUC = 6. CONCLUSIONS: The pharmacokinetics of KOS-862 were similar in this combination study to those seen in previous monotherapy studies using the same route and time of administration. We have described the MTD of this schedule. The neurotoxicity seen with this regimen should be considered prior to its administration in unselected populations.

High-dose-intensity MVAC for Advanced Renal Medullary Carcinoma: Report of Three Cases and Literature Review.

OBJECTIVES: Renal medullary carcinoma is a rare and highly aggressive cancer that is characteristically resistant to most forms of chemotherapy. This pediatric tumor, exclusively affecting individuals who carry at least one sickle hemoglobin allele, carries a uniformly fatal outcome, usually within a matter of weeks, and no effective therapies have been reported. METHODS: We report on the use of a high-dose-intensity regimen of methotrexate, vinblastine, doxorubicin, and cisplatin in 3 patients. RESULTS: All 3 patients were able to tolerate multiple cycles of therapy and achieved at least a partial response and longer survival than predicted from the historical precedent. CONCLUSIONS: Our results have shown that this regimen provides a tolerable therapy with efficacy to promote survival for several months and suggest that highly intensive regimens of chemotherapy might bring additional benefit to the young patients with these rare tumors.