Treatment sequencing in metastatic castrate-resistant prostate cancer

Six different treatments have demonstrated improved survival in phase III trials targeted to patients with metastatic castration-resistant prostate cancer （mCRPC）. Front-line therapeutic options for mCRPC include docetaxel, sipuleuceI-T, abiraterone and radium-223. Post-docetaxel options include cabazitaxel, abiraterone, enzalutamide and radium-223. Despite much progress in recent years, much is yet unknown and debates occur over optimal treatment choices and sequences. None of the new agents have been compared to one another, thus physicians in practice today must make choices based on non-randomized comparisons, toxicity considerations and various assumptions. Abiraterone is now moving into the front line mCRPC space given recent regulatory approvals and enzalutamide will follow soon. Both of the hormonal agents have less toxicity when compared to chemotherapeutic options and both of these hormonal agents are expected to be used in a considerable number of mCRPC patients in the years ahead. Little data are available for the post-abiraterone or post-enzalutamide setting. In this review the currently available sequencing data are summarized and interpreted. It is now clear that cross resistance is a potential issue between various treatments, especially those agents that target the androgen axis. This review highlights the need for additional studies to optimize the current treatments for these patients.     

Evolving landscape and novel treatments in metastatic castrate-resistant prostate cancer

Treatment options for castrate-resistant prostate cancer (CRPC) have advanced in recent years and significantly improved the outlook for patients with this aggressive and lethal disease. Further understanding of the biology of CRPC has led to several new targeted therapies and continues to emphasize the importance of androgen receptor (AR) directed therapy. The treatment landscape is rapidly changing and further biologically rationale, biomarker-based ongoing clinical trials are needed. We review the recent results of major clinical trials in CRPC. New and investigational agents now in clinical evaluation are reviewed including inhibitors of angiogenesis, microtubules, chaperones, AR and intracellular kinases, as well as immunotherapy, radiopharmaceuticals and bone-targeted agents. The recent improvement in prognosis for CRPC brings continued optimism for further improvements. Thoughtful planning of clinical trials and further understanding of the mechanisms of resistance to therapies will allow for continued progress in patient care.     

Phase II trial of vinorelbine and estramustine in the treatment of metastatic hormone-resistant prostate cancer

The purpose of this study was to investigate the efficacy and safety of combination chemotherapy using estramustine and vinorelbine in chemotherapy-na?ve patients with hormone-resistant prostate cancer (HRPC). The patients (n = 54) received oral estramustine 840 mg/day on Days 1 to 14 and IV vinorelbine 25 mg/m(2) on Days 1 and 8 of every 3 wk cycle. The median number of cycles per patient was 9 (range, 1 to 27). Fifty-three patients were evaluable for toxicity and survival and 52 for prostate specific antigen (PSA) response. Median age was 68 (range, 46-80). PSA sustained decrease >50% was seen in 52% of patients (95% CI: 38-66%). A complete response was seen in 3 and a partial response in 12 of 25 patients with measurable disease, for an overall objective response of 60% (95% CI: 41-79%). Improvement in performance status was observed in 30 out of 43 evaluable for clinical benefit response. The median duration of response was 7 mo and median time to progression was 6 mo. The median survival time was 15 mo. The most common adverse event was mild gastrointestinal toxicity. In general, toxicity G3-4 was low: granulocytopenia Grade 3-4 (8%), thrombocytopenia Grade 3 (6%), and anemia Grade 3 (13%). Other Grade 3 toxicities included deep vein thrombosis (4%), hepatic (2%), cardiac ischemia (2%), fatigue (6%), and sensory neuropathy (2%). There were 2 treatment-related deaths (4%). We conclude that vinorelbine and estramustine as used in this trial is an efficacious and well-tolerated therapeutic regimen in the management of HRPC.     

Phase II trial of GM-CSF + thalidomide in patients with androgen-independent metastatic prostate cancer

BACKGROUND: Androgen-independent metastatic prostate cancer is a major therapeutic dilemma. Granulocyte-macrophage colony stimulating factor (GM-CSF) and thalidomide have some biologic activity as single agents in this disease subset. We performed a Phase II trial of this combination to assess its toxicity and potential utility as an immunomodulatory approach to management of advanced prostate cancer. METHODS: Twenty-two patients were treated with GM-CSF 250 microg administered SC on Monday, Wednesday and Friday of each week. Thalidomide was escalated to reach the study dose of 200 mg/day. Patients were assessed every 4 weeks with therapy continuing to a maximum of 6 months. RESULTS: All 22 patients had a decrement in PSA at 2 weeks postinitiation of therapy. Five patients had a > or =50% decline (56, 64,66,66, and 94%, respectively) from baseline verified at 4 weeks post best response. This corresponds to an observed response rate of 23% (95% confidence interval 8-45%). Therapy was well tolerated with the majority of patients experiencing only one event. CONCLUSIONS: The combination of GM-CSF + thalidomide is relatively well tolerated and has the potential to produce antitumor activity in a population of patients with metastatic, androgen independent prostate cancer. This nonchemotherapy combination should be explored in a subset of patients with less advanced disease.     

Twists and turns on the way to progress in metastatic castrate-resistant prostate cancer

Harnessing the body＇s immune system for the treatment of metastatic cancer has been a dream since the late 19th century [1]. Since that time progress has been intermittent and mostly disappointing. Interferon and Interleukin-2 represented steps forward but in retrospect the steps were not large and rarely are these agents used in the clinic today except as the control arm of randomized studies designed to demonstrate that a new drug is better.     

Phase II trial of paclitaxel and uracil--tegafur in metastatic breast cancer. TEGATAX trial

This Phase II trial investigated the combination paclitaxel (P) and uracil-tegafur (UFT) in patients with metastatic breast cancer (MBC).

Methods

Main eligibility criteria included HER-2 negative MBC, ECOG performance status of 0-2, exposure to 1-2 prior chemotherapy regimen in the metastatic setting, previous exposure to an anthracycline containing regimen either at metastatic or adjuvant setting. Each 35-day cycle consisted of P at 80 mg/m² by intravenous infusion on days 1, 8, 15, 22 and 29 and oral UFT at 300 mg/m² TID (three time a day) from days 1-28 and oral folinic acid at 90 mg QD (one a day).

Results

Between March 2003 and December 2007, 31 patients were enrolled. Median age was 66 years (range 44-78). All tumours were HER-2 negative and 7% were triple negative (ER, PgR, HER-2). The majority of patients had visceral disease (81%). All patients had received an anthracycline containing regimen and 74% had a previous docetaxel containing treatment. Median of 4 and 3 cycles of P and UFT were administered with a relative dose intensity of 85.3% and 94.3%, respectively. Twelve (40%)(95% CI: 22.5-57.5) confirmed ORR were observed. Stable and progression disease were reported in 43% and 17% of cases. Median Response duration was 8.4 month (95% CI: 4.9-11.7), median Time to progression was 9.5 months (95% CI: 6.6-13.8) and median Overall Survival was 23.5 months (95% CI: 16.8-37.2). Thirteen pts (43%) experienced a grade 3 or 4 adverse events (AEs): One death occurred related to the study drugs (febrile neutropenia). Chemotherapy was discontinued due to toxicity in 30% of pts

Conclusions

Accrual was closed in January 2008 due to concerns regarding the degree and accumulative nature of AEs. Nonetheless, the ORR is encouraging and warranted further studies with adapted doses and schedules.     

A phase 1/1b study of satraplatin (JM-216) in combination with docetaxel in patients with advanced solid tumors and metastatic castrate-resistant prostate cancer

BackgroundSatraplatin is an oral platinum with potential advantages over other platinum agents. This study investigated the combination of satraplatin and docetaxel in a phase 1 study of patients with advanced solid tumor malignancies followed by a phase 1b study in men with chemotherapy naïve metastatic castrate-resistant prostate cancer (CRPC).MethodsIn this single institution phase 1/1b study, patients received docetaxel on day 1 and satraplatin on days 1–5 of a 21-day cycle ± granulocyte colony stimulating factor (GCSF). For phase 1b, prednisone 10 mg daily was added.ResultsTwenty-nine patients received treatment. Based on 3 dose limiting toxicities (DLT) (grade 4 neutropenia) in 13 patients at dose levels 1 and ?1 (docetaxel 60 mg/m² plus satraplatin 40 mg/m² and docetaxel 60 mg/m² plus satraplatin 50 mg/m²) GCSF was administered with subsequent cohorts. A dose level of docetaxel 60 mg/m² plus satraplatin 50 mg/m² with GCSF was the starting dose level for phase 1b. At the highest dose in the phase 1b (docetaxel 75 mg/m² plus satraplatin 50 mg/m²) there were no DLTs.ConclusionThe combination of satraplatin and docetaxel is feasible in solid tumor malignancies. In advanced malignancies, the recommended phase 2 dose is docetaxel 60 mg/m² IV day 1 with satraplatin 40 mg/m²/d PO days 1–5, without G-CSF, and Docetaxel 70 mg/m² IV day 1 with Satraplatin 50 mg/m²/day PO days 1–5, with G-CSF support, repeated in 3-week cycles. For patients with CRPC the recommended phase 2 dose is docetaxel 75 mg/m² IV day 1 with satraplatin 50 mg/m²/d PO days 1–-5, with G-CSF and prednisone 10 mg daily, repeated in 3-week cycles.     

Reappraisal of glucocorticoids in castrate-resistant prostate cancer

Recent reports and discussions of .preclinical prostate cancer models have emphasized the possibility that enzalutamide resistance may be mediated by glucocorticoid receptors （GR）.In both in vitro and xenograft animal studies, it is possible to show that the GR is up-regulated in prostate cancer cell lines and that dexamethasone reverses enzalutamide induced growth inhibition. In these model systems, GR agonists can induce a subset of androgen receptor target genes including prostate-specific antigen. These investigators also report a correlation between GR expression in patient-derived prostate cancer specimens and clinical response to enzalutamide. The authors discuss the possibility that these findings have important clinical relevance. We note that the current clinical evidence for GR mediating drug resistance or disease progression in patients with castrate-resistant prostate cancer （CRPC） is very limited at best.     

Phase I trial with a combination of docetaxel and Sm-lexidronam in patients with castration-resistant metastatic prostate cancer

Background

This study was designed to evaluate toxicity and preliminary efficacy of 2 cycles of concomitant standard dose/schedule of ¹⁵³Sm-lexidronam plus Q 3 weeks schedule escalating doses of docetaxel in metastatic castration-resistant prostate cancer (mCRPC).

Methods

mCRPC patients with progressive bone metastases were treated in 4 cohorts. Docetaxel doses were escalated from 50, 50, 0 mg/m² (on days 1, 22, 43, per 12-week cycle) to 75, 75, 75 mg/m². ¹⁵³Sm-lexidronam was administered on days 2 (Q 12 weeks) at dose of 1 mCi/kg/cycle (maximum of 2 cycles).

Results

Thirteen patients received an average of 3.6 doses of docetaxel (range, 2–6 doses, median 4) and 1.5 doses of ¹⁵³Sm-lexidronam (range, 1–2, median 2). Toxicity was primarily hematologic. There were total 35 episodes grade 3/4 neutropenia with a median 7 (range 7–14) days to recovery to ≤grade 1. One dose limiting grade 3 thrombocytopenia occurred on cohorts 3 and 4. Eight of 13 (62%) patients had PSA > 50% decrease as best response during the treatment. Median time to bone disease progression was 5.2 months (range 91 days–10 months+); 6/13 (46%) patients had stable/improved bone scans at 6 months and 6/6 (100%) symptomatic patients had improvement in pain.

Conclusions

Concurrent 6-month administration of 4 doses (75 mg/m²) of standard Q 3 weeks schedule of docetaxel with 2 Q 3 months infusions of 1 mCi/Kg ¹⁵³Sm-lexidronam is feasible with reversible bone marrow suppression, and deserves further testing in mCRPC patients with extensive bone metastasis.     

A single-center,multidisciplinary experience with radium-223 dichloride in men with metastatic castrate-resistant prostate cancer

IntroductionWe aimed to investigate several clinical and biochemical parameters, including palliative external beam radiation therapy (EBRT) to predict survival in patients with metastatic castrate-resistant prostate cancer (mCRPC) treated with radium-223 (²²³Ra).MethodsWe tested known and possible prognostic parameters, including palliative EBRT, both prior and concurrent to ²²³Ra. Logrank test (Kaplan-Meier method) and Cox regression analysis were used to predict overall survival (OS).ResultsA total of 133 patients were treated with ²²³Ra; median age was 72 years. Median OS was 9.0 (95% confidence interval [CI] 7.4–10.6) months. By univariate analysis (log-rank test), baseline Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1 (p=0.001), ≥5 cycles of ²²³Ra (p<0.001), baseline hemoglobin (Hb) ≥120 g/L (p <0.001), baseline total alkaline phosphatase (tALP) <110 U/L (p=0.001), and any prostate-specific antigen (PSA) decline at week 12 (p=0.013) were associated with increased OS. EBRT prior and/or concurrent to ²²³Ra showed a trend (p=0.051) towards inferior OS by univariate analysis only. By multivariate analysis, significant factors were PS 0–1 (hazard ratio [HR] 1.94, 95% CI 1.3–2.9, p=0.001), Hb ≥120 g/L (HR 0.5, 95% CI 0.3–0.9, p=0.011), and absence of docetaxel use prior to ²²³Ra (HR 1.86, 95% CI 1.08–3.22, p=0.026). With baseline Hb, tALP, and ECOG PS, we were able to divide patients into three groups with different median OS (months): 23.0 (95% CI 12.8–33.2), 8.0 (95% CI 6.7–9.3), and 5.0 (95% CI 3.1–6.9) for low-, intermediate-, and high-risk, respectively (p<0.001).ConclusionsWe found that ²²³Ra therapy can result in an OS of close to two years in carefully selected patients. Earlier administration of ²²³Ra therapy to fitter patients with mCRPC should be tested.