Phase III Trial of PROSTVAC in Asymptomatic or Minimally Symptomatic Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: PROSTVAC, a viral vector-based immunotherapy, prolonged median overall survival (OS) by 8.5 months versus placebo in metastatic castration-resistant prostate cancer in a phase II study. This phase III study further investigated those findings. PATIENTS AND METHODS: Patients were randomly assigned to PROSTVAC (Arm V; n = 432), PROSTVAC plus granulocyte-macrophage colony-stimulating factor (Arm VG; n = 432), or placebo (Arm P; n = 433), stratified by prostate-specific antigen (less than 50 ng/mL v 50 ng/mL or more) and lactate dehydrogenase (less than 200 v 200 U/L or more). Primary end point was OS. Secondary end points were patients alive without events (AWE)-namely, radiographic progression, pain progression, chemotherapy initiation, or death-at 6 months and safety. The study design was a superiority trial of PROSTVAC (Arm V or Arm VG) versus Arm P. Three interim analyses were planned. RESULTS: At the third interim analysis, criteria for futility were met and the trial was stopped early. Neither active treatment had an effect on median OS (Arm V, 34.4 months; hazard ratio, 1.01; 95% CI, 0.84 to 1.20; P = .47; Arm VG, 33.2 months; hazard ratio, 1.02; 95% CI, 0.86 to 1.22; P = .59; Arm P, 34.3 months). Likewise, AWE at 6 months was similar (Arm V, 29.4%; odds ratio, 0.96; 95% CI, 0.71 to 1.29; Arm VG, 28.0%; odds ratio, 0.89; 95% CI, 0.66 to 1.20; placebo, 30.3%). Adverse events were similar for the treatment and placebo groups, with the most common being injection site reactions (62% to 72%) and fatigue (21% to 24%). Arrhythmias were the most common cardiac-related events (1.4% to 3.5%). There were no reports of either myocarditis or pericarditis. Serious treatment-related events occurred in less than 1% of all patients. CONCLUSION: Whereas PROSTVAC was safe and well tolerated, it had no effect on OS or AWE in metastatic castration-resistant prostate cancer. Combination therapy is currently being explored in clinical trials.

Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer.

BACKGROUND: Men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising prostate-specific antigen (PSA) level are at high risk for metastasis. We hypothesized that enzalutamide, which prolongs overall survival among patients with metastatic, castration-resistant prostate cancer, would delay metastasis in men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level. METHODS: In this double-blind, phase 3 trial, we randomly assigned, in a 2:1 ratio, men with nonmetastatic, castration-resistant prostate cancer and a PSA doubling time of 10 months or less who were continuing androgen-deprivation therapy to receive enzalutamide (at a dose of 160 mg) or placebo once daily. The primary end point was metastasis-free survival (defined as the time from randomization to radiographic progression or as the time to death without radiographic progression). RESULTS: A total of 1401 patients (median PSA doubling time, 3.7 months) underwent randomization. As of June 28, 2017, a total of 219 of 933 patients (23%) in the enzalutamide group had metastasis or had died, as compared with 228 of 468 (49%) in the placebo group. The median metastasis-free survival was 36.6 months in the enzalutamide group versus 14.7 months in the placebo group (hazard ratio for metastasis or death, 0.29; 95% confidence interval, 0.24 to 0.35; P<0.001). The time to the first use of a subsequent antineoplastic therapy was longer with enzalutamide treatment than with placebo (39.6 vs. 17.7 months; hazard ratio, 0.21; P<0.001; such therapy was used in 15% vs. 48% of patients) as was the time to PSA progression (37.2 vs. 3.9 months; hazard ratio, 0.07; P<0.001; progression occurred in 22% vs. 69% of patients). At the first interim analysis of overall survival, 103 patients (11%) receiving enzalutamide and 62 (13%) receiving placebo had died. Adverse events of grade 3 or higher occurred in 31% of the patients receiving enzalutamide, as compared with 23% of those receiving placebo. CONCLUSIONS: Among men with nonmetastatic, castration-resistant prostate cancer with a rapidly rising PSA level, enzalutamide treatment led to a clinically meaningful and significant 71% lower risk of metastasis or death than placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, NCT02003924 .).

Long-Term Antitumor Activity and Safety of Enzalutamide Monotherapy in Hormone Naïve Prostate Cancer: 3-Year Open Label Followup Results.

PURPOSE: A phase 2 study of enzalutamide monotherapy in patients with hormone naïve prostate cancer demonstrated high prostate specific antigen response rates at 25 weeks, 1 year and 2 years with minimal effects on total body bone mineral density and favorable safety. In this followup analysis we evaluated enzalutamide antitumor activity and safety at 3 years. MATERIALS AND METHODS: In a single arm analysis 67 patients with hormone naïve prostate cancer and noncastrate testosterone (230 ng/dl or greater) received enzalutamide 160 mg per day orally until disease progression or unacceptable toxicity. The primary end point was the prostate specific antigen response (80% or greater decline from baseline). RESULTS: No patients discontinued treatment during year 3. Of 42 patients with prostate specific antigen assessments at 3 years 38 (90.5%, 95% CI 77.4-97.3) maintained a prostate specific antigen response. Of 26 patients with metastases at baseline 17 (65.4%) had a complete or partial response as the best overall response during 3 years. In patients who completed the 3-year visit minimal mean changes from baseline were observed in total body bone mineral density or bone mineral density of the femoral neck, trochanter, spine L1-L4 or forearm (range -2.7% to -0.1%). At 3 years total body fat had increased a mean of 16.5%, total lean body mass had decreased a mean of -6.5% and global health status had minimally decreased from baseline. Common adverse events were gynecomastia, fatigue, hot flush and nipple pain. CONCLUSIONS: Enzalutamide antitumor activity was maintained in patients with hormone naïve prostate cancer at 3 years. Overall bone mineral density, global health status and safety results were similar to those at 2 years.

[Metastatic adenocarcinoma in preputium of a patient with oesophageal cancer]. / Metastatisk adenokarcinom i præputiumresektat fra en patient med øsofaguscancer

Secondary or acquired phimosis usually occurs as part of a benign disease. We present a case of secondary phimosis caused by metastasis from a newly diagnosed oesophageal adenocarcinoma. The patient presented with clinical suspicion of infection in the preputial space, but histopathology revealed dilated lymphatic vessels with peripheral embolisms of epithelial tumour cells. This case report emphasizes the importance of establishing the cause of secondary phimosis by histopath-ological examination for possible malignancy.

Long-term Efficacy and Safety of Enzalutamide Monotherapy in Hormone-naïve Prostate Cancer: 1- and 2-Year Open-label Follow-up Results.

BACKGROUND: 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. OBJECTIVE: To determine the long-term efficacy and safety of enzalutamide monotherapy at 1 and 2 yr. DESIGN, SETTING, AND PARTICIPANTS: Open-label, single-arm study in patients with HNPC and noncastrate testosterone (≥230 ng/dl). INTERVENTION: Oral enzalutamide 160mg/d until disease progression or unacceptable toxicity. OUTCOME MEASUREMENTS AND ANALYSIS: PSA response (≥80% decline from baseline) assessed at 1 yr (49 wk) and 2 yr (97 wk). RESULTS AND LIMITATIONS: 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. CONCLUSIONS: 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. PATIENT SUMMARY: 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. TRIAL REGISTRATION: NCT01302041.

Enzalutamide monotherapy in hormone-naive prostate cancer: primary analysis of an open-label, single-arm, phase 2 study.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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.

Enzalutamide treatment in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy and abiraterone acetate.

OBJECTIVE: The aim of this study was to record prostate-specific antigen (PSA) response and overall survival (OS) for a group of metastatic castration-resistant prostate cancer (mCRPC) patients treated with enzalutamide following progression after abiraterone treatment in the post-chemotherapy setting. MATERIAL AND METHODS: Twenty-four mCRPC patients with progression after abiraterone treatment following primary docetaxel therapy received enzalutamide 160 mg/day. The percentage PSA response was recorded following first line docetaxel, abiraterone and enzalutamide treatment. Fischer's exact test, Mann-Whitney U test and linear regression model were used to test for differences in PSA response. RESULTS: All patients had a follow-up of at least 3 months. The median PSA response following 1 month of enzalutamide was -12% (range -56% to 76%), while the median best PSA response was -22% (-76% to 76%). Forty-six percent had a greater than 30% decrease in PSA. The PSA response to enzalutamide did not correlate with the number of prior cancer treatments (p = 0.57), time from diagnosis to mCRPC (p = 0.11) or prior response to docetaxel (p = 0.67). However, patients treated with second line cabazitaxel had an inferior PSA response to enzalutamide (p = 0.03), and there was a trend for the PSA response to abiraterone to correlate with the PSA response to the succeeding enzalutamide (B = 0.22, p = 0.05). The median OS was 4.8 months. CONCLUSIONS: Previous abiraterone therapy is associated with a less marked fall in PSA following enzalutamide therapy in post-chemotherapy mCRPC patients compared with reported results in randomized trials. Larger prospective studies of sequencing are warranted.

Ease of removal of thermo-expandable prostate stents.

OBJECTIVE: To report the ease of removal of the Memokath 028 prostatic stent (Engineers & Doctors A/S, Hornbaek, Denmark), an important attribute of the 'ideal' prostatic stent. PATIENTS AND METHODS: Data on patients who had had a Memokath 028 stent removed in three different centres in Europe over an 8-year period were collected retrospectively. Standardized forms were used to record relevant information from each physician's patient files. RESULTS: Ninety-three patients had their stents removed at the three reporting centres; the mean indwelling time of their stent was 12.9 months, and most stents were inserted for symptomatic benign prostate disease. Reasons for removal included recurrent outlet or storage-type urinary symptoms, migration of the stent, stent-related pain, recurrent urosepsis and detrusor failure. The stents were removed on a day-case basis in 32% of patients. Topical anaesthesia or no anaesthesia was used in 48%. Of these patients, only 9% described moderate discomfort or worse. The procedure took a mean of 11 min and was felt to be easy or fairly easy in 90% of patients. CONCLUSIONS: These data show the ease of removal of the Memokath 028 stent, reinforce its overall success in achieving the requirements of the ideal intraprostatic stent, and further emphasize the advantages of this implant over the epithelializing, permanent intraprostatic stent.