Phase Ib/II Study of Enzalutamide with Samotolisib (LY3023414) or Placebo in Patients with Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: To report efficacy and safety of samotolisib (LY3023414; PI3K/mTOR dual kinase and DNA-dependent protein kinase inhibitor) plus enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) following cancer progression on abiraterone. PATIENTS AND METHODS: In this double-blind, placebo-controlled phase Ib/II study (NCT02407054), following a lead-in segment for evaluating safety and pharmacokinetics of samotolisib and enzalutamide combination, patients with advanced castration-resistant prostate cancer with progression on prior abiraterone were randomized to receive enzalutamide (160 mg daily)/samotolisib (200 mg twice daily) or placebo. Primary endpoint was progression-free survival (PFS) assessed by Prostate Cancer Clinical Trials Working Group criteria (PCWG2). Secondary and exploratory endpoints included radiographic PFS (rPFS) and biomarkers, respectively. Log-rank tests assessed treatment group differences. RESULTS: Overall, 13 and 129 patients were enrolled in phase Ib and II, respectively. Dose-limiting toxicity was not reported in patients during phase Ib and mean samotolisib exposures remained in the targeted range despite a 35% decrease when administered with enzalutamide. In phase II, median PCWG2-PFS and rPFS was significantly longer in the samotolisib/enzalutamide versus placebo/enzalutamide arm (3.8 vs. 2.8 months; P = 0.003 and 10.2 vs. 5.5 months; P = 0.03), respectively. Patients without androgen receptor splice variant 7 showed a significant and clinically meaningful rPFS benefit in the samotolisib/enzalutamide versus placebo/enzalutamide arm (13.2 months vs. 5.3 months; P = 0.03). CONCLUSIONS: Samotolisib/enzalutamide has tolerable side effects and significantly improved PFS in patients with mCRPC with cancer progression on abiraterone, and this may be enriched in patients with PTEN intact and no androgen receptor splice variant 7.

A multi-institutional prospective trial in the USA confirms that the 4Kscore accurately identifies men with high-grade prostate cancer.

BACKGROUND: The 4Kscore combines measurement of four kallikreins in blood with clinical information as a measure of the probability of significant (Gleason ≥7) prostate cancer (PCa) before prostate biopsy. OBJECTIVE: To perform the first prospective evaluation of the 4Kscore in predicting Gleason ≥7 PCa in the USA. DESIGN, SETTING, AND PARTICIPANTS: Prospective enrollment of 1012 men scheduled for prostate biopsy, regardless of prostate-specific antigen level or clinical findings, was conducted at 26 US urology centers between October 2013 and April 2014. INTERVENTION: The 4Kscore. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was Gleason ≥7 PCa on prostate biopsy. The area under the receiver operating characteristic curve, risk calibration, and decision curve analysis (DCA) were determined, along with comparisons of probability cutoffs for reducing the number of biopsies and their impact on delaying diagnosis. RESULTS AND LIMITATIONS: Gleason ≥7 PCa was found in 231 (23%) of the 1012 patients. The 4Kscore showed excellent calibration and demonstrated higher discrimination (AUC 0.82) and net benefit compared to a modified Prostate Cancer Prevention Trial Risk Calculator 2.0 model and standard of care (biopsy for all men) according to DCA. A possible reduction of 30-58% in the number biopsies was identified with delayed diagnosis in only 1.3-4.7% of Gleason ≥7 PCa cases, depending on the threshold used for biopsy. Pathological assessment was performed according to the standard of care at each site without centralized review. CONCLUSION: The 4Kscore showed excellent diagnostic performance in detecting significant PCa. It is a useful tool in selecting men who have significant disease and are most likely to benefit from a prostate biopsy from men with no cancer or indolent cancer. PATIENT SUMMARY: The 4Kscore provides each patient with an accurate and personalized measure of the risk of Gleason ≥7 cancer to aid in decision-making regarding the need for prostate biopsy.

Emerging Therapeutic for the Treatment of Skeletal-related Events Associated With Metastatic Castrate-resistant Prostate Cancer.

Prostate cancer is the most prevalent cancer in US and European men and the second leading cause of cancer death in those populations. It is somewhat unique in that nearly all patients who succumb to the disease will ultimately develop bone metastasis. Morbidity from bone metastasis-referred to as skeletal-related events, which include fractures, cord compression, radiation to bone, and surgery to bone-leads to significant costs and impaired quality of life. This article reviews three agents and the roles they play in the ever-changing armamentarium of treatments for metastatic castrate-resistant prostate cancer (mCRPC). The potential benefits of these agents are discussed, as well as the continuing use of these agents and their earlier introduction in the patient with progressive mCRPC with bone metastasis.

Toremifene to reduce fracture risk in men receiving androgen deprivation therapy for prostate cancer.

PURPOSE: Androgen deprivation therapy is associated with fracture risk in men with prostate cancer. We assessed the effects of toremifene, a selective estrogen receptor modulator, on fracture incidence in men receiving androgen deprivation therapy during a 2-year period. MATERIALS AND METHODS: In this double-blind, placebo controlled phase III study 646 men receiving androgen deprivation therapy for prostate cancer were assigned to toremifene (80 mg by mouth daily) and 638 were assigned to placebo. Subjects were followed for 2 years. The primary study end point was new vertebral fractures. Secondary end points included fragility fractures, bone mineral density and lipid changes. RESULTS: The 2-year incidence of new vertebral fractures was 4.9% in the placebo group vs 2.5% in the toremifene group, a significant relative risk reduction of 50% (95% CI -1.5 to 75.0, p = 0.05). Toremifene significantly increased bone mineral density at the lumbar spine, hip and femoral neck vs placebo (p <0.0001 for all comparisons). There was a concomitant decrease in markers of bone turnover (p <0.05 for all comparisons). Toremifene also significantly improved lipid profiles. Venous thromboembolic events occurred more frequently with toremifene than placebo with 7 subjects (1.1%) in the placebo group experiencing a venous thromboembolic event vs 17 (2.6%) in the toremifene group. Other adverse events were similar between the groups. CONCLUSIONS: Toremifene significantly decreased the incidence of new vertebral fractures in men receiving androgen deprivation therapy for prostate cancer. It also significantly improved bone mineral density, bone turnover markers and serum lipid profiles.

Sarcopenia during androgen-deprivation therapy for prostate cancer.

PURPOSE: To characterize changes in lean body mass (LBM) in men with prostate cancer receiving androgen-deprivation therapy (ADT). PATIENTS AND METHODS: We prospectively evaluated LBM in a prespecified substudy of a randomized controlled trial of denosumab to prevent fractures in men receiving ADT for nonmetastatic prostate cancer. LBM was measured by total-body dual-energy x-ray absorptiometry at study baseline and at 12, 24, and 36 months. The analyses included 252 patients (132, denosumab; 120, placebo) with a baseline and at least one on-study LBM assessment. Patients were stratified by age (< 70 v ≥ 70 years) and by ADT duration (≤ 6 v > 6 months). RESULTS: Median ADT duration was 20.4 months at study baseline. Mean LBM decreased significantly from baseline, by 1.0% at month 12 (95% CI, 0.4% to 1.5%; P < .001; n = 248), by 2.1% at month 24 (95% CI, 1.5% to 2.7%; P < .001; n = 205), and by 2.4% at month 36 (95% CI, 1.6% to 3.2%; P < .001; n = 168). Men age ≥ 70 years (n = 127) had significantly greater changes in LBM at all measured time points than younger men. At 36 months, LBM decreased by 2.8% in men age ≥ 70 years and by 0.9% in younger men (P = .035). Men with ≤ 6 months of ADT at study entry (n = 36) had a greater rate of decrease in LBM compared with men who had received more than 6 months of ADT at study entry (3.7% v 2.0%; P = .0645). CONCLUSION: In men receiving ADT, LBM decreased significantly after 12, 24, and 36 months.

The role of distal third radius dual energy X-ray absorptiometry (DXA) and central DXA in evaluating for osteopenia and osteoporosis in men receiving androgen deprivation therapy for prostate cancer.

The authors assessed the use of distal third radius dual energy X-ray absorptiometry (DXA) concomitantly with central (hip and lumbar spine) DXA to identify men with osteopenia or osteoporosis receiving androgen deprivation therapy (ADT) for prostate cancer. Initial classification with central DXA demonstrated 60 (17%) normal, 187 (55%) osteopenic, and 96 (28%) osteoporotic patients. Sixteen of 60 (27%) normal patients were reclassified as osteopenic (14) or osteoporotic (2), and 20 of 187 (11%) osteopenic patients were reclassified as osteoporotic with the combination of central DXA plus distal third radius DXA. The difference in reclassification was statistically significant. The addition of distal third radius to central DXA scanning in men with bone loss associated with ADT identifies a statistically significant number of men being reclassified as having osteopenia or osteoporosis. Combined central and distal third radius DXA scanning should be considered routine in the evaluation of all men suspected of bone loss associated with ADT. This has specific significant clinical relevance because of the large number of men with nonevaluable central DXA studies. Fracture risk prediction and treatment recommendations based on this reclassification will need to be determined by follow-up studies.

Toremifene to reduce fracture risk in men receiving androgen deprivation therapy for prostate cancer.

PURPOSE: Androgen deprivation therapy is associated with fracture risk in men with prostate cancer. We assessed the effects of toremifene, a selective estrogen receptor modulator, on fracture incidence in men receiving androgen deprivation therapy during a 2-year period. MATERIALS AND METHODS: In this double-blind, placebo controlled phase III study 646 men receiving androgen deprivation therapy for prostate cancer were assigned to toremifene (80 mg by mouth daily) and 638 were assigned to placebo. Subjects were followed for 2 years. The primary study end point was new vertebral fractures. Secondary end points included fragility fractures, bone mineral density and lipid changes. RESULTS: The 2-year incidence of new vertebral fractures was 4.9% in the placebo group vs 2.5% in the toremifene group, a significant relative risk reduction of 50% (95% CI -1.5 to 75.0, p = 0.05). Toremifene significantly increased bone mineral density at the lumbar spine, hip and femoral neck vs placebo (p <0.0001 for all comparisons). There was a concomitant decrease in markers of bone turnover (p <0.05 for all comparisons). Toremifene also significantly improved lipid profiles. Venous thromboembolic events occurred more frequently with toremifene than placebo with 7 subjects (1.1%) in the placebo group experiencing a venous thromboembolic event vs 17 (2.6%) in the toremifene group. Other adverse events were similar between the groups. CONCLUSIONS: Toremifene significantly decreased the incidence of new vertebral fractures in men receiving androgen deprivation therapy for prostate cancer. It also significantly improved bone mineral density, bone turnover markers and serum lipid profiles.

Treatment of bicalutamide-induced breast events.

Bicalutamide is a competitive nonsteroidal androgen receptor antagonist. In the European Union and a number of other countries, bicalutamide 150 mg per day is approved as an adjuvant to primary treatments (radical prostatectomy or radiotherapy) or as monotherapy as an alternative to surgical or medical castration in men with locally advanced, nonmetastatic prostate cancer. The ongoing bicalutamide Early Prostate Cancer (EPC) program has shown that breast events, defined as gynecomastia, breast pain or both, are a significant limitation of bicalutamide. Nearly 90% of patients experienced one or both symptoms and nearly 16% of patients withdrew from the EPC program as a consequence of bicalutamide-induced breast events. Tamoxifen, anastrozole and radiotherapy have all been studied as options for the treatment of breast events. To date, tamoxifen appears to be the superior agent in terms of outcomes; however, further studies are still required to determine the optimal dose and timing of tamoxifen administration for both prophylaxis and treatment. In addition, the impact on prostate cancer control remains uncertain. An ongoing clinical trial using toremifene to prevent morphometric vertebral fractures in men undergoing medical and/or surgical castration will provide some additional data on the effects of selective estrogen receptor modulators in men with prostate cancer.

Contemporary prostate biopsy complication rates in community-based urology practice.

OBJECTIVES: To evaluate whether the increased number of rectal perforations associated with contemporary transrectal ultrasound-guided, 12-core prostate biopsy, with a periprostatic block, is associated with a greater rate of postprocedural complications. METHODS: We prospectively studied 1000 patients undergoing contemporary transrectal ultrasound-guided prostate biopsy and compared the rates of complicated urinary tract infection and significant rectal bleeding with the rates in our previous report of complications using a then-standard, 6-core biopsy technique, without a periprostatic block. RESULTS: Three patients developed complicated urinary tract infections, two of which were with ciprofloxacin-resistant organisms. This was not a significant different statistically from our earlier report. Seven patients had significant rectal bleeding requiring endoscopic intervention. This rate also was not significantly different statistically from our earlier report. CONCLUSIONS: Our infection and rectal bleeding complications associated with contemporary transrectal ultrasound-guided prostate biopsy were low. We experienced a small, nonstatistically significant, increase in the complicated urinary tract infection rate and a small, nonstatistically significant, increase in the rectal bleeding rate in association with the transition from an eight-core, no periprostatic block, technique to the contemporary technique.

Histoplasma phimosis: an uncommon presentation of a not uncommon pathogen.

Infection from Histoplasma capsulatum is usually subclinical, but it also can be disseminated in patients with a compromised immune status. Involvement of the external genitalia is a rare finding, occurring by direct contact or hematogenous spread. We present a case of histoplasma posthitis in a 71-year-old man, manifesting with the extremely unusual presentation of phimosis. The diagnosis was confirmed using an immunohistochemical stain.

Bicalutamide 150 mg maintains bone mineral density during monotherapy for localized or locally advanced prostate cancer.

PURPOSE: We evaluated changes in bone mineral density (BMD), fat-free mass (FFM) and serum lipid levels during bicalutamide 150 mg monotherapy compared with medical castration for 2 years. MATERIALS AND METHODS: A total of 103 men with localized or locally advanced prostate cancer (T1-T4, Nx, M0) for whom immediate androgen deprivation was indicated were enrolled in this prospective, multicenter, open-label, parallel group study. Patients were randomized to bicalutamide 150 mg once daily (51) or medical castration with a luteinizing hormone releasing hormone analogue (52) for 96 weeks. Primary end points were mean percent change from baseline in lumbar spine BMD, hip BMD and FFM at 96 weeks. Mean changes in lipid parameters with time were also evaluated. RESULTS: BMD was maintained during bicalutamide 150 mg monotherapy (+2.42% for lumbar spine BMD and +1.13% for hip BMD at week 96), while castration was associated with a progressive loss in BMD (-5.40% and -4.39% at week 96, respectively, both p <0.0001 at week 96). There was no significant difference between bicalutamide 150 mg and castration in mean percent change from baseline in FFM (-1.56% and -3.86%, respectively, at week 96, p = 0.31), although there was a trend for greater progressive loss over time with castration. Mean changes in lipid parameters were small and similar in the 2 groups. CONCLUSIONS: Bicalutamide 150 mg monotherapy may offer an important advantage compared to castration in terms of bone loss and body composition for patients who require long-term androgen deprivation for localized or locally advanced prostate cancer.