Advances in targeted alpha therapy for prostate cancer.

Amongst therapeutic radiopharmaceuticals, targeted alpha therapy (TαT) can deliver potent and local radiation selectively to cancer cells as well as the tumor microenvironment and thereby control cancer while minimizing toxicity. In this review, we discuss the history, progress, and future potential of TαT in the treatment of prostate cancer, including dosimetry-individualized treatment planning, combinations with small-molecule therapies, and conjugation to molecules directed against antigens expressed by prostate cancer cells, such as prostate-specific membrane antigen (PSMA) or components of the tumor microenvironment. A clinical proof of concept that TαT is efficacious in treating bone-metastatic castration-resistant prostate cancer has been demonstrated by radium-223 via improved overall survival and long-term safety/tolerability in the phase III ALSYMPCA trial. Dosimetry calculation and pharmacokinetic measurements of TαT provide the potential for optimization and individualized treatment planning for a precision medicine-based cancer management paradigm. The ability to combine TαTs with other agents, including chemotherapy, androgen receptor-targeting agents, DNA repair inhibitors, and immuno-oncology agents, is under investigation. Currently, TαTs that specifically target prostate cancer cells expressing PSMA represents a promising therapeutic approach. Both PSMA-targeted actinium-225 and thorium-227 conjugates are under investigation. The described clinical benefit, safety and tolerability of radium-223 and the recent progress in TαT trial development suggest that TαT occupies an important new role in prostate cancer treatment. Ongoing studies with newer dosimetry methods, PSMA targeting, and novel approaches to combination therapies should expand the utility of TαT in prostate cancer treatment.

Relationship between patient-reported outcomes and clinical outcomes in metastatic castration-resistant prostate cancer: post hoc analysis of COU-AA-301 and COU-AA-302.

Background: Patient-reported outcomes (PROs) are used to assess benefit-risk in drug development. The relationship between PROs and clinical outcomes is not well understood. We aim to elucidate the relationships between changes in PRO measures and clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC). Patients and methods: We investigated relationships between changes in self-reported fatigue, pain, functional well-being (FWB), physical well-being (PWB) and prostate cancer-specific symptoms with overall survival (OS) and radiographic progression-free survival (rPFS) after 6 and 12 months of treatment in COU-AA-301 (N = 1195) or COU-AA-302 (N = 1088). Eligible COU-AA-301 patients had progressed after docetaxel and had Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2. Eligible COU-AA-302 patients had no prior chemotherapy and ECOG PS 0 or 1. Patients were treated with abiraterone acetate (1000 mg/day) plus prednisone (10 mg/day) or prednisone alone daily. Association between self-reported fatigue, pain and functional status, and OS and/or rPFS, using pooled data regardless of treatment, was assessed. Cox proportional hazard regression modeled time to death or radiographic progression. Results: In COU-AA-301 patients, PRO improvements were associated with longer OS and longer time to radiographic progression versus worsening or stable PROs (P < 0.0001). In multivariate models, all except pain intensity remained associated with OS. Pain intensity, PWB and FWB improvements remained associated with rPFS. In COU-AA-302 patients, worsening PROs were associated with higher likelihood of radiographic progression (P ≤ 0.025) compared with improved or stable PROs. In multivariate models, worsening PWB remained associated with worse rPFS. The 12-month analysis confirmed the 6-month results. Conclusions: PROs are significantly associated with clinically relevant time-to-event efficacy outcomes in clinical trials and may complement and help predict traditional clinical practice methods for monitoring patients for disease progression.

Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide.

BACKGROUND: Mutations in the androgen receptor (AR) ligand-binding domain (LBD), such as F877L and T878A, have been associated with resistance to next-generation AR-directed therapies. ARN-509-001 was a phase I/II study that evaluated apalutamide activity in castration-resistant prostate cancer (CRPC). Here, we evaluated the type and frequency of 11 relevant AR-LBD mutations in apalutamide-treated CRPC patients. PATIENTS AND METHODS: Blood samples from men with nonmetastatic CRPC (nmCRPC) and metastatic CRPC (mCRPC) pre- or post-abiraterone acetate and prednisone (AAP) treatment (≥6 months' exposure) were evaluated at baseline and disease progression in trial ARN-509-001. Mutations were detected in circulating tumor DNA using a digital polymerase chain reaction-based method known as BEAMing (beads, emulsification, amplification and magnetics) (Sysmex Inostics' GmbH). RESULTS: Of the 97 total patients, 51 had nmCRPC, 25 had AAP-naïve mCRPC, and 21 had post-AAP mCRPC. Ninety-three were assessable for the mutation analysis at baseline and 82 of the 93 at progression. The overall frequency of detected AR mutations at baseline was 7/93 (7.5%) and at progression was 6/82 (7.3%). Three of the 82 (3.7%) mCRPC patients (2 AAP-naïve and 1 post-AAP) acquired AR F877L during apalutamide treatment. At baseline, 3 of the 93 (3.2%) post-AAP patients had detectable AR T878A, which was lost after apalutamide treatment in 1 patient who continued apalutamide treatment for 12 months. CONCLUSIONS: The overall frequency of detected mutations at baseline (7.5%) and progression (7.3%) using the sensitive BEAMing assay was low, suggesting that, based on this assay, AR-LBD mutations such as F877L and T878A are not common contributors to de novo or acquired resistance to apalutamide. CLINICALTRIALS.GOV IDENTIFIER: NCT01171898.

Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015.

The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer (APC) management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection. Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary Material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with APC in clinical trials should be encouraged.

Sunitinib in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic, castration-resistant prostate cancer: a phase 1/2 clinical trial.

BACKGROUND: This phase 1/2 study assessed sunitinib combined with docetaxel (Taxotere) and prednisone in chemotherapy-naive metastatic, castration-resistant prostate cancer (mCRPC) patients. PATIENTS AND METHODS: To determine the recommended phase 2 dose (RP2D), 25 patients in four dose escalation cohorts received 3-week cycles of sunitinib (2 weeks on, 1 week off), docetaxel and prednisone, preceded by a 4-week sunitinib 50 mg/day lead in. RP2D was evaluated in 55 additional patients. The primary end point was prostate-specific antigen (PSA) response rate. RESULTS: One phase 1 dose-limiting toxicity occurred (grade 3 hyponatremia). The RP2D was sunitinib 37.5 mg/day, docetaxel 75 mg/m(2) and prednisone 5 mg b.i.d. During phase 2, confirmed PSA responses occurred in 31 patients [56.4% (95% confidence interval 42.3-69.7)]. Median time to PSA progression was 9.8 months. Forty-one patients (75%) were treated >3 months, 12 (22%) completed the study (16 cycles) and 43 (78%) discontinued (36% for disease progression and 27% adverse events). The most frequent treatment-related grade 3/4 adverse events were neutropenia (53%; 15% febrile) and fatigue/asthenia (16%). Among 33 assessable patients, 14 (42.4%) had confirmed partial response. Median progression-free and overall survivals were 12.6 and 21.7 months, respectively. CONCLUSION: This combination was moderately well tolerated, with promising response rate and survival benefit, justifying further investigation in mCRPC.

Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases.

BACKGROUND: Osteonecrosis of the jaw (ONJ) has been reported in patients receiving bisphosphonates for metastatic bone disease. ONJ incidence, risk factors, and outcomes were evaluated in a combined analysis of three phase III trials in patients with metastatic bone disease receiving antiresorptive therapies. PATIENTS AND METHODS: Patients with bone metastases secondary to solid tumors or myeloma were randomly assigned to receive either s.c. denosumab (120 mg) or i.v. zoledronic acid (4 mg) every 4 weeks. On-study oral examinations were conducted by investigators at baseline and every 6 months. Oral adverse events were adjudicated by an independent blinded committee of dental experts. RESULTS: Of 5723 patients enrolled, 89 (1.6%) patients were determined to have ONJ: 37 (1.3%) received zoledronic acid and 52 (1.8%) received denosumab (P = 0.13). Tooth extraction was reported for 61.8% of patients with ONJ. ONJ treatment was conservative in >95% of patients. As of October 2010, ONJ resolved in 36.0% of patients (29.7% for zoledronic acid and 40.4% for denosumab). CONCLUSIONS: In this combined analysis of three prospective trials, ONJ was infrequent, management was mostly conservative, and healing occurred in over one-third of the patients. Educating physicians about oral health before and during bone-targeted therapy may help reduce ONJ incidence and improve outcomes.

New developments in castrate-resistant prostate cancer.

Castrate-resistant prostate cancer (CRPC) occurs when disease progresses in the presence of castrate levels of androgens and remains sensitive to further hormonal manipulation. For many years the treatment of CRPC was limited to the use of docetaxel for metastatic disease. However, this has recently changed with the approval of several new agents. Sipuleucel-T, an immunotherapeutic vaccine, is now available in the US for patients with non-metastatic CRPC and abiraterone, an oral enzyme inhibitor of androgen biosynthesis, as well as cabazitaxel, a cytotoxic chemotherapeutic, have been approved for the treatment of metastatic CRPC. Also, denosumab, a subcutaneous antibody, is now an option for the treatment of patients with CRPC with bone metastases, in addition to zoledronic acid, an intravenous bisphosphonate. Further treatment advances for metastatic CRPC therapeutics are in late stage phase III development. These include therapies affecting the androgen receptor (MDV3100) as well as additional immune-based therapeutics, PROSTVAC and ipilimumab. A broad range of agents is also emerging under the term targeted therapies. The endothelin-A receptor antagonist zibotentan, the tyrosine kinase inhibitors dasatinib, sorafenib and cabozantinib, the anti-angiogenic agent aflibercept, and the clusterin inhibitor custirsen, are all currently being tested for efficacy in metastatic CRPC. The mechanism of action of these and other promising agents are discussed alongside current therapeutic options and their potential place in the treatment landscape for CRPC is considered.

FSH suppression and tumour control in patients with prostate cancer during androgen deprivation with a GnRH agonist or antagonist.

BACKGROUND: Gonadotropin releasing hormone (GnRH) antagonists suppress follicle-stimulating hormone (FSH) to lower levels than GnRH agonists. This may partially explain the differences between these agents on prostate cancer outcomes. In this post-hoc analysis, FSH and prostate specific antigen (PSA) responses and the impact of cross-over from leuprolide to degarelix were evaluated from a 1-year comparative study (CS21) and its extension study (CS21A). MATERIALS AND METHODS: Overall, 610 patients were enrolled in CS21, wherein PSA and FSH levels were evaluated monthly. CS21A evaluated 386 patients, including those previously treated with degarelix (n = 251) who continued to receive degarelix, and those previously treated with leuprolide (n = 135) who crossed-over to receive degarelix. PSA and FSH levels were evaluated in CS21A for 3 months after cross-over. The associations between measurements were assessed using Spearman's correlation coefficient. The impact of class variables on FSH suppression were evaluated using Analysis of Variance. RESULTS: Rapid PSA and FSH suppression was observed and maintained in the degarelix arm (CS21 and CS21A), while patients on leuprolide experienced rising PSA during CS21. Patients crossed-over from leuprolide to degarelix achieved a suppression of FSH and a significant PSA decrease. PSA and FSH levels were significantly (p < .05) correlated at months 1, 3, 6, 12 and 13 in the degarelix arm. CONCLUSIONS: Significant FSH suppression with GnRH antagonists may explain its advantage over GnRH agonists in terms of better prostate cancer control. The effect of profound FSH suppression is analogous to the need for profound testosterone suppression for tumor control.

Effect of denosumab versus zoledronic acid in preventing skeletal-related events in patients with bone metastases by baseline characteristics.

BACKGROUND: Analyses of phase III trials showed that denosumab was superior to zoledronic acid (ZA) in preventing skeletal-related events (SREs) irrespective of age, history of SREs, or baseline pain status. This analysis assessed the risk of SREs across additional baseline characteristics. PATIENTS AND METHODS: Patients (N = 5543) from three phase III trials who had breast cancer, prostate cancer, or other solid tumours and one or more bone metastasis were included. Superiority of denosumab versus ZA in reducing risk of first SRE and first and subsequent SREs was assessed in subgroups defined by the Eastern Cooperative Oncology Group performance status (ECOG PS), bone metastasis location, bone metastasis number, visceral metastasis presence/absence, and urinary N-telopeptide (uNTx) level using Cox proportional hazards and Anderson-Gill models. Subgroups except bone metastasis location were also assessed for each solid tumour type. RESULTS: Compared with ZA, denosumab significantly reduced the risk of first SRE across all subgroups (hazard ratio [HR] ranges: ECOG PS, 0.79-0.84; bone metastasis location, 0.78-0.83; bone metastasis number, 0.78-0.84; visceral metastasis presence/absence, 0.80-0.82; uNTx level, 0.73-0.86) and reduced the risk of first and subsequent SREs in all subgroups (HR ranges: ECOG PS, 0.76-0.83; bone metastasis location, 0.78-0.84; bone metastasis number, 0.79-0.81; visceral metastasis presence/absence, 0.79-0.81; uNTx level, 0.74-0.83). Similar results were observed in subgroups across tumour types. CONCLUSION: Denosumab was superior to ZA in preventing SREs in patients with bone metastases from advanced cancer, regardless of ECOG PS, bone metastasis number, baseline visceral metastasis presence/absence, and uNTx level.

A comparison of borderline and nonborderline alcoholic patients.

Attempts to document systemically the presence of borderline personality disorder in alcoholic patients were made in 94 alcoholic patients consecutively admitted to an inpatient alcoholism program. Operational diagnoses of borderline or not borderline used Gunderson's semistructured Diagnostic Interview for Borderlines (DIB). With the use of conservative criteria, 12.8% of alcoholic patients could be designated as having borderline disorders. Borderline alcoholics were significantly younger and were more likely to have a history of drug abuse, suicide attempts, and accidents. Diminished satisfaction with self and family life and a greater tendency to experience craving across a variety of situations was reported.

Inhibitory effects of interferon on mouse megakaryocytic progenitor cells in culture.

Mouse bone marrow cells were grown in plasma clots, megakaryocyte formation was stimulated with human urinary erythropoietin (Ep). The expression of megakaryocyte colony forming units (CFUM) and of single megakaryocyte forming units (M) was evaluated after seven days in culture. Usually ten times more M than CFUM were found. Megakaryocytic colony formation showed a linear dependence on cell dose from 0.5 to 2 X 10(5) cells/clot. The colony size frequency distribution exhibited a single peak in the two-cell size class, followed by a continuous decrease, suggesting that cell division may occur asynchronously in cells making up a colony. Mouse L cell interferon (IF) in doses from 10 to 1000 U/ml was included in clots together with Ep. This resulted in a biphasic, dose dependent reduction of colony formation and of single megakaryocyte formation. At all doses tested CFUM were more sensitive to IF than M. These observations are best explained by a differential inhibitory effect of IF on replication of two or more classes of megakaryocytic progenitor cells.

Constancy of erythroid burst forming unit (BFUE) levels in the blood of hematologically normal individuals.

Repeated determination of circulating blood BFUE levels in 7 hematologically normal individuals, during a 6 to 16 month period, showed their respective levels to be maintained within narrow limits (coefficient of variation did not exceed 15.1%). However, males differed from each other 3-fold and females as much as 12-fold in the number of BFUE/ml blood. These differences may reflect various sizes of the early erythroid progenitor compartment, which in the presence of different levels of humoral regulators of erythropoiesis are capable of maintaining a normal rate of red cell production. Our findings suggest that the observation of changes of the blood BFUE level of individuals, over a period of time, may be indicative of a change in their erythropoiesis and may shed some light on the physiological role of the peripheral blood BFUE.

Suppressive effect of interferon on erythroid cell proliferation.

The effect of interferon on mouse and human in vitro erythropoiesis was investigated using the mouse marrow CFU-E and the human blood BFU-E systems, respectively. Homologous interferons were found to have a marked inhibitory effect on mouse CFU-E and human BFU-E proliferation. This inhibitory effect was dose related and independent of the erythropoietin concentration used. The effective concentration of human interferon was within the range observed in humans following viral infections. It is suggested that interferon may play a role in the mechanism of the acute erythroblastopenic crisis observed at times in patients with chronic anemia following viral infections.

Suppression of mouse erythroid colony formation by L1210 leukemia cells.

The effect of L1210 transplantable leukemic cells on in vitro formation of erythroid colonies from CD2F1 mouse bone marrow progenitor cells (CFU-E) was investigated. Clonal cell culture was carried out by a methylcellulose technique. Human urinary erythropoietin served as the stimulator. After 44 hours of incubation aggregates of eight or more erythroid cells were scored as colonies. The number of CFU-E which could be demonstrated in marrow cells from mice that had been injected intravenously 6 days before with 5 x 10(4) L1210 cells was far below that obtained from normal marrow cells. When 1.3 x 10(5) marrow cells from leukemic mice or L1210 ascites cells were cultured with an equal amount of normal cells, the number of CFU-E expressed was reduced by 51% and by 86%, respectively, relative to controls with normal cells only. Neither lethally irradiated L1210 cells (4500 rad) nor L1210 cell conditioned media suppressed erythroid colony formation. It is suggested that in L1210 leukemia erythropoiesis is decreased because of a cell-to-cell inhibitory action of the leukemia cells on CFU-E.

Compensatory hypoventilation in metabolic alkalosis.

Although hyperventilation is a well-known compensatory mechanism in metabolic acidosis, compensatory hypoventilation has been inconsistent and controversial in metabolic alkalosis. Six healthy subjects were studied under baseline conditions and during steady-state metabolic acidosis (seven episodes) and alkalosis (14 episodes). Minute ventilation (VE) fell in metabolic alkalosis and rose in metabolic acidosis. These changes in ventilation were entirely due to reduction and elevation of tidal volume (VT) respectively, while respiratory frequency (f) remained unchanged. Alveolar ventilation fell during metabolic alkalosis and resulted in elevation of arterial PCO2 in all subjects. The ventilatory response to arterial PCO2 in all subjects. The ventilatory response to CO2 breathing was also diminished. There was a linear relationship between PaCO2 and plasma [HCO-3] in metabolic acidosis and alkalosis which was defined as PaCO2 (mm Hg = 0.7 [HCO-a] + 20 (+/- SEM), r = 0.95. Although arterial PO2 and plasma [K+] fell during metabolic alkalosis, minute ventilation did not change upon breathing oxygen and there was no correlation between changes in plasma [K+] and plasma H+ regulation.

Renal cell metastases versus liver hemangioma.

We present the case of a man with presumed metastatic renal cell carcinoma based on radiologic examination and weight loss, who refused treatment of any kind for one year. A surgical exploration to control hematuria revealed a Stage I tumor.

The best suture for hypospadias?

In a study designed to determine the best suture for use in hypospadias surgery, polydioxanone (PDS), chromic catgut, and polyglycolic acid (Dexon) were studied under similar conditions in the penile foreskin of 16 baboons. Gross and microscopic observations were made at intervals of six to forty-eight days. The wounds sutured with catgut were all healed by twenty-four days with complete suture resorption and no evidence of scar formation. Both polyglycolic acid and polydioxanone sutures showed delayed resorption, wound abscesses, and granulomas. Catgut remains the best available suture to use in the penile foreskin. Polyglycolic acid and polydioxanone sutures, because of their prolonged resorption and excess reaction, should not be used in hypospadias surgery.

Perirenal lipoma versus renal cell carcinoma.

Pure renal and perirenal lipomas are rare. They arise from renal cortex, capsule, or perirenal tissue, and may be difficult to distinguish from renal adenocarcinomas. We report on a patient who presented with a renal mass that had the radiologic findings suggestive of a renal cell carcinoma, but proved to be a simple lipoma.