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.

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.

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.

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.

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.

Chemotherapy for prostate cancer: when should a urologist refer a patient to a medical oncologist?

The last few years have seen considerable evolution in treatment options and therapeutic strategies for patients with castrate-resistant prostate cancer (CRPC). One major change was the expansion of chemotherapeutic options with the approval of cabazitaxel, representing the first chemotherapeutic therapy after docetaxel to demonstrate improved survival in patients with CRPC. A number of other noncytotoxic therapies have either recently been approved or are in advanced development for treating this patient population. Offering novel mechanisms of action, these new agents make considerably more expansive and complex the decisions regarding when to treat, which agents to use, and the order in which they are administered. A pivotal decision point for urologists who treat patients with advanced prostate cancer has been timing the patient's referral to an oncologist for chemotherapy. Although clinical guidelines regard chemotherapy as only appropriate for prostate cancer patients with symptomatic metastatic disease, increasing evidence points to the possibility that a subgroup of patients may benefit from an earlier introduction of chemotherapy. At the same time, additional treatment options that may either precede chemotherapy or follow initial chemotherapeutic failure mean that urologists must closely monitor their patients' health status to match specific clinical profiles with specific treatment options. With the increase in number and variety of therapeutic approaches, the role of the urologist has been expanded, in part, owing to the opportunity for urologists to administer treatments previously unavailable, and also owing to the growing importance of working cooperatively with oncologists and as a member of a multidisciplinary team.

New considerations for ADT in advanced prostate cancer and the emerging role of GnRH antagonists.

Androgen deprivation therapy (ADT) is first-line treatment for metastatic prostate cancer (PCa). Gonadotrophin-releasing hormone (GnRH) agonists are the most commonly used ADT but have several theoretical physiologic disadvantages (e.g. initial testosterone surge, potential microsurges upon repeat administration). Testosterone surge delays the intended serologic endpoint of testosterone suppression and may exacerbate clinical symptoms. GnRH antagonists were developed with a view toward overcoming these potential adverse physiologic events. This review evaluates GnRH agonists and antagonists, assessing the potential future role of antagonists in PCa and strategies to minimize ADT adverse events (AEs). Evidence was identified via PubMed search (by GnRH agent and other ADT-related terms), from review article bibliographies, and authors' therapy area knowledge, with articles included by author consensus. Degarelix shows similar efficacy to a GnRH agonist in achieving and maintaining castration, with faster onset and without testosterone surge/microsurges. Phase III data showed that, in the first treatment year, degarelix displayed a lower risk of PSA failure or death (composite endpoint), lower levels of the bone marker serum alkaline phosphatase (in baseline metastatic disease), and fewer musculoskeletal AEs than the agonist leuprolide. Also, crossing over from leuprolide to degarelix after 1 year reduced the risk of PSA failure or death. ADT displays an AE spectrum which can impact quality of life as well as causing significant morbidities. Strategies to improve ADT tolerability have become increasingly important including: a holistic management approach, improved diet and exercise, more specific monitoring to detect and prevent testosterone depletion toxicities, and intermittent ADT allowing hormonal recovery between treatment periods. Clinical studies suggest possible benefits of GnRH antagonists over agonists based on different mechanisms of action. GnRH antagonists should now be considered as an alternative first-line ADT option in advanced PCa. Intermittent ADT and a holistic treatment approach are promising strategies to improve ADT tolerability.

Effect of abiraterone acetate plus prednisone on the QT interval in patients with metastatic castration-resistant prostate cancer.

PURPOSE: Abiraterone is the active metabolite of the pro-drug abiraterone acetate (AA) and a selective inhibitor of CYP17, a key enzyme in testosterone synthesis, and improves overall survival in postdocetaxel metastatic castration-resistant prostate cancer (mCRPC). This open-label, single-arm phase 1b study was conducted to assess the effect of AA and abiraterone on the QT interval. METHODS: The study was conducted in 33 patients with mCRPC. Patients received AA 1,000 mg orally once daily + prednisone 5 mg orally twice daily. Electrocardiograms (ECGs) were collected in triplicate using 12-lead Holter monitoring. Baseline ECGs were obtained on Cycle 1 Day-1. Serial ECG recordings and time-matched pharmacokinetic (PK) blood samples were collected over 24 h on Cycle 1 Day 1 and Cycle 2 Day 1. Serial PK blood samples were also collected over 24 h on Cycle 1 Day 8. RESULTS: After AA administration, the upper bound of the 2-sided 90 % confidence interval (CI) for the mean baseline-adjusted QTcF change was <10 ms; no patients discontinued due to QTc prolongation or adverse events. No apparent relationship between change in QTcF and abiraterone plasma concentrations was observed [estimated slope (90 % CI): 0.0031 (-0.0040, 0.0102)]. CONCLUSIONS: There is no significant effect of AA plus prednisone on the QT/QTc interval in patients with mCRPC.

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.

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.

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.

Androgen deprivation therapy and estrogen deficiency induced adverse effects in the treatment of prostate cancer.

Androgen deprivation therapy (ADT) is the standard of care for metastatic prostate cancer and is increasingly used to treat asymptomatic patients with prostate-specific antigen recurrence after failed primary therapy. Although effective, ADT is associated with multiple adverse effects, many of which are related to the estrogen deficiency that occurs as a result of treatment. These include increased fracture risk, hot flashes, gynecomastia, serum lipid changes and memory loss. By providing clinicians with a greater awareness of the estrogen deficiency induced adverse effects from ADT, they can proactively intervene on the physical and psychological impact these effects have on patients.

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.

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.

Evolution of pre-treatment stenting and local anesthesia for extracorporeal shock wave lithotripsy at a single university center.

Evolution of the extracorporeal shock wave lithotripsy technique involves not just second generation technology but operator innovations and experience. Retrospective analysis of the first 512 treatments at a university medical stone unit using the Dornier HM3 lithotriptor was compared to 3 intervals of 100 consecutive treatments during the next 2-year period (1985 to 1987). Patient referral and selection as well as treatment techniques and rates of endourological interventions were analyzed. Patient demographics, stone types and retreatment rates remained constant during 2,500 treatments. However, the use of local anesthesia and internal ureteral stents became increasingly common. Of the 1987 cohort 29% were treated with the patient under local anesthesia, and 23 of the 44 with a stent (52%) received internal ureteral stents. Other treatment trends identified during the study period included increasing number of large (greater than 2 cm.) and multiple stones treated; increasing use of internal and external ureteral catheters before treatment, fewer stents for small, mobile renal calculi and decreasing length of hospital stay (2.7 to 2.1 days) with increasing use of stents before lithotripsy. The increasing average number of shock waves per treatment (1,382 versus 1,580) during the study period can be attributed to the larger proportion of patients with high stone burdens and the impact of an increased number of operators with more varied criteria for endoscopy and treatment end point.

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.