Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial.

BACKGROUND: Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2). PATIENTS AND METHODS: Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints [time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS)] were assessed. RESULTS: Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 19.5 versus 10.9 months; hazard ratio (HR) = 0.55 [95% confidence interval (CI) 0.39-0.78]; nominal P = 0.0007} consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population [HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months]. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed. CONCLUSIONS: MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients.

Clinical outcomes in men of diverse ethnic backgrounds with metastatic castration-resistant prostate cancer.

BACKGROUND: We have shown previously in multivariable analysis that black men had 19% lower risk of death than white men with metastatic castration-resistant prostate cancer (mCRPC) treated with a docetaxel and prednisone (DP)-based regimen. The primary goal of this analysis was to compare progression-free survival (PFS), biochemical PFS, ≥50% decline in prostate-specific antigen (PSA) from baseline and objective response rate (ORR) in white, black and Asian men with mCRPC treated with a DP-based regimen. PATIENTS AND METHODS: Individual patient data from 8820 mCRPC men randomized on nine phase III trials to a DP-containing regimen were combined. Race used in the analysis was based on self-report. End points were PFS, biochemical PSA, ≥50% decline in PSA from baseline and ORR. The proportional hazards and the logistic regression models were employed to assess the prognostic importance of race in predicting outcomes adjusting for established prognostic factors. RESULTS: Of 8820 patients, 7528 (85%) were white, 500 (6%) were black, 424 were Asian (5%) and 368 (4%) had race unspecified. Median PFS were 8.3 [95% confidence interval (CI) 8.2-8.5], 8.2 (95% CI 7.4-8.8) and 8.3 (95% CI 7.6-8.8) months in white, black and Asian men, respectively. Median PSA PFS were 9.9 (95% CI 9.7-10.4), 8.5 (95% CI 8.0-10.3) and 11.1 (95% CI 9.9-12.5) months in white, black and Asian men, respectively. CONCLUSIONS: We observed no differences in clinical outcomes by race and ethnic groups in men with mCRPC enrolled on these phase III clinical trials with DP.

Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer.

BACKGROUND: In the SPARTAN study, compared with placebo, apalutamide added to ongoing androgen deprivation therapy significantly prolonged metastasis-free survival (MFS) and time to symptomatic progression in patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC). Overall survival (OS) results at the first interim analysis (IA1) were immature, with 104 of 427 (24%) events required for planned final OS analysis. Here, we report the results of a second pre-specified interim analysis (IA2). METHODS: One thousand two hundred and seven patients with nmCRPC were randomized 2 : 1 to apalutamide (240 mg daily) or placebo. The primary end point of the study was MFS. Subsequent therapy for metastatic CRPC was permitted. When the primary end point was met, the study was unblinded. Patients receiving placebo who had not yet developed metastases were offered open-label apalutamide. At IA2, pre-specified analysis of OS was undertaken, using a group-sequential testing procedure with O'Brien-Fleming-type alpha spending function. Safety and second progression-free survival (PFS2) were assessed. RESULTS: Median follow-up was 41 months. With 285 (67% of required) OS events, apalutamide was associated with an improved OS compared with placebo (HR 0.75; 95% CI 0.59-0.96; P = 0.0197), although the P-value did not cross the pre-specified O'Brien-Fleming boundary of 0.0121. Apalutamide improved PFS2 (HR 0.55; 95% CI 0.45-0.68). At IA2, 69% of placebo-treated and 40% of apalutamide-treated patients had received subsequent life-prolonging therapy for metastatic CRPC. No new safety signals were observed. CONCLUSION: In patients with nmCRPC, apalutamide was associated with a 25% reduction in risk of death compared with placebo. This OS benefit was observed despite crossover of placebo-treated patients and higher rates of subsequent life-prolonging therapy for the placebo group.

Soil Moisture Data Assimilation to Estimate Irrigation Water Use.

Knowledge of irrigation is essential to support food security, manage depleting water resources, and comprehensively understand the global water and energy cycles. Despite the importance of understanding irrigation, little consistent information exists on the amount of water that is applied for irrigation. In this study, we develop and evaluate a new method to predict daily to seasonal irrigation magnitude using a particle batch smoother data assimilation approach, where land surface model soil moisture is applied in different configurations to understand how characteristics of remotely sensed soil moisture may impact the performance of the method. The study employs a suite of synthetic data assimilation experiments, allowing for systematic diagnosis of known error sources. Assimilation of daily synthetic soil moisture observations with zero noise produces irrigation estimates with a seasonal bias of 0.66% and a correlation of 0.95 relative to a known truth irrigation. When synthetic observations were subjected to an irregular overpass interval and random noise similar to the Soil Moisture Active Passive satellite (0.04 cm3 cm-3), irrigation estimates produced a median seasonal bias of <1% and a correlation of 0.69. When systematic biases commensurate with those between NLDAS-2 land surface models and Soil Moisture Active Passive are imposed, irrigation estimates show larger biases. In this application, the particle batch smoother outperformed the particle filter. The presented framework has the potential to provide new information into irrigation magnitude over spatially continuous domains, yet its broad applicability is contingent upon identifying new method(s) of determining irrigation schedule and correcting biases between observed and simulated soil moisture, as these errors markedly degraded performance.

MMSET/WHSC1 enhances DNA damage repair leading to an increase in resistance to chemotherapeutic agents.

MMSET/WHSC1 is a histone methyltransferase (HMT) overexpressed in t(4;14)+ multiple myeloma (MM) patients, believed to be the driving factor in the pathogenesis of this MM subtype. MMSET overexpression in MM leads to an increase in histone 3 lysine 36 dimethylation (H3K36me2), and a decrease in histone 3 lysine 27 trimethylation (H3K27me3), as well as changes in proliferation, gene expression and chromatin accessibility. Prior work linked methylation of histones to the ability of cells to undergo DNA damage repair. In addition, t(4;14)+ patients frequently relapse after regimens that include DNA damage-inducing agents, suggesting that MMSET may play a role in DNA damage repair and response. In U2OS cells, we found that MMSET is required for efficient non-homologous end joining as well as homologous recombination. Loss of MMSET led to loss of expression of several DNA repair proteins, as well as decreased recruitment of DNA repair proteins to sites of DNA double-strand breaks (DSBs). By using genetically matched MM cell lines that had either high (pathological) or low (physiological) expression of MMSET, we found that MMSET-high cells had increased damage at baseline. Upon addition of a DNA-damaging agent, MMSET-high cells repaired DNA damage at an enhanced rate and continued to proliferate, whereas MMSET-low cells accumulated DNA damage and entered cell cycle arrest. In a murine xenograft model using t(4;14)+ KMS11 MM cells harboring an inducible MMSET shRNA, depletion of MMSET enhanced the efficacy of chemotherapy, inhibiting tumor growth and extending survival. These findings help explain the poorer prognosis of t(4;14) MM and further validate MMSET as a potential therapeutic target in MM and other cancers.

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.

Inhibition of the androgen receptor by mineralocorticoids at levels physiologically achieved in serum in patients treated with abiraterone acetate.

BACKGROUND: Abiraterone acetate (AA), a highly potent CYP17A1 inhibitor, has demonstrated marked clinical benefit in patients with metastatic castration-resistant prostate cancer (CRPC). Phase I trials of AA without prednisone showed significant elevation of serum mineralocorticoid concentrations. The aim of this study was to elucidate the biological significance of elevated mineralocorticoid levels on androgen receptor (AR) activity in prostate cancer (PC) cells. METHODS: Fluorescence resonance energy transfer (FRET) assay was used to assess the effect of mineralocorticoids on androgen-induced conformational change of the AR. LAPC4, LNCaP and LN-AR cells that were cultured and treated with androgens were exposed to mineralocorticoids at varying concentrations, including levels measured in the serum of AA-treated patients in a phase I trial. AR-dependent transcriptional activity and cell growth were measured in these cell lines to determine the biological impact of mineralocorticoids on PC cells. RESULTS: Corticosterone (CS) and deoxycorticosterone (DOC) inhibited androgen-induced conformational change of the AR in the FRET assay. CS inhibited AR-dependent transcriptional activity and cell growth at concentrations comparable to those measured in the serum of AA-treated patients. DOC inhibited AR transcriptional activity and cell growth at 10-fold greater concentrations than measured in the serum of AA-treated patients. CONCLUSIONS: Mineralocorticoids directly inhibit androgen-induced conformational change of the AR. CS inhibits AR transcriptional activity and PC cell growth at concentrations found in the serum of patients treated with AA. Further investigation of the potential therapeutic implications of mineralocorticoids in AA-treated CRPC patients is warranted.

Time to disease-related pain and first opioid use in patients with metastatic castration-resistant prostate cancer treated with sipuleucel-T.

BACKGROUND: Sipuleucel-T has demonstrated improved overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). This analysis examined the effect of sipuleucel-T on time to disease-related pain (TDRP) and time to first use of opioid analgesics (TFOA) in mCRPC using data pooled from three randomized phase III studies in men with asymptomatic or minimally symptomatic mCRPC (D9901 (NCT00005947), D9902A (NCT01133704), D9902B (IMPACT; NCT00065442)). METHODS: Four-hundred and twenty-eight asymptomatic patients were analyzed for TDRP; 737 patients were analyzed for TFOA. Pain status was collected using logs adjudicated by blinded, independent reviewers. Opioid use for cancer-related pain was identified from medically reviewed reports of concomitant medication. Disease-related pain was defined as pain post enrollment. TDRP and TFOA were analyzed using the Kaplan-Meier method and Cox regression. RESULTS: Treatment with sipuleucel-T was not associated with a significant difference in TDRP (hazard ratio (HR)=0.819; 95% confidence interval (CI): 0.616-1.089; P=0.170; median TDRP 5.6 months for sipuleucel-T and 5.3 months for control, respectively), although 39.3% of sipuleucel-T-treated patients and 18.9% of control patients were pain-free at 12 months. However, there was a significant delay in TFOA with sipuleucel-T (HR=0.755; 95% CI: 0.579-0.985; P=0.038). Median TFOA for sipuleucel-T was 12.6, and 9.7 months for control, with 50.6% and 43.1% opioid-free at 12 months, respectively. Kaplan-Meier curves for both end points began to diverge at 6 months. CONCLUSIONS: Sipuleucel-T was associated with longer TFOA but not significantly longer TDRP. Both end points demonstrated evidence of a delayed treatment effect, consistent with an active immunotherapy.

A phase II trial of cisplatin (C), gemcitabine (G) and gefitinib for advanced urothelial tract carcinoma: results of Cancer and Leukemia Group B (CALGB) 90102.

BACKGROUND: This phase II trial (Cancer and Leukemia Group B 90102) sought to determine the efficacy of cisplatin, standard infusion of gemcitabine and gefitinib in patients with advanced urothelial carcinoma. PATIENTS AND METHODS: Eligible patients had previously untreated measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status of zero to two and creatinine clearance >50 ml/min. Treatment consisted of cisplatin 70 mg/m(2) day 1 and gemcitabine 1000 mg/m(2) on days 1 and 8 given every 3 weeks concurrent with gefitinib 500 mg/day orally for six cycles. Maintenance gefitinib 500 mg/day was continued for responding or stable disease. RESULTS: Fifty-four of 58 patients were assessable. Twelve patients (22%) had node-only disease, and 25 (46%) had an ECOG performance status of zero. There were 23 objective responses for an overall response rate of 42.6% [95% confidence interval (CI) 29.2% to 56.8%]. The median survival time was 15.1 months (95% CI 11.1-21.7 months) and the median time to progression was 7.4 months (95% CI 5.6-9.2 months). CONCLUSIONS: The combination of cisplatin, gemcitabine and gefitinib is well tolerated and active in advanced transitional cell carcinoma. The addition of gefitinib does not appear to improve response rate or survival in comparison to historical controls of cisplatin and gemcitabine alone.

Phase II study of bortezomib in patients with previously treated advanced urothelial tract transitional cell carcinoma: CALGB 90207.

BACKGROUND: There is no standard second-line treatment for advanced urothelial carcinoma (UC). Response rates to second-line chemotherapy for advanced UC are low and response duration is short. Bortezomib is a proteasome inhibitor with preclinical activity against UC. PATIENTS AND METHODS: Treatment consisted of bortezomib 1.3 mg/m(2) i.v. twice weekly for two consecutive weeks, followed by a 1-week break. The primary end point was objective response rate (complete response + partial response) by Response Evaluation Criteria in Solid Tumors criteria. Secondary end points included safety, toxicity, and progression-free and overall survival. RESULTS: In all, 25 patients with advanced UC previously treated with combination chemotherapy were enrolled in a multi-institutional single-arm trial from December 2003 through April 2005. Only 29% of patients had node-only metastases. Grade 3/4 drug-related toxic effects included thrombocytopenia (4%), anemia (8%), lymphopenia (8%), sensory neuropathy (6%), hyperglycemia (4%), hypernatremia (4%), fatigue (4%), neuropathic pain (6%), dehydration (4%), and vomiting (4%). No objective responses were observed [95% confidence interval (CI) = 0-12]. The median time to progression was 1.4 months (95% CI = 1.1-2.0 months), and the median survival time was 5.7 months (95% CI = 3.6-8.4 months). There were no treatment-related deaths. CONCLUSION: Although bortezomib is well tolerated, it does not have antitumor activity as second-line therapy in UC.

Androgen deprivation therapy in locally advanced and metastatic prostate cancer.

Numerous studies have been performed testing the efficacy of early androgen deprivation (AD) in patients with localized and locally advanced prostate cancer. A systematic review of recent publications that report on the use of AD in non-metastatic prostate cancer patients was performed. Recently published mature randomized trials of AD plus local therapy were evaluated plus 2 large datasets on the use of AD for patients with serologic relapse after local therapy. Four mature randomized studies demonstrate an overall survival benefit to the use of AD in conjunction with definitive local therapy (3 with radiation and 1 with surgery). One retrospective analysis suggests that AD administered at early after serologic progression improves overall survival, and one retrospective analysis shows a reduction in metastasis-free survival but has not yet shown an overall survival benefit. In virtually all analyses, patients with high-risk features benefited from early AD when compared to deferred therapy. Consideration of AD is therefore warranted early in the clinical course of high-risk patients.

Biodiversity in urban habitat patches.

We examined the biodiversity of urban habitats in Birmingham (England) using a combination of field surveys of plants and carabid beetles, genetic studies of four species of butterflies, modelling the anthropochorous nature of the floral communities and spatially explicit modelling of selected mammal species. The aim of the project was to: (i) understand the ecological characteristics of the biota of cities model, (ii) examine the effects of habitat fragment size and connectivity upon the ecological diversity and individual species distributions, (iii) predict biodiversity in cities, and (iv) analyse the extent to which the flora and fauna utilise the 'urban greenways' both as wildlife corridors and as habitats in their own right. The results suggest that cities provide habitats for rich and diverse range of plants and animals, which occur sometimes in unlikely recombinant communities. The studies on carabids and butterflies illustrated the relative importance of habitat quality on individual sites as opposed to site location within the conurbation. This suggests that dispersal for most of our urban species is not a limiting factor in population persistence, although elements of the woodland carabid fauna did appear to have some geographical structuring. Theoretical models suggested that dormice and water voles may depend on linear habitats for dispersal. The models also indicated that other groups, such as small and medium sized mammals, may use corridors, although field-based research did not provide any evidence to suggest that plants or invertebrates use urban greenways for dispersal. This finding indicates the importance of identifying a target species or group of species for urban greenways intended as dispersal routeways rather than as habitat in their own right. Their importance for most groups is rather that greenways provide a chain of different habitats permeating the urban environment. We suggest that planners can have a positive impact on urban biodiversity by slowing the pace of redevelopment and by not hurrying to tidy up and redevelop brownfield sites.

Kinetics of development and characteristics of antibodies induced in cancer patients against yeast expressed rDNA derived granulocyte macrophage colony stimulating factor (GM-CSF).

We have determined the presence and kinetics of granulocyte macrophage colony stimulating factor (GM-CSF) antibodies induced after repeated administration of a yeast expressed GM-CSF product in prostate cancer patients with minimal recurrent disease using a panel of assays for detection and characterization of antibodies. Results showed that all 15 prostate cancer patients treated with GM-CSF developed GM-CSF reactive antibodies during the course of therapy. Most patients (87%) developed GM-CSF reactive antibodies within 3 months while in other patients (13%), these antibodies were induced after additional cycles of GM-CSF treatment. For most patients, the timing of occurrence of these antibodies was the same regardless of whether the ELISA or surface plasmon resonance (SPR) assays were used for detection. However, in two patients, the recognition of GM-CSF reactive antibodies by SPR assays preceded their detection by ELISA. A significant number of patients (n=9, 60%) developed GM-CSF antibodies which neutralized the biological activity of GM-CSF in vitro in a cell-line based bioassay. These antibodies also recognized GM-CSF protein from different expression systems including the non-glycosylated protein from E. coli indicating that the antibody response is directed towards the amino acid backbone of the protein. A significant effect of GM-CSF antibodies on PSA modulation was not observed in this small cohort of patients despite an alteration in PSA levels in some treated patients. The study design used here did not allow conclusions regarding the relationship between neutralizing antibodies and the PSA levels which were used as a marker for clinical outcome. Implementation of a clinical strategy which permits monitoring for antibody development and for levels of a relevant pre-determined clinical marker at appropriate time-points is necessary for assessing the impact of antibody development on the therapeutic efficacy of the protein.

Immunogenicity of GM-CSF products in cancer patients following immunostimulatory therapy with GM-CSF.

There is a high risk of developing neutralising and non-neutralising antibodies when GM-CSF is used as an immunomodulatory agent in non-immunocompromised patients. The presence of neutralising antibodies may seriously hamper the clinical response of the patients. This must be taken into account when designing protocols if the biological activity of the exogenously administered GM-CSF is not to be impaired and the endogenous production of GM-CSF is not to be inactivated. Assessment of production of neutralising antibodies during cytokine therapy is important for predicting the clinical response to progressive therapy. Use of validated assays is imperative for evaluation of antibodies generated following therapy with a particular protein.

The evolving role of androgen deprivation therapy in the management of prostate cancer.

Androgen deprivation therapy (ADT) plays a central role in the management of prostate cancer. ADT is the mainstay of treatment for metastatic disease; the most common method is gonadal suppression via luteinizing hormone release hormone (LH) agonists, with or without antiandrogens. Antiandrogen monotherapy remains investigational, as is the appropriate role of 5alphareductase inhibition for prostate cancer. Intermittent ADT offers the promise of improved quality of life and reduced cost without a decrease found to date in oncologic efficacy. A growing menu of options exists for secondary androgen deprivation after disease progression on primary therapy: these include high-dose antiandrogens, estrogens, and adrenal androgen suppressants. ADT is being used with increasing frequency as primary monotherapy in patients with localized disease, but only small, nonrandomized studies of highly selected patients have been reported to date. Neoadjuvant ADT (NADT) has been demonstrated in prospective, multi-institutional trials to improve outcomes for patients with high-risk or locally advanced disease undergoing external-beam radiotherapy. Trials for patients with lower-risk, localized disease are still ongoing. Neoadjuvant therapy does not improve outcomes for patients with localized disease opting for radical prostatectomy (RP) and has not been well studied in association with brachytherapy. The side effects of ADT can be managed increasingly successfully; in particular, the introduction of zoledronate may reduce the impact of ADT-associated osteoporosis. Finally, contemporary practice pattern data suggest that use of ADT is increasing across patient risk groups, both in contexts where such therapy is well supported by current evidence and in others where it is not.

The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: a comparison to pamidronate.

Bisphosphonates are the treatment of choice for lytic bone lesions associated with breast cancer. In contrast, bone lesions associated with prostate cancer are predominately osteoblastic. Zoledonic acid (Zol) is a new-generation bisphosphonate that is approximately 2-3 orders of magnitude more potent than pamidronate (Pam) in preclinical models and has demonstrated clinical efficacy in patients with both lytic and blastic lesions. Zoledonic acid (4 mg via 15 min infusion) every 3-4 weeks was directly compared to Pam (90 mg via 2 hr infusion) in 767 patients with breast cancer and bone metastases. The primary endpoint was the proportion of patients experiencing a skeletal-related event (SRE) over 13 months. Zoledonic acid was as effective as Pam, and the proportion of Zol-treated patients with an SRE (42% in the hormonal therapy strata and 44% in the chemotherapy strata) was comparable to the original studies comparing Pam to placebo. Among 371 breast cancer patients receiving hormonal therapy, the proportion of patients with an SRE was 47% for Pam vs. 57% for placebo (P = 0.057), and among 380 patients treated with chemotherapy, the proportions with an SRE were 43% for Pam vs. 56% for placebo (P = 0.008) at 12 months. Zoledronic acid (4 mg) has been compared to placebo in a randomized Phase III trial involving 422 men with hormone-refractory prostate cancer metastatic to bone. Zoledonic acid demonstrated a significant advantage over placebo for median time to first SRE (median not reached for Zol vs. 321 days for placebo; P = 0.011), the proportion of patients with an SRE over 15 months (33 vs. 44% for placebo; P = 0.021), and mean skeletal morbidity rate (number of SREs/time, 0.08 vs. 1.49 for placebo; P = 0.006). In addition, the effects of Zol were apparent early. At 3 months, only 12% of Zol-treated patients had an SRE vs. 23% for placebo (P = 0.003), and at 6 months, the proportions were 21 vs. 31% for placebo (P = 0.025). In contrast, a previous study of Pam in 236 prostate cancer patients found that Pam was no more effective than placebo in reducing bone pain or SREs over 6 months. In these studies, Zol was well tolerated with a safety profile similar to other IV bisphosphonates. In conclusion, Zol is the first bisphosphonate to demonstrate efficacy in both lytic and blastic disease. The unique properties of this novel agent should be further explored in future clinical trials.