Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial.

BACKGROUND: The interim analysis of the ENZAMET trial of testosterone suppression plus either enzalutamide or standard nonsteroidal antiandrogen therapy showed an early overall survival benefit with enzalutamide. Here, we report the planned primary overall survival analysis, with the aim of defining the benefit of enzalutamide treatment in different prognostic subgroups (synchronous and metachronous high-volume or low-volume disease) and in those who received concurrent docetaxel. METHODS: ENZAMET is an international, open-label, randomised, phase 3 trial conducted at 83 sites (including clinics, hospitals, and university centres) in Australia, Canada, Ireland, New Zealand, the UK, and the USA. Eligible participants were males aged 18 years or older with metastatic, hormone-sensitive prostate adenocarcinoma evident on CT or bone scanning with 99mTc and an Eastern Cooperative Oncology Group performance status score of 0-2. Participants were randomly assigned (1:1), using a centralised web-based system and stratified by volume of disease, planned use of concurrent docetaxel and bone antiresorptive therapy, comorbidities, and study site, to receive testosterone suppression plus oral enzalutamide (160 mg once per day) or a weaker standard oral non-steroidal antiandrogen (bicalutamide, nilutamide, or flutamide; control group) until clinical disease progression or prohibitive toxicity. Testosterone suppression was allowed up to 12 weeks before randomisation and for up to 24 months as adjuvant therapy. Concurrent docetaxel (75 mg/m2 intravenously) was allowed for up to six cycles once every 3 weeks, at the discretion of participants and physicians. The primary endpoint was overall survival in the intention-to-treat population. This planned analysis was triggered by reaching 470 deaths. This study is registered with ClinicalTrials.gov, NCT02446405, ANZCTR, ACTRN12614000110684, and EudraCT, 2014-003190-42. FINDINGS: Between March 31, 2014, and March 24, 2017, 1125 participants were randomly assigned to receive non-steroidal antiandrogen (n=562; control group) or enzalutamide (n=563). The median age was 69 years (IQR 63-74). This analysis was triggered on Jan 19, 2022, and an updated survival status identified a total of 476 (42%) deaths. After a median follow-up of 68 months (IQR 67-69), the median overall survival was not reached (hazard ratio 0·70 [95% CI 0·58-0·84]; p<0·0001), with 5-year overall survival of 57% (0·53-0·61) in the control group and 67% (0·63-0·70) in the enzalutamide group. Overall survival benefits with enzalutamide were consistent across predefined prognostic subgroups and planned use of concurrent docetaxel. The most common grade 3-4 adverse events were febrile neutropenia associated with docetaxel use (33 [6%] of 558 in the control group vs 37 [6%] of 563 in the enzalutamide group), fatigue (four [1%] vs 33 [6%]), and hypertension (31 [6%] vs 59 [10%]). The incidence of grade 1-3 memory impairment was 25 (4%) versus 75 (13%). No deaths were attributed to study treatment. INTERPRETATION: The addition of enzalutamide to standard of care showed sustained improvement in overall survival for patients with metastatic hormone-sensitive prostate cancer and should be considered as a treatment option for eligible patients. FUNDING: Astellas Pharma.

Stereotactic Radiotherapy and Short-course Pembrolizumab for Oligometastatic Renal Cell Carcinoma-The RAPPORT Trial.

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is an option for oligometastatic clear cell renal cell carcinoma (ccRCC) but is limited by a lack of prospective clinical trial data. OBJECTIVE: The RAPPORT trial evaluated the safety and efficacy of total metastatic irradiation followed by short-course anti-programmed death receptor-1 immunotherapy in patients with oligometastatic ccRCC. DESIGN SETTING, AND PARTICIPANTS: RAPPORT was a single-arm multi-institutional phase I/II trial (NCT02855203). Patients with two or fewer lines of prior systemic therapy and one to five oligometastases from ccRCC were eligible. INTERVENTION: A single fraction of 20 Gy SABR (or if not feasible, ten fractions of 3 Gy) was given to all metastatic sites, followed by pembrolizumab 200 mg administered Q3W for eight cycles. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The endpoints were adverse events (AEs), disease control rate (DCR) for at least 6 mo, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The Kaplan-Meier method was used for time-to-event endpoints. Freedom from local progression (FFLP) was assessed per lesion adding patient as a cluster effect. RESULTS AND LIMITATIONS: Thirty evaluable patients, with a median age of 62 yr, were enrolled. The median follow-up was 28 mo. There were 44% of patients with intermediate-risk and 56% with favorable-risk disease. Eighty-three oligometastases were irradiated (median three per patient): eight adrenal, 11 bone, 43 lung, 12 lymph node, and nine soft tissue. Four patients (13%) had grade 3 treatment-related AEs: pneumonitis (n = 2), dyspnea (n = 1), and elevated alkaline phosphatase/alanine transaminase (n = 1). There were no grade 4 or 5 AEs. FFLP at 2 yr was 92%. ORR was 63% and DCR was 83%. Estimated 1- and 2-yr OS was 90% and 74%, respectively, and PFS was 60% and 45%, respectively. Limitations include a single-arm design and selected patient population. CONCLUSIONS: SABR and short-course pembrolizumab in oligometastatic ccRCC is well tolerated, with excellent local control. Durable responses and encouraging PFS were observed, warranting further investigation. PATIENT SUMMARY: The RAPPORT trial investigated the combination of high-dose precision radiotherapy and a short course of immunotherapy in patients with low-volume metastatic kidney cancer. We found that this treatment regimen was well tolerated, with excellent cancer control in sites of known disease. A proportion of patients were free from cancer relapse in the longer term, and these encouraging findings warrant further investigation.

Value of Early Circulating Tumor Cells Dynamics to Estimate Docetaxel Benefit in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients.

Circulating tumor cell (CTC) enumeration and changes following treatment have been demonstrated to be superior to PSA response in determining mCRPC outcome in patients receiving AR signaling inhibitors but not taxanes. We carried out a pooled analysis of two prospective studies in mCRPC patients treated with docetaxel. CTCs were measured at baseline and 3-6 weeks post treatment initiation. Cox regression models were constructed to compare 6-month radiographical progression-free survival (rPFS), CTCs and PSA changes predicting outcome. Among the subjects, 80 and 52 patients had evaluable baseline and post-treatment CTC counts, respectively. A significant association of higher baseline CTC count with worse overall survival (OS), PFS and time to PSA progression (TTPP) was observed. While CTC response at 3-6 weeks (CTC conversion (from ≥5 to <5 CTCs), CTC30 (≥30% decline in CTC) or CTC0 (decline to 0 CTC)) and 6-month rPFS were significantly associated with OS (all p < 0.005), the association was not significant for PSA30 or PSA50 response. CTC and PSA response were discordant in over 50% of cases, with outcome driven by CTC response in these patients. The c-index values for OS were superior for early CTC changes compared to PSA response endpoints, and similar to 6-month rPFS. Early CTC declines were good predictors of improved outcomes in mCRPC patients treated with docetaxel in this small study, offering a superior and/or earlier estimation of docetaxel benefit in comparison to PSA or rPFS that merits further confirmation in larger studies.

Overall Survival of Men with Metachronous Metastatic Hormone-sensitive Prostate Cancer Treated with Enzalutamide and Androgen Deprivation Therapy.

Men who initially present with localized prostate cancer and later develop metachronous metastases have a better prognosis than men with de novo metastatic disease and often have a low burden of disease on conventional imaging. Some have disease amenable to metastasis-directed therapy for lymph node or bone metastases, a strategy used by some because no documented overall survival (OS) benefit of combination systemic therapy in this setting. We report data for patients prospectively classified as "M0" at initial diagnosis from the interim analysis of the ENZAMET trial, with 34 mo of median follow-up for survivors. A total of 312 (28%) of the 1125 enrolled patients were classified as M0 at diagnosis, and 205 (66%) of the 312 patients had low-volume disease at study entry as per the CHAARTED criteria. The hazard ratio for OS, that is, HR(OS), was 0.56 (95% confidence interval [CI]: 0.29-1.06) with the addition of enzalutamide for all patients with metachronous metastatic hormone-sensitive prostate cancer, and for the low-volume subset the HR(OS) was 0.40 (95% CI: 0.16-0.97). The 3-yr OS was 83% without and 89% with enzalutamide for all patients with metachronous metastases, and 83% and 92%, respectively, for the low-volume subset. Intensification of hormonal therapy should strongly be considered for these men. PATIENT SUMMARY: Many men present with prostate cancer that has spread to distant sites beyond the prostate gland years after their initial diagnosis and treatment, while others have distant spread at the time the cancer is diagnosed. On average, men whose cancer comes back years after the initial diagnosis often survive much longer than men whose cancer has been found to spread to distant sites when it is first diagnosed. In this report, we demonstrate strong evidence for the first time that the survival of men whose cancer comes back years later is improved when drugs such as enzalutamide or apalutamide are added to testosterone suppression in this setting.

Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer.

BACKGROUND: Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival in men with castration-resistant prostate cancer. It is not known whether adding enzalutamide to testosterone suppression, with or without early docetaxel, will improve survival in men with metastatic, hormone-sensitive prostate cancer. METHODS: In this open-label, randomized, phase 3 trial, we assigned patients to receive testosterone suppression plus either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy (standard-care group). The primary end point was overall survival. Secondary end points included progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events. RESULTS: A total of 1125 men underwent randomization; the median follow-up was 34 months. There were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group (hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.86; P = 0.002). Kaplan-Meier estimates of overall survival at 3 years were 80% (based on 94 events) in the enzalutamide group and 72% (based on 130 events) in the standard-care group. Better results with enzalutamide were also seen in PSA progression-free survival (174 and 333 events, respectively; hazard ratio, 0.39; P<0.001) and in clinical progression-free survival (167 and 320 events, respectively; hazard ratio, 0.40; P<0.001). Treatment discontinuation due to adverse events was more frequent in the enzalutamide group than in the standard-care group (33 events and 14 events, respectively). Fatigue was more common in the enzalutamide group; seizures occurred in 7 patients in the enzalutamide group (1%) and in no patients in the standard-care group. CONCLUSIONS: Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel. (Funded by Astellas Scientific and Medical Affairs and others; ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684; ClinicalTrials.gov number, NCT02446405; and EU Clinical Trials Register number, 2014-003190-42.).

Characterization of the ERG-regulated Kinome in Prostate Cancer Identifies TNIK as a Potential Therapeutic Target.

Approximately 50% of prostate cancers harbor the TMPRSS2:ERG fusion, resulting in elevated expression of the ERG transcription factor. Despite the identification of this subclass of prostate cancers, no personalized therapeutic strategies have achieved clinical implementation. Kinases are attractive therapeutic targets as signaling networks are commonly perturbed in cancers. The impact of elevated ERG expression on kinase signaling networks in prostate cancer has not been investigated. Resolution of this issue may identify novel therapeutic approaches for ERG-positive prostate cancers. In this study, we used quantitative mass spectrometry-based kinomic profiling to identify ERG-mediated changes to cellular signaling networks. We identified 76 kinases that were differentially expressed and/or phosphorylated in DU145 cells engineered to express ERG. In particular, the Traf2 and Nck-interacting kinase (TNIK) was markedly upregulated and phosphorylated on multiple sites upon ERG overexpression. Importantly, TNIK has not previously been implicated in prostate cancer. To validate the clinical relevance of these findings, we characterized expression of TNIK and TNIK phosphorylated at serine 764 (pS764) in a localized prostate cancer patient cohort and showed that nuclear enrichment of TNIK (pS764) was significantly positively correlated with ERG expression. Moreover, TNIK protein levels were dependent upon ERG expression in VCaP cells and primary cells established from a prostate cancer patient-derived xenograft. Furthermore, reduction of TNIK expression and activity by silencing TNIK expression or using the TNIK inhibitor NCB-0846 reduced cell viability, colony formation and anchorage independent growth. Therefore, TNIK represents a novel and actionable therapeutic target for ERG-positive prostate cancers that could be exploited to develop new treatments for these patients.

E6AP promotes prostate cancer by reducing p27 expression.

Prostate cancer (PC) is the most common cancer in men. Elevated levels of E3 ligase, E6-Associated Protein (E6AP) were previously linked to PC, consistent with increased protein expression in a subset of PC patients. In cancers, irregular E3 ligase activity drives proteasomal degradation of tumor suppressor proteins. Accordingly, E3 ligase inhibitors define a rational therapy to restore tumor suppression. The relevant tumor suppressors targeted by E6AP in PC are yet to be fully identified. In this study we show that p27, a key cell cycle regulator, is a target of E6AP in PC. Down regulation of E6AP increases p27 expression and enhances its nuclear accumulation in PC. We demonstrate that E6AP regulates p27 expression by inhibiting its transcription in an E2F1-dependent manner. Concomitant knockdown of E6AP and p27 partially restores PC cell growth, supporting the contribution of p27 to the overall effect of E6AP on prostate tumorigenesis. Overall, we unravelled the E6AP-p27 axis as a new promoter of PC, exposing an attractive target for therapy through the restoration of tumor suppression.

Circulating tumor cell biomarker panel as an individual-level surrogate for survival in metastatic castration-resistant prostate cancer.

PURPOSE: Trials in castration-resistant prostate cancer (CRPC) need new clinical end points that are valid surrogates for survival. We evaluated circulating tumor cell (CTC) enumeration as a surrogate outcome measure. PATIENTS AND METHODS: Examining CTCs alone and in combination with other biomarkers as a surrogate for overall survival was a secondary objective of COU-AA-301, a multinational, randomized, double-blind phase III trial of abiraterone acetate plus prednisone versus prednisone alone in patients with metastatic CRPC previously treated with docetaxel. The biomarkers were measured at baseline and 4, 8, and 12 weeks, with 12 weeks being the primary measure of interest. The Prentice criteria were applied to test candidate biomarkers as surrogates for overall survival at the individual-patient level. RESULTS: A biomarker panel using CTC count and lactate dehydrogenase (LDH) level was shown to satisfy the four Prentice criteria for individual-level surrogacy. Twelve-week surrogate biomarker data were available for 711 patients. The abiraterone acetate plus prednisone and prednisone-alone groups demonstrated a significant survival difference (P = .034); surrogate distribution at 12 weeks differed by treatment (P < .001); the discriminatory power of the surrogate to predict mortality was high (weighted c-index, 0.81); and adding the surrogate to the model eliminated the treatment effect on survival. Overall, 2-year survival of patients with CTCs < 5 (low risk) versus patients with CTCs ≥ 5 cells/7.5 mL of blood and LDH > 250 U/L (high risk) at 12 weeks was 46% and 2%, respectively. CONCLUSION: A biomarker panel containing CTC number and LDH level was shown to be a surrogate for survival at the individual-patient level in this trial of abiraterone acetate plus prednisone versus prednisone alone for patients with metastatic CRPC. Additional trials are ongoing to validate the findings.

Phase II randomized study of figitumumab plus docetaxel and docetaxel alone with crossover for metastatic castration-resistant prostate cancer.

PURPOSE: Figitumumab is a human IgG2 monoclonal antibody targeting insulin-like growth factor 1 receptor (IGF-1R), with antitumor activity in prostate cancer. This phase II trial randomized chemotherapy-naïve men with progressing castration-resistant prostate cancer to receive figitumumab every 3 weeks with docetaxel/prednisone (Arm A) or docetaxel/prednisone alone (Arm B1). At progression on Arm B1, patients could cross over to the combination (Arm B2). EXPERIMENTAL DESIGN: Prostate-specific antigen (PSA) response was the primary endpoint; response assessment on the two arms was noncomparative and tested separately; H0 = 0.45 versus HA = 0.60 (α = 0.05; ß = 0.09) for Arm A; H0 = 0.05 versus HA = 0.20 (α = 0.05, ß = 0.10) for Arm B2. A comparison of progression-free survival (PFS) on Arms A and B1 was planned. RESULTS: A total of 204 patients were randomized and 199 treated (Arm A: 97; Arm B1: 102); 37 patients crossed over to Arm B2 (median number of cycles started: Arm A = 8; B1 = 8; B2 = 4). PSA responses occurred in 52% and 60% of Arms A and B1, respectively; the primary PSA response objective in Arm A was not met. Median PFS was 4.9 and 7.9 months, respectively (HR = 1.44; 95% confidence interval, 1.06-1.96). PSA response rate was 28% in Arm B2. The figitumumab combination appeared more toxic, with more treatment-related grade 3/4 adverse events (75% vs. 56%), particularly hyperglycemia, diarrhea, and asthenia, as well as treatment-related serious adverse events (41% vs. 15%), and all-causality grade 5 adverse events (18% vs. 8%). CONCLUSION: IGF-1R targeting may merit further evaluation in this disease in selected populations, but combination with docetaxel is not recommended.

Utilizing pharmacokinetics/pharmacodynamics modeling to simultaneously examine free CCL2, total CCL2 and carlumab (CNTO 888) concentration time data.

The chemokine ligand 2 (CCL2) promotes angiogenesis, tumor proliferation, migration, and metastasis. Carlumab is a human IgG1κ monoclonal antibody with high CCL2 binding affinity. Pharmacokinetic/pharmacodynamic data from 21 cancer patients with refractory tumors were analyzed. The PK/PD model characterized the temporal relationships between serum concentrations of carlumab, free CCL2, and the carlumab-CCL2 complex. Dose-dependent increases in total CCL2 concentrations were observed and were consistent with shifting free CCL2. Free CCL2 declined rapidly after the initial carlumab infusion, returned to baseline within 7 days, and increased to levels greater than baseline following subsequent doses. Mean predicted half-lives of carlumab and carlumab-CCL2 complex were approximately 2.4 days and approximately 1 hour for free CCL2. The mean dissociation constant (KD ), 2.4 nM, was substantially higher than predicted by in vitro experiments, and model-based simulation revealed this was the major factor hindering the suppression of free CCL2 at clinically viable doses.

The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) is implicated in DNA repair and transcription regulation. Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. We investigated the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity of niraparib. METHODS: In a phase 1 dose-escalation study, we enrolled patients with advanced solid tumours at one site in the UK and two sites in the USA. Eligible patients were aged at least 18 years; had a life expectancy of at least 12 weeks; had an Eastern Cooperative Oncology Group performance status of 2 or less; had assessable disease; were not suitable to receive any established treatments; had adequate organ function; and had discontinued any previous anticancer treatments at least 4 weeks previously. In part A, cohorts of three to six patients, enriched for BRCA1 and BRCA2 mutation carriers, received niraparib daily at ten escalating doses from 30 mg to 400 mg in a 21-day cycle to establish the maximum tolerated dose. Dose expansion at the maximum tolerated dose was pursued in 15 patients to confirm tolerability. In part B, we further investigated the maximum tolerated dose in patients with sporadic platinum-resistant high-grade serous ovarian cancer and sporadic prostate cancer. We obtained blood, circulating tumour cells, and optional paired tumour biopsies for pharmacokinetic and pharmacodynamic assessments. Toxic effects were assessed by common toxicity criteria and tumour responses ascribed by Response Evaluation Criteria in Solid Tumors (RECIST). Circulating tumour cells and archival tumour tissue in prostate patients were analysed for exploratory putative predictive biomarkers, such as loss of PTEN expression and ETS rearrangements. This trial is registered with ClinicalTrials.gov, NCT00749502. FINDINGS: Between Sept 15, 2008, and Jan 14, 2011, we enrolled 100 patients: 60 in part A and 40 in part B. 300 mg/day was established as the maximum tolerated dose. Dose-limiting toxic effects reported in the first cycle were grade 3 fatigue (one patient given 30 mg/day), grade 3 pneumonitis (one given 60 mg/day), and grade 4 thrombocytopenia (two given 400 mg/day). Common treatment-related toxic effects were anaemia (48 patients [48%]), nausea (42 [42%]), fatigue (42 [42%]), thrombocytopenia (35 [35%]), anorexia (26 [26%]), neutropenia (24 [24%]), constipation (23 [23%]), and vomiting (20 [20%]), and were predominantly grade 1 or 2. Pharmacokinetics were dose proportional and the mean terminal elimination half-life was 36·4 h (range 32·8-46·0). Pharmacodynamic analyses confirmed PARP inhibition exceeded 50% at doses greater than 80 mg/day and antitumour activity was documented beyond doses of 60 mg/day. Eight (40% [95% CI 19-64]) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% [7-93]) of four mutation carriers with breast cancer. Antitumour activity was also reported in sporadic high-grade serous ovarian cancer, non-small-cell lung cancer, and prostate cancer. We recorded no correlation between loss of PTEN expression or ETS rearrangements and measures of antitumour activity in patients with prostate cancer. INTERPRETATION: A recommended phase 2 dose of 300 mg/day niraparib is well tolerated. Niraparib should be further assessed in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARP-mediated transcription in cancer. FUNDING: Merck Sharp and Dohme.

A first-in-human, first-in-class, phase I study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 in patients with solid tumors.

PURPOSE: The CC-chemokine ligand 2 (CCL2) is highly expressed in various malignancies and promotes carcinogenesis. Blocking CCL2 has preclinical antitumor activity. A phase 1 trial of carlumab (CNTO 888), a human anti-CCL2 IgG1κ mAb, was conducted to evaluate the safety, tolerability, pharmacokinetic-pharmacodynamic profile, and antitumor activity. METHODS: Patients with advanced solid malignancy received escalating doses of carlumab 0.3, 1, 3, 10, or 15 mg/kg by 90-min intravenous infusion on days 1, 28, and every 2 weeks thereafter (dose escalation) or 10 or 15 mg/kg every 2 weeks (dose-expansion). Pharmacodynamic assessments were also performed. RESULTS: Forty-four patients received 206 doses of carlumab. MTD was not established. Carlumab-related adverse events included grade 1-2 fatigue (9 %), nausea (7 %), headache (7 %), vomiting (5 %), and pruritus (5 %). The recommended phase II dose was 15 mg/kg every 2 weeks. Carlumab concentrations declined bi-exponentially with a terminal half-life of 6.6-9.6 days. Free CCL2 was transiently suppressed, while total CCL2 increased dose-dependently >1,000-fold post-treatment. A patient with ovarian cancer and a patient with prostate cancer achieved CA125 and PSA reductions of >50 % and RECIST SD for 10.5 and 5 months, respectively. Two other patients had RECIST SD for 7.2 and 15.7 months. CONCLUSIONS: Carlumab was well tolerated with evidence of transient free CCL2 suppression and preliminary antitumor activity.

Prognostic value of blood mRNA expression signatures in castration-resistant prostate cancer: a prospective, two-stage study.

BACKGROUND: Biomarkers are urgently needed to dissect the heterogeneity of prostate cancer between patients to improve treatment and accelerate drug development. We analysed blood mRNA expression arrays to identify patients with metastatic castration-resistant prostate cancer with poorer outcome. METHODS: Whole blood was collected into PAXgene tubes from patients with castration-resistant prostate cancer and patients with prostate cancer selected for active surveillance. In stage I (derivation set), patients with castration-resistant prostate cancer were used as cases and patients under active surveillance were used as controls. These patients were recruited from The Royal Marsden Hospital NHS Foundation Trust (Sutton, UK) and The Beatson West of Scotland Cancer Centre (Glasgow, UK). In stage II (validation-set), patients with castration-resistant prostate cancer recruited from the Memorial Sloan-Kettering Cancer Center (New York, USA) were assessed. Whole-blood RNA was hybridised to Affymetrix U133plus2 microarrays. Expression profiles were analysed with Bayesian latent process decomposition (LPD) to identify RNA expression profiles associated with castration-resistant prostate cancer subgroups; these profiles were then confirmed by quantative reverse transcriptase (qRT) PCR studies and correlated with overall survival in both the test-set and validation-set. FINDINGS: LPD analyses of the mRNA expression data divided the evaluable patients in stage I (n=94) into four groups. All patients in LPD1 (14 of 14) and most in LPD2 (17 of 18) had castration-resistant prostate cancer. Patients with castration-resistant prostate cancer and those under active surveillance comprised LPD3 (15 of 31 castration-resistant prostate cancer) and LDP4 (12 of 21 castration-resistant prostate cancer). Patients with castration-resistant prostate cancer in the LPD1 subgroup had features associated with worse prognosis and poorer overall survival than patients with castration-resistant prostate cancer in other LPD subgroups (LPD1 overall survival 10·7 months [95% CI 4·1-17·2] vs non-LPD1 25·6 months [18·0-33·4]; p<0·0001). A nine-gene signature verified by qRT-PCR classified patients into this LPD1 subgroup with a very low percentage of misclassification (1·2%). The ten patients who were initially unclassifiable by the LPD analyses were subclassified by this signature. We confirmed the prognostic utility of this nine-gene signature in the validation castration-resistant prostate cancer cohort, where LPD1 membership was also associated with worse overall survival (LPD1 9·2 months [95% CI 2·1-16·4] vs non-LPD1 21·6 months [7·5-35·6]; p=0·001), and remained an independent prognostic factor in multivariable analyses for both cohorts. INTERPRETATION: Our results suggest that whole-blood gene profiling could identify gene-expression signatures that stratify patients with castration-resistant prostate cancer into distinct prognostic groups. FUNDING: AstraZeneca, Experimental Cancer Medicine Centre, Prostate Cancer Charity, Prostate Cancer Foundation.

PARP inhibitors: mechanism of action and their potential role in the prevention and treatment of cancer.

The use of poly(ADP-ribose) polymerase (PARP) inhibitors provided proof-of-concept for a synthetic lethal anti-cancer strategy as a result of their efficacy and favourable toxicity profile in BRCA1/2 mutation carriers. Efforts are underway to identify a broader group of patients with genomic susceptibility that may benefit from these agents. In an endeavour to enhance anti-tumour effects, PARP inhibitors have been combined with traditional cytotoxic therapy and radiotherapy; however, optimization of dosing schedules for these combination regimens remains key to maximizing benefit whilst mitigating the potential for increased toxicity. With ongoing clinical experience of PARP inhibition, mechanisms of resistance to these therapies are being elucidated and specific challenges to long-term administration of these drugs will need to be addressed. Development of robust predictive biomarkers of response for optimal patient selection and rational combination strategies must be pursued if the full potential of these agents is to be realized.

The emerging role of poly(ADP-Ribose) polymerase inhibitors in cancer treatment.

Poly(ADP-ribose) polymerase (PARP) is a critical DNA repair enzyme involved in DNA single-strand break repair via the base excision repair pathway. PARP inhibitors have been shown to sensitize tumors to DNA-damaging agents and to also selectively kill homologous recombination repair-defective cancers, such as those arising in BRCA1 and BRCA2 mutation carriers. Recent proof-of-concept clinical studies have demonstrated the safety and substantial antitumor activity of the PARP inhibitor, olaparib in BRCA1/2 mutation carriers, highlighting the wide therapeutic window that can be achieved with this synthetic lethal strategy. Likewise, the PARP inhibitor, BSI-201, in combination with carboplatin and gemcitabine have produced promising results in "triple-negative" breast cancers. There are also currently numerous other PARP inhibitors in clinical development. The potential broader therapeutic application of these approaches to a wide range of sporadic tumors harboring specific defects in the homologous recombination repair pathway has generated a great deal of excitement within the oncology community. This review discusses the rationale for targeting PARP and details the strategies and challenges involved in the clinical development of such inhibitors and their future potential applications in cancer medicine.

HGF/c-MET targeted therapeutics: novel strategies for cancer medicine.

The hepatocyte growth factor/mesenchymal-epithelial transition factor (HGF/c-MET) receptor tyrosine kinase (RTK) pathway plays a pleotropic role in cell proliferation, migration, invasion, angiogenesis and survival. Although it has critical physiological functions in embryonic development and tissue repair, this signaling cascade is frequently deregulated in a wide range of tumors. Aberrant HGF/c-MET signaling, driven by various mechanisms, including constitutive activation and over-expression, has multifunctional effects in oncogenesis and is implicated in the acquisition of an aggressive phenotype with metastatic potential. The central role of c-MET activity in cancer progression, as well as disparities between quiescent HGF/c-MET signaling in normal tissue and overexpression in tumor may provide a degree of tumor selectivity for therapeutic intervention, making HGF or c-MET inhibition an attractive proposition in oncology. This review focuses on the underlying oncogenic role of aberrant HGF/c-MET signaling in malignant progression, as well as recent preclinical and clinical data on the different strategies employed in inhibiting HGF/c-MET function.

Baseline circulating tumor cell counts significantly enhance a prognostic score for patients participating in phase I oncology trials.

BACKGROUND: High circulating tumor cell (CTC) counts are associated with poor prognosis in several cancers. Enrollment of patients on phase I oncology trials requires a careful assessment of the potential risks and benefits. Many patients enrolled on such trials using established eligibility criteria have a short life expectancy and are less likely to benefit from trial participation. We hypothesized that the incorporation of CTC counts might improve patient selection for phase I trials. METHODS: This retrospective analysis evaluated patients who had baseline CTCs enumerated prior to their starting on a phase I trial. CTCs were enumerated using the CellSearch System. RESULTS: Between January 2006 and December 2009 a total of 128 patients enrolled in phase I trials had CTC counts evaluated. Higher CTC counts as a continuous variable independently correlated with risk of death in this patient population (P = 0.006). A multivariate point-based risk model was generated using CTCs as a dichotomous variable (≥3 or <3), and incorporated other established prognostic factors, including albumin <35 g/L, lactate dehydrogenase greater than upper limit of normal, and >2 metastatic sites. Comparison of receiver operating characteristic curves demonstrated that the addition of baseline CTC counts improved the performance of the prospectively validated Royal Marsden Hospital phase I prognostic score, which now identifies three risk groups (P < 0.0001): good prognosis [score 0-1, median overall survival (OS) 63.7 weeks], intermediate prognosis (score 2-3, median OS 37.3 weeks), and poor prognosis (score 4, median OS 13.4 weeks). CONCLUSION: CTC enumeration improved the performance of a validated prognostic score to help select patients for phase I oncology trials.

Poly(ADP-ribose) polymerase (PARP) inhibitors: Exploiting a synthetic lethal strategy in the clinic.

Poly(ADP-ribose) polymerase (PARP) is an attractive antitumor target because of its vital role in DNA repair. The homologous recombination (HR) DNA repair pathway is critical for the repair of DNA double-strand breaks and HR deficiency leads to a dependency on error-prone DNA repair mechanisms, with consequent genomic instability and oncogenesis. Tumor-specific HR defects may be exploited through a synthetic lethal approach for the application of anticancer therapeutics, including PARP inhibitors. This theory proposes that targeting genetically defective tumor cells with a specific molecular therapy that inhibits its synthetic lethal gene partner should result in selective tumor cell killing. The demonstration of single-agent antitumor activity and the wide therapeutic index of PARP inhibitors in BRCA1 and BRCA2 mutation carriers with advanced cancers provide strong evidence for the clinical application of this approach. Emerging data also indicate that PARP inhibitors may be effective in sporadic cancers bearing HR defects, supporting a substantially wider role for PARP inhibitors. Drugs targeting this enzyme are now in pivotal clinical trials in patients with sporadic cancers. In this article, the evidence supporting this antitumor synthetic lethal strategy with PARP inhibitors is reviewed, evolving resistance mechanisms and potential molecular predictive biomarker assays are discussed, and the future development of these agents is envisioned.

Envisioning the future of early anticancer drug development.

The development of novel molecularly targeted cancer therapeutics remains slow and expensive with many late-stage failures. There is an urgent need to accelerate this process by improving early clinical anticancer drug evaluation through modern and rational trial designs that incorporate predictive, pharmacokinetic, pharmacodynamic, pharmacogenomic and intermediate end-point biomarkers. In this article, we discuss current approaches and propose strategies that will potentially maximize benefit to patients and expedite the regulatory approvals of new anticancer drugs.

Poly(ADP-ribose) polymerase inhibitors in cancer treatment: a clinical perspective.

Inbuilt mechanisms of DNA surveillance and repair are integral to the maintenance of genomic stability. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that plays a critical role in DNA damage response processes. PARP inhibition has been successfully employed as a novel therapeutic strategy to enhance the cytotoxic effects of DNA-damaging agents. We have shown that PARP inhibition has substantial single agent antitumour activity with a wide therapeutic index in homologous DNA repair-defective tumours such as those arising in BRCA1 and BRCA2 mutation carriers. This is the first successful clinical application of a synthetic lethal approach to targeting cancer. Exploitation of defects in DNA repair pathways through targeted inhibition of salvage repair pathways is an exciting anticancer approach, with potentially broad clinical applicability. Several PARP inhibitors are now in clinical development. This review outlines the biological function and rationale of targeting PARP, details pre-clinical and clinical data and discusses the promises and challenges involved in developing these antitumour agents.