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.

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).

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.

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.

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).

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.

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.

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.

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).

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 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.

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.

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.

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.

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 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.

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.

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.

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.