The changing face of cancer therapeutics improved : outcome and decreased toxicity with Molecular Targeted Drugs

The treatment of patients with cancer has largely involved the administration of cytotoxic drugs with narrow therapeutic indices, with little selectivity for cancer cells over normal proliferating cells. The primary exception to this has been the successful administration of hormonal manipulation to treat breast and prostate malignancies. The development of hormonal manipulation arose from the observation by Sir George Beatson that breast carcinomas improved after bilateral oophorectomy. This led to the use of Tamoxifen and more recently aromatase inhibitors and oestrogen receptor antagonists. These targeted therapeutics are characterised by their ability to induce selective tumour cell death and achieve patient benefit with low toxicity, and have had a significant impact on the outcome of patients with early and advanced oestrogen receptor positive breast cancer. Further advances in the understanding of tumour cell biology, the sequencing of the human genome, and the characterisation of the molecular differences between malignant and normal cells have, over the past two decades, resulted in the identification of a large number of critically important molecular targets. As with the identification of the importance of oestrogens and the oestrogen receptor, this has accelerated the development of molecularly targeted therapeutics and is rapidly revolutionising cancer medicine (Table 1). This brief review will describe some of the most important advances achieved and will attempt to predict what future cancer therapeutics will entail.peer-reviewe

Macrophage Inflammatory Protein-1&alpha: An Inhibitor of Clonogenic Epidermal Keratinocyte Proliferation

Chemokines display a wide range of diverse functions and MIP-1alpha is no exception. It is not only a potent inflammatory molecule but also an inhibitor of primitive haemopoietic cell proliferation. The studies described in this thesis focus on the activity of MIP-1alpha on keratinocyte proliferation. These experiments have shown that a pure form of MIP-1alpha, derived from COS 7 cells by transient transfection, inhibits the proliferation of clonogenic human epidermal keratinocytes in vitro. This activity is fully reversible by specific anti- MIP-1alpha polyclonal antibodies. Despite this, the pure bacterial recombinant preparation of MIP-1alpha is largely inactive. In order to investigate this discrepancy, studies analysing the difference between these two MIP-1alpha preparations have been carried out. These studies suggest that the activation of the keratinocyte inhibitory function of MIP-1alpha results through a subtle structural modification which may involve the truncation of the amino-terminal amino acids. The potential role of MIP-1alpha in epithelial tissues in vivo is also discussed

Chromatin to Clinic: The Molecular Rationale for PARP1 Inhibitor Function.

Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors were recently shown to have potential clinical impact in a number of disease settings, particularly as related to cancer therapy, treatment for cardiovascular dysfunction, and suppression of inflammation. The molecular basis for PARP1 inhibitor function is complex, and appears to depend on the dual roles of PARP1 in DNA damage repair and transcriptional regulation. Here, the mechanisms by which PARP-1 inhibitors elicit clinical response are discussed, and strategies for translating the preclinical elucidation of PARP-1 function into advances in disease management are reviewed

Cabazitaxel shows a consistently greater survival benefit compared to mitoxantrone in patients with mCRPC

Cel. Niniejsza analiza — wtórna do badania TROPIC — ma na celu ocenę czasu przeżycia całkowitego (overall survival, OS) po zastosowaniu kabazytakselu w podgrupach chorych, u których od początku nie uzyskano odpowiedzi na docetaksel (D) i odstawiono docetaksel D z powodu progresji choroby, oraz u chorych, u których uzyskano początkowo odpowiedź na D, lecz u których wystąpiła progresja nowotworu w czasie < 3 miesiące od ostatniej dawki D. U takich pacjentów uzyskanie korzyści z ponownego leczenia D jest mało prawdopodobne, dlatego też potrzebują oni nowych opcji terapeutycznych, takich jak kabazytaksel. Metody. Z 755 chorych z przerzutami raka gruczołu krokowego opornego na kastrację (metastatic castration-resistant prostate cancer, mCRPC), włączonych do badania TROPIC, u 362 (47,9%) nie zaobserwowano początkowej odpowiedzi na D i przerwano jego podawanie. U 155 (20,5%) — w ocenie badacza — obserwowano początkowo od­powiedź na leczenie D, lecz wystąpiła progresja w czasie < 3 miesiące od ostatniej dawki D, a 238 (31,5%) nie należało do żadnej z tych podgrup. Wszystkich pacjentów zrandomizowano do grup otrzymujących kabazytaksel w dawce 25 mg/m2 lub mitoksantron w dawce 12 mg/m2 podawanych dożylnie co 3 tygodnie oraz prednizon, przyjmowany doustnie w dawce 10 mg/dzień. Wyniki. W każdej z podgrup mediana czasu przeżycia całkowitego (OS) dla chorych otrzymujących kabazytaksel była zawsze większa niż w grupie otrzymującej mitoksantron. Największą korzyść wydłużenia czasu przeżycia całkowitego w porównaniu z grupą otrzymującą mitoksantron obserwowano w podgrupie chorych, u których początkowo zaob­serwowano odpowiedź na D, a następnie progresję w czasie < 3 miesiące od ostatniej dawki D {mediana 15,7 miesiąca w porównaniu z 11,6 miesiąca, współczynnik ryzyka HR (hazard ratio) 0,52; 95% przedział ufności CI (confidence interval) [0,35–0,76]}. Mediana czasu przeżycia wolnego od progresji była także znacząco lepsza w tej podgrupie w porównaniu z grupą otrzymującą mitoksantron (2,6 miesiąca w porównaniu z 1,4 miesiąca, HR 0,66 (0,48–0,91). Wniosek. Kabazytaksel w skojarzeniu z prednizonem wykazuje konsekwentnie korzystniejsze działanie na czas prze­życia w porównaniu z leczeniem mitoksantronem w skojarzeniu z prednizonem w każdej z podgrup, w szczególności u chorych, u których zaobserwowano odpowiedź na D zastosowany w pierwszej linii i u których doszło do progresji w czasie < 3 miesiące od ostatniej dawki D, a także u chorych bez początkowej odpowiedzi na D, którzy przerwali jego przyjmowanie w celu kontroli progresji choroby.Aim. This sub analysis of TROPIC study evaluates overall survival (OS) under cabazitaxel in patients who had no initial response to docetaxel (D ) and discontinued D for disease progression and those who initially responded to D but experienced disease progression < 3 months since last D dose. These patients are believed unlikely to benefit from D re-treatment and need new treatment options such as cabazitaxel. Methods. Of the 755 patients with metastatic castration-resistant prostate cancer (mCRPC) enrolled in TROPIC study, 362 (47.9%) had no initial response to D and discontinued it for disease progression, 155 (20.5%) had an initial response to D therapy according to investigator judgment but progressed < 3 months since last D dose and 238 (31.5%) did not belong to these two subgroups. All patients were randomized to receive cabazitaxel 25 mg/m2 or mitoxantrone 12 mg/m2 both every 3 weeks and prednisone 10 mg per os daily. Results. Median OS with cabazitaxel was consistently longer than with mitoxantrone in all subgroups. The highest survival benefit versus mitoxantrone was observed for patients who initially responded to D and then progres­sed < 3 months since last D dose (median OS 15.7 versus 11.6 months, Hazard ratio (HR) 0.52 [95% CI 0.35–0.76]). Median PFS was also significantly improved in the latter subgroup compared to mitoxantrone (2.6 versus 1.4 months, HR 0.66 [0.48–0.91]). Conclusion. Cabazitaxel plus prednisone consistently shows a greater survival benefit compared to mitoxantrone plus prednisone whatever the subgroup considered, including responders to first-line D who progressed < 3 months since last D and pts without initial response to D who discontinued it for disease progression

Olaparib for the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer and Alterations in BRCA1 and/or BRCA2 in the PROfound Trial

Olaparib; Castration-resistant prostate cancerOlaparib; Cáncer de próstata resistente a la castraciónOlaparib; Càncer de pròstata resistent a la castracióPurpose Phase III PROfound trial (ClinicalTrials.gov identifier: NCT02987543) met its primary and key secondary objectives, demonstrating significantly longer radiographic progression-free survival (rPFS) and overall survival (OS) with olaparib monotherapy versus abiraterone or enzalutamide (control) in patients with metastatic castration-resistant prostate cancer (mCRPC) with alterations in BRCA1, BRCA2 (BRCA), and/or ATM (cohort A) whose disease had progressed on prior next-generation hormonal agent (NHA). We report exploratory post hoc analysis of the subgroup of patients with mCRPC with BRCA alterations in PROfound. Methods All patients had an alteration in a homologous recombination repair gene by tumor tissue testing, of which 160 had underlying BRCA alterations. rPFS and OS were estimated using the Kaplan-Meier method. Confirmed objective response rate and safety were also assessed. Results Olaparib was associated with longer rPFS (hazard ratio [HR], 0.22 [95% CI, 0.15 to 0.32]) and OS (HR, 0.63 [95% CI, 0.42 to 0.95]) than control. There was an rPFS benefit with olaparib in all zygosity subgroups (biallelic [n = 88]; HR, 0.08 [95% CI, 0.04 to 0.16], heterozygous [n = 15] and unknown [n = 57]; HR, 0.30 [95% CI, 0.16 to 0.60]). Patients with BRCA2 homozygous deletions experienced prolonged responses to olaparib (n = 16; median rPFS, 16.6 months [95% CI, 9.3 to not reached]). Some evaluations are limited by small patient numbers. Germline DNA analysis was performed for 112 (70%) patients; risk of disease progression was similar for patients with germline (n = 61; HR, 0.08 [95% CI, 0.03 to 0.18]) and somatic (n = 51; HR, 0.16 [95% CI, 0.07 to 0.37]) BRCA alterations. Conclusion In all subgroups assessed, olaparib improved outcomes versus abiraterone or enzalutamide for patients with mCRPC with BRCA alterations whose disease had progressed on previous NHA.Supported by AstraZeneca and is part of an alliance between AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ

First-in-human Phase 1 open label study of the BET inhibitor ODM-207 in patients with selected solid tumours

Background Bromodomain and extra-terminal domain (BET) proteins are reported to be epigenetic anti-cancer drug targets. This first-in-human study evaluated the safety, pharmacokinetics and preliminary anti-tumour activity of the BET inhibitor ODM-207 in patients with selected solid tumours. Methods This was an open-label Phase 1 study comprised of a dose escalation part, and evaluation of the effect of food on pharmacokinetics. ODM-207 was administered orally once daily. The dose escalation part was initiated with a dose titration in the initial cohort, followed by a 3 + 3 design. Results Thirty-five patients were treated with ODM-207, of whom 12 (34%) had castrate-resistant prostate cancer. One dose-limiting toxicity of intolerable fatigue was observed. The highest studied dose achieved was 2 mg/kg due to cumulative toxicity observed beyond the dose-limiting toxicity (DLT) treatment window. Common AEs included thrombocytopenia, asthenia, nausea, anorexia, diarrhoea, fatigue, and vomiting. Platelet count decreased proportionally to exposure with rapid recovery upon treatment discontinuation. No partial or complete responses were observed. Conclusions ODM-207 shows increasing exposure in dose escalation and was safe at doses up to 2 mg/kg but had a narrow therapeutic window.Peer reviewe

Statin and metformin use and outcomes in patients with castration-resistant prostate cancer treated with enzalutamide: A meta-analysis of AFFIRM, PREVAIL and PROSPER

Castration-resistant prostate cancer; Metformin; Overall survivalCàncer de pròstata resistent a la castració; Metformina; Supervivència globalCáncer de próstata resistente a la castración; Metformina; Supervivencia globalBackground: Statins and metformin are commonly prescribed for patients, including those with prostate cancer. Preclinical and epidemiologic studies of each agent have suggested anti-cancer properties. Methods: Patient data from three randomised, double-blind, placebo-controlled, phase III studies evaluating enzalutamide (AFFIRM, PREVAIL and PROSPER) in patients with castration-resistant prostate cancer were included in this analysis. This post hoc, retrospective study examined the association of statin and metformin on radiographic progression-free survival (rPFS), metastasis-free survival (MFS), toxicity and overall survival (OS). After adjusting for available clinical prognostic variables, multivariate analyses were performed on pooled data from AFFIRM and PREVAIL, all three trials pooled, and each trial individually, to assess differential efficacy in these end-points associated with the baseline use of these medications. Results: In the multivariate analysis of the individual trials, OS and rPFS/MFS were not significantly influenced by statin or metformin use in AFFIRM or PROSPER. However, in PREVAIL, OS was significantly influenced by statin (hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.59-0.89) and rPFS was significantly influenced by metformin (HR, 0.48; 95% CI 0.34-0.70). In pooled analyses, improved OS was significantly associated with statin use but not metformin use for AFFIRM+PREVAIL trials (HR 0.83; 95% CI 0.72-0.96) and AFFIRM+PREVAIL+PROSPER (HR 0.75; 95% CI 0.66-0.85). Conclusions: The association between statin or metformin use and rPFS, MFS and OS was inconsistent across three trials. Analyses of all three trials pooled and AFFIRM+PREVAIL pooled revealed that statin but not metformin use was significantly associated with a reduced risk of death in enzalutamide-treated patients. Additional prospective, controlled studies are warranted.This study was sponsored by Pfizer Inc. (New York, NY, USA) and Astellas Pharma, Inc. (Northbrook, IL, USA), the co-developers of enzalutamide. Medical writing and editorial support funded by the sponsors were provided by Stephanie Vadasz, PhD, and Dena McWain of Ashfield MedComms (an Ashfield Health company), Lauren Rainer, BSc, and Julie B. Stimmel, PhD, of Onyx (a Prime Global agency)

Management of Patients with Advanced Prostate Cancer. Part I: Intermediate-/High-risk and Locally Advanced Disease, Biochemical Relapse, and Side Effects of Hormonal Treatment: Report of the Advanced Prostate Cancer Consensus Conference 2022

Hormonal treatment; Prostate cancer; Side effectsTratamiento hormonal; Cáncer de próstata; Efectos secundariosTractament hormonal; Càncer de pròstata; Efectes secundarisBackground Innovations in imaging and molecular characterisation and the evolution of new therapies have improved outcomes in advanced prostate cancer. Nonetheless, we continue to lack high-level evidence on a variety of clinical topics that greatly impact daily practice. To supplement evidence-based guidelines, the 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) surveyed experts about key dilemmas in clinical management. Objective To present consensus voting results for select questions from APCCC 2022. Design, setting, and participants Before the conference, a panel of 117 international prostate cancer experts used a modified Delphi process to develop 198 multiple-choice consensus questions on (1) intermediate- and high-risk and locally advanced prostate cancer, (2) biochemical recurrence after local treatment, (3) side effects from hormonal therapies, (4) metastatic hormone-sensitive prostate cancer, (5) nonmetastatic castration-resistant prostate cancer, (6) metastatic castration-resistant prostate cancer, and (7) oligometastatic and oligoprogressive prostate cancer. Before the conference, these questions were administered via a web-based survey to the 105 physician panel members (“panellists”) who directly engage in prostate cancer treatment decision-making. Herein, we present results for the 82 questions on topics 1–3. Outcome measurements and statistical analysis Consensus was defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. Results and limitations The voting results reveal varying degrees of consensus, as is discussed in this article and shown in the detailed results in the Supplementary material. The findings reflect the opinions of an international panel of experts and did not incorporate a formal literature review and meta-analysis. Conclusions These voting results by a panel of international experts in advanced prostate cancer can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers prioritise areas for future research. Diagnostic and treatment decisions should always be individualised based on patient and cancer characteristics (disease extent and location, treatment history, comorbidities, and patient preferences) and should incorporate current and emerging clinical evidence, therapeutic guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2022 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials

A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors

Advanced Solid Tumors; PI3K beta/delta inhibitorTumores sólidos avanzados; Inhibidor de PI3K beta/deltaTumors sòlids avançats; Inhibidor de PI3K beta/deltaPurpose: To characterize safety and tolerability of the selective PI3Kβ inhibitor AZD8186, identify a recommended phase II dose (RP2D), and assess preliminary efficacy in combination with abiraterone acetate or vistusertib. Patients and Methods: This phase I open-label study included patients with advanced solid tumors, particularly prostate cancer, triple-negative breast cancer, and squamous non–small cell lung cancer. The study comprised four arms: (i) AZD8186 monotherapy dose finding; (ii) monotherapy dose expansion; (iii) AZD8186/abiraterone acetate (with prednisone); and (iv) AZD8186/vistusertib. The primary endpoints were safety, tolerability, and identification of the RP2D of AZD8186 monotherapy and in combination. Secondary endpoints included pharmacokinetics (PK), pharmacodynamics, and tumor and prostate-specific antigen (PSA) responses. Results: In total, 161 patients were enrolled. AZD8186 was well tolerated across all study arms, the most common adverse events being gastrointestinal symptoms. In the monotherapy dose-finding arm, four patients experienced dose-limiting toxicities (mainly rash). AZD8186 doses of 60-mg twice daily [BID; 5 days on, 2 days off (5:2)] and 120-mg BID (continuous and 5:2 dosing) were taken into subsequent arms. The PKs of AZD8186 were dose proportional, without interactions with abiraterone acetate or vistusertib, and target inhibition was observed in plasma and tumor tissue. Monotherapy and combination therapy showed preliminary evidence of limited antitumor activity by imaging and, in prostate cancer, PSA reduction. Conclusions: AZD8186 monotherapy had an acceptable safety and tolerability profile, and combination with abiraterone acetate/prednisone or vistusertib was also tolerated. There was preliminary evidence of antitumor activity, meriting further exploration of AZD8186 in subsequent studies in PI3Kβ pathway–dependent cancers.This study was sponsored by AstraZeneca. We thank the patients and their doctors and caregivers who participated in this study. We acknowledge support in Cambridge from Cancer Research UK, Experimental Cancer Medicine Center, NIHR Biomedical Research Center, and NIHR Cambridge Clinical Research Center. Research at the Christie NHS Foundation Trust was supported by the NIHR Manchester Clinical Research Facility and Manchester Experimental Cancer Medicine Center award. We also thank Martine Roudier (AstraZeneca) for providing analysis data of tumor tissue biopsies, and Wolfram Brugger and Caroline Kennedy (AstraZeneca, Cambridge, UK). Abiraterone acetate was kindly provided by Janssen. Medical writing and editorial assistance were provided by Bioscript Medical, Macclesfield, UK, and funded by AstraZeneca