Metastatic Hormone-resistant Prostate Cancer Research Articles

Outcomes of Black (B) versus White (W) patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) treated with androgen deprivation therapy (ADT) with or without orteronel (Ort): Analysis of pt-level data from SWOG-1216 phase 3 trial.

6532 Background: Despite more aggressive prostate cancer (PCa) at presentation and higher mortality in real world, B pts with metastatic hormone resistant PCa did not have inferior outcomes than W pts when both were enrolled in clinical trials (PMID: 33951180). In the phase 3 S1216 trial, treatment with Ort, a novel CYP17 axis inhibitor, significantly improved progression-free survival (PFS) but not overall survival (OS) compared to bicalutamide (Bic) in pts with mHSPC receiving ADT. This trial enrolled the greatest number of B pts in a phase 3 trial in this setting to-date. We hypothesized that given comparable access to care as experienced in a clinical trial, outcomes in B pts would be similar to those of W pts in the mHSPC setting. Methods: Eligibility: Pts with mHSPC were enrolled. Only pts self-identifying as B or W were included in this analysis. PFS and OS for each group were estimated using Kaplan-Meier method. A multivariate analysis (MVA) adjusting for disease characteristics was conducted using a Cox proportional hazards model. Results: Among 1279 participants, 135 (10.6%) were B; 1077 (84.2%) were W. B and W were equally distributed between treatment arms, and had respectively similar proportion of pts with Gleason score ≥8 (61.3 vs 62.1%), Zubrod score ≥2 (5.1 vs 3.4%) and extensive disease (48.1 vs 48.7%). However, B pts, as compared to W, were younger (65.8 vs 68.4 yrs, p=0.001) and had a higher median baseline PSA (54.7 vs 26.7 ng/mL; p<0.001). PSA responses (≤ 0.2 ng/mL) at month 7 were similar in both groups (p=0.296). Overall, B vs W had similar median PFS (2.3 vs 2.9 yrs, p=0.71) and OS (5.5 vs 6.3 yrs, p=0.65). MVA confirmed similar PFS and OS after adjusting for known prognostic factors (Table). No interaction between race and treatment was observed (P-value interaction PFS= 0.77 and OS= 0.91). Conclusions: We demonstrate that even though B pts present with more aggressive disease in mHSPC setting, they did not have statistically significant worse OS and PFS than W pts and treatment effect was also similar for both racial groups. Equitable access to care may negate historical differences in outcomes among B vs W pts with advanced PCa. Funding: NIH/NCI/NCTN grant U10CA180888, U10CA180819; and Millennium Pharmaceuticals (Takeda Oncology). Univariate and MVA of PFS and OS. [Table: see text]

The Case | Hematuria, proteinuria, and renal insufficiency in metastatic prostate cancer

A 75-year-old man with metastatic hormone-resistant prostate cancer and well-controlled hypertension on amlodipine presented with lower limb swelling for 2 weeks. Two years before presentation, he had surgical resection of a destructive bony metastasis in the right innominate bone, followed by stereotactic whole-body radiation therapy and anti-androgen and gonadotropin-releasing hormone antagonists. Despite an 8-month course of prostate-specific membrane antigen (PSMA)–targeted radioligand therapy with 177Lu-PSMA (total 1154 mCi over 6 doses) that was completed 2 months before presentation, the cancer remained progressive.

Comparison of Weekly Low Dose Docetaxel with the Standard Protocol in Hormone-resistant Metastatic Prostate Cancer.

To evaluate and compare the effects and toxicity of weekly low dose with three weekly standard doses of docetaxel in hormone-resistant metastatic prostate cancer. Descriptive study. University of Health Sciences, Ankara Training and Research Hospital, Ankara, Turkey, from January 2013 to July 2021. The study was conducted on 79 patients with refractory prostate cancer. Patients were assessed in 2 groups. One group was treated with the classical standard Docetaxel dose 75 mg/m2/day (every 3-week) + Prednisolone 10 mg/day (daily), whereas the second group consisting of elderly and poor performance status received a low dose Docetaxel 25 mg/m2/day (weekly, 1-week interval) + Prednisolone 10 mg/day (daily). The overall survival and toxicity profile differences between the low dose protocol in this study and the standard treatment protocol were compared. Survival times in both groups were found as 44.3 months and 35.5 months in 1-week and 3-week interval groups, respectively (p = 0.09). The rate of hematologic toxicity associated with systemic treatment was 10% in the 1-week interval treatment group and 41% in the 3-week group (p = 0.002). In particular, the febrile neutropenia was 30.8% in the 3-week interval group and 2.5% (p = 0.001) in the 1-week interval group. The study showed that instead of using docetaxel in the standard dose and range, it is more tolerated in elderly and poor performance patients when administered in the revised dose. The disrupting effects of chemotherapy are overperforming, especially in such patients. Metastatic prostate cancer, Hormone resistant prostate cancer, Weekly docetaxel.

Abstract 228: A precision dosing application for patients treated with docetaxel and G-CSF

Abstract Purpose Produce a precision dosing application for clinicians to control neutropenia in patients treated with both docetaxel and G-CSF. Context Chemotherapy induced neutropenia (CIN) poses serious harm to patients due to the heightened risk of severe infection. Accordingly, chemotherapy dose is assessed at the beginning of each cycle. The therapeutic window of chemotherapy is determined from population studies, with an individual's dose often scaled by their body surface area. This leads to a large number of patients being over- or under- dosed. We previously developed an application [1] which uses weekly neutrophil counts from the first cycle of docetaxel treatment to predict the level of neutropoenia in subsequent cycles for a given dose of docetaxel. However, in the original app the administration of G-CSF, used as a prophylactic treatment for neutropenia, was not considered. G-CSF administration lacks standardisation and the COVID-19 pandemic has created a highly risk averse environment to infections, raising the prospects that a clinician will administer G-CSF. MethodsAiming to predict the level of neutropenia after the first cycle we draw from models in the literature of CIN for G-CSF treated patients [2,3,4]. We adapt the G-CSF induced feedback effect on neutrophil development in these models to account for features specific to docetaxel patients; notably the rebound in neutrophils above baseline seen after nadir [5], and the apparent short maturation time of neutrophils [4]. Using data in the public domain from the comparator arm of a phase III clinical trial for metastatic hormone-resistant prostate cancer (clinical trial number NCT00617669), we identify 27 patients treated with docetaxel and G-CSF with weekly blood tests in the first and second cycle. We calibrate our model by minimising a Bayesian objective function to establish a model that predicts the neutrophil count in the second docetaxel cycle from the first. We then simulate the effect of different combinations of docetaxel, G-CSF, and the timing of G-CSF administration. Conclusions Current progress includes a model which captures the rebound above baseline in neutrophil count seen in docetaxel patients. We will show that our model captures the effect of filgrastim and pegfilgrastim on neutrophil counts, and can determine how a docetaxel patient may best benefit from G-CSF treatment and/or a change in dose of docetaxel.

A precision dosing application for prostate cancer patients treated with docetaxel and G-CSF.

e13585 Background: The aim of this study is to produce a precision dosing application for clinicians to control neutropenia in prostate cancer patients treated with both docetaxel and G-CSF. Chemotherapy-induced neutropenia (CIN) poses serious harm to patients due to the heightened risk of severe infection. Accordingly, chemotherapy dose is assessed at the beginning of each cycle. The therapeutic window of chemotherapy is determined from population studies, with an individual’s dose often scaled by their body surface area. This leads to a large number of patients being over- or under- dosed. We previously developed an application [1] which uses weekly neutrophil counts from the first cycle of docetaxel treatment to predict the level of neutropoenia in subsequent cycles for a given dose of docetaxel. However, in the original app the administration of G-CSF, used as a prophylactic treatment for neutropenia, was not considered. G-CSF administration lacks standardisation and the COVID-19 pandemic has created a highly risk adverse environment to infections, raising the prospects that a clinician will administer G-CSF. Methods: We adapted and combined representations of endogenous and exogenous G-CSF action on CIN from the literature [2,3,4] to capture the inherent feedback effect of circulating neutrophils on progenitor proliferation as well as the stimulatory action of G-CSF injection on proliferation and maturation of progenitor cells. Using data in the public domain from the comparator arm of a phase III clinical trial for metastatic hormone-resistant prostate cancer (NCT00617669), we identified 134 patients treated with docetaxel with recorded weekly blood tests in the first and second cycle, including 27 also receiving G-CSF. We calibrated individualised patient models against neutrophil counts measured in the first cycle by minimising a Bayesian objective function and evaluated their ability to predict the levels observed in the second cycle. Results: The model was able to capture the main features of endogenous and exogenous G-CSF action on neutrophil count described in the literature, including endogenous-G-CSF-mediated rebound above baseline after chemotherapy-induced depletion [4], rapid rise in neutrophil count following exogenous G-CSF administration [5], as well as reduced chemotherapy-induced depletion and earlier recovery under G-CSF treatment compared to chemotherapy alone [5]. Conclusions: This tool has the potential to help determine how a docetaxel patient may best benefit from G-CSF treatment and/or a change in dose of docetaxel.

Prevalence of oligoprogression in metastatic hormone-resistant prostate cancer patients on androgen targeted therapies: Could targeted radiotherapy improve patient outcomes?

110 Background: Androgen receptor-targeted therapies (ART) such as Abiraterone and Enzalutamide have shifted the management paradigm of metastatic castrate-resistant prostate cancer (mCRPC). These treatments are well-tolerated with less toxicities compared to chemotherapy, therefore methods to delay chemotherapy are beneficial to patients. Patients eventually become resistant to ARTs, and some patients will progress in a limited number of sites. This study investigated the prevalence of oligoprogressive disease (OPD) amenable to Stereotactic-body radiotherapy (SBRT). OPD is defined as ≤3 metastatic lesions which are progressing or new whilst all other sites of disease are well-controlled by ART. Methods: Retrospective analysis of electronic patient records and imaging studies of 95 patients treated with ART for mCRPC between April 2015 – 2017 from a single centre was undertaken. Data was analysed at the time of first tumour progression on ART. Results: The median (IQR) age of patients was 78.8 (74.4-83.6) years. OPD was found in 27 (28%) patients, 18 (19%) had lesions suitable for SBRT (Table). Seventeen (63%) patients were treated with abiraterone, 10 (27%) patients with enzalutamide. Median (IQR) time from starting ART to OPD was 16.4 (8.6-19.9) months. Five (19%) patients had 3 sites of OPD, 8 (29%) patients had 2 sites of OPD and 14 (52%) patients had 1 site of OPD. Nineteen patients continued ART beyond OPD for ≥3months. OPD was diagnosed using CT scan (56%), whole body diffusion-weighted MRI (22%), choline PET/CT (19%) and bone scan (3%). Six (22%) patients were treated with radiotherapy for OPD, 3 as participants of the TRAP trial (NCT03644303). Median time to subsequent progression after OPD for the 3 patients treated off trial with radiotherapy was 20.5 months. The OPD lesions treated with radiotherapy included the prostate (2 patients, 30 Gy in 5 and 24 Gy in 4 fractions) and para-aortic lymph node (1 patient, 30 Gy in 5 fractions). Median time to subsequent progression after OPD for those who did not receive radiotherapy was 6.4 months. There was no significant difference between median overall survival between patients with OPD and those who progressed with > 3 lesions (7 vs 9.2 years, P= 0.54). Ten (66%) patients who progressed after initial OPD on continuation of ART progressed with further OPD (≤3 lesions including original OPD lesion). Conclusions: OPD is prevalent in patients on ART for mCRPC. The most frequent site of OPD was in bone and majority of patients had only 1 site of OPD at presentation. These results identify a cohort of patients who may benefit from SBRT to maximise ART treatment. Fourteen (14%) patients met entry criteria for TRAP trial which is currently testing the role of SBRT to sites of OPD in mCRPC. [Table: see text]

Abstract 4789: Predicting sensitivity to Lantern Pharma’s pipeline drug candidate LP-184 using the Response Algorithm for Drug Positioning and Rescue

Abstract LP-184 is a DNA Damage Repair inhibitor being developed by Lantern Pharma primarily as a non-hormone, non-chemotherapy option for the growing indication of taxane- and hormone-resistant metastatic prostate cancer. LP-184 is a next-generation analog of Irofulven with broad anti-tumor activity that counteracts multi-drug resistance pathways and is potentially synergistic with many classes of anticancer agents. LP-184 has a favorable therapeutic index and pharmacokinetic profile. Knowledge about its shared mechanism of action with Irofulven and potential biomarkers implicated in induction of bioactivation and synthetic lethal interactions is available. To advance LP-184 into clinical stages and achieve accelerated approval, Lantern Pharma is employing its proprietary Artificial Intelligence (AI)-driven technology. Lantern Pharma has developed a technology platform termed RADRTM that can be used to construct responder/ non-responder profiles based on gene expression signatures and predict true responders before conducting a clinical trial in order to achieve higher success rates. RADRTM is an Al-based machine learning approach for candidate biomarker identification and patient stratification. RADRTM is a combination of three automated modules working sequentially to generate drug- and tumor-specific gene signatures predictive of response. RADRTM emphasizes the integration of biological knowledge, data-driven feature selection, and robust Al algorithms to derive biomarkers in a hypothesis-free manner. In analytic demonstrations, RADRTM was able to achieve an average accuracy of 85% in validation tests using preclinical datasets associated with selected solid tumor indications and approved drugs. As part of RADRTM drug model building and development, we used a dataset showing preclinical efficacy of our pipeline oncology candidate LP-184. We obtained baseline cell line gene expression profiles covering more than 18,000 transcripts per cell line and corresponding LP-184 sensitivity records from the NCI60 cancer cell line panel. Using RADRTM, we derived a panel of 10 genes whose expression levels are predictive of overall response at an accuracy of 100%. Thus, RADRTM was able to identify the top 10 genes for prediction of either drug sensitivity or insensitivity, demonstrating the hypothesis-free identification of biomarkers with biological relevance and statistical rigor and having highest possible prediction accuracy. Genes from the final 10 predictive list were found to be functionally involved in LP-184-specific induction of bioactivation and are in agreement with its mechanism of action. These preliminary biomarker analyses will be further validated using LP-184 sensitivity and pre-treatment gene expression data derived from ex vivo models of fresh prostate tumor biopsy samples. Citation Format: Aditya Kulkarni, Umesh Kathad, Yuvanesh Vedaraju, Barry Henderson, Gregory Tobin, Panna Sharma, Arun Asaithambi. Predicting sensitivity to Lantern Pharma’s pipeline drug candidate LP-184 using the Response Algorithm for Drug Positioning and Rescue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4789.

Abstract 677: A precision dosing application for prostate cancer chemotherapy

Abstract The therapeutic window of chemotherapy drugs is commonly established at a population level and patient dose selection is often simply scaled with Body Surface Area. Due to large inter-individual physiological variability, this leads to a significant number of patients being under or over-dosed. While a limited number of precision dosing techniques exist to tailor patient-specific treatment, they typically require costly additonal tests which severly restrict their use in clinical practice. Focusing on the use of docetaxel in metastatic castrate-resistant prostate cancer, we have developed a demonstrator for precision dosing which relies only on routine blood tests that are already universally available in most health systems and could thus fit within the current clinical practice to improve patient outcome at a low cost. This tool was developed using publicly available data from Project Datasphere for the comparator arm of a phase III clinical trial for metastatic hormone-resistant prostate cancer (NCT00617669). This cohort includes 412 patients who were treated with Docetaxel between 2008 and 2011 in cycles of 21 days with weekly blood tests in the first cycle. A population PK/PD model for Docetaxel and leukocyte population was assembled based on literature [1,2]. Individual patient parameters including Docetaxel AUC were estimated by calibrating this model with weekly measured blood count using a Bayesian approach. Survival and toxicity Cox models were developed using estimated PK/PD parameters as well as biomarker levels. They allowed estimations of gains in prognostic as well as toxicity risks associated with modifying patient dose after the first chemotherapy cycle. These models will be made available through a web application to support clinicians in their decision to refine patient doses. Concordance levels of the order of 0.7 were obtained for the survival and toxicity models, with significant predictive variables including Docetaxel AUC, patient liver markers as well as PSA. Patients with low estimated hematologic toxicity (neutrophil count not dropping under 1 billion/L for more than 5 days) presented a median overall survival time of 461 days, against 563 days for patients with higher hematologic toxicity. Patients with low estimated Docetaxel AUC (<1.5 µg.h/mL) presented a median overall survival time of 455 days, against 587 days for patients with higher estimated Docetaxel AUC. For some patients, the models predicted gains in prognosis without severe toxicity when increasing the dose. We have developed a precision dosing app for Docetaxel in prostate cancer which requires a single weekly classical blood test in the first chemotherapy cycle. This app has the potential to significantly improve patient outcome at low cost without disrupting current clinical practice.

Abiraterone acetate for early stage metastatic prostate cancer: patient selection and special considerations.

In recent years, therapeutic advances, together with new medication sequences and combinations, have improved outcomes for prostate cancer. For a long time, androgen deprivation therapy (ADT) has been the standard of care for newly diagnosed, metastatic prostate cancer, first as a standalone therapy and then in combination with taxane-based regimens. More recently, the addition of abiraterone acetate to ADT to achieve complete androgen blockade has proven beneficial for the treatment of metastatic hormone-resistant prostate cancer and metastatic hormone-sensitive prostate cancer (mHSPC). In this review, we summarize recent findings on the early use of abiraterone in mHSPC and discuss survival benefits as reported in clinical trials. On the basis of existing data, abiraterone in combination with ADT could be considered a new standard of care for patients affected by mHSPC.

LINE-1-encoded reverse Transcriptase as a target in cancer therapy.

LINE-1 elements account for about 17% of the human genome and harbour two open reading frames: ORF1, encoding a 40 kDa RNA-binding protein, and ORF2, coding for a 150 kDa protein with reverse transcriptase (RT) activity. LINE-1s are highly expressed in embryos and tumor cells while being virtually silent in differentiated tissues and, consistently, both ORF-1p and ORF-2p have been detected in human cancers. RT-encoding ORF2 is expressed early in pre-neoplastic lesions suggesting that RT expression may be a potential cause, rather than a consequence, of cancer onset. Experimental data emerging from in vitro and in vivo studies confirm this view. Preclinical work showed that RT inhibition reduces proliferation, promotes differentiation of cancer cells and antagonizes tumor progression in murine models. Moreover, a recent phase II trial on metastatic hormone-resistant prostate cancer patients has confirmed the anticancer efficacy of RT inhibitors. Together, these data indicate that LINE-1-encoded RT emerges as a potential therapeutic target for a large spectrum of cancers and RT inhibitors as effective tools in a novel anti-cancer, non-cytotoxic, differentiation therapy.

Chlorine dioxide as a possible adjunct to metabolic treatment

A first patient with metastatic adenocarcinoma of the pancreas has decided, on his own, to refuse chemotherapy but to treat himself with lipoic acid, hydroxycitrate combined with oral ingestion of chlorine dioxide. His blood tests and radiological examinations have almost normalized and the disease is stable at 18 months. Another patient with hormone resistant metastatic prostate cancer has experienced a sharp drop in PSA level as well as improved medical condition. From extensive literature review, the mechanism of action of chlorine dioxide is unknown. It is our hypothesis (albeit unproven) that chlorine dioxide results in tumor cell acidification of the alkaline pH of cancer cells.

Neuronal Trans-Differentiation in Prostate Cancer Cells.

Neuroendocrine (NE) differentiation in prostate cancer (PCa) is an aggressive phenotype associated with therapy resistance. The complete phenotype of these cells is poorly understood. Clinical classification is based predominantly on the expression of standard NE markers. We analyzed the phenotype of NE carcinoma of the prostate utilizing in vitro methods, in silico, and immunohistochemical analyses of human disease. LNCaP cells, subjected to a variety of stressors (0.1% [v/v] fetal bovine serum, cyclic AMP) induced a reproducible phenotype consistent with neuronal trans-differentiation. Cells developed long cytoplasmic processes resembling neurons. As expected, serum deprived cells had decreased expression in androgen receptor and prostate specific antigen. A significant increase in neuronal markers also was observed. Gene array analysis demonstrated that LNCaP cells subjected to low serum or cAMP showed statistically significant manifestation of a human brain gene expression signature. In an in silico experiment using human data, we identified that only hormone resistant metastatic prostate cancer showed enrichment of the "brain profile." Gene ontology analysis demonstrated categories involved in neuronal differentiation. Three neuronal markers were validated in a large human tissue cohort. This study proposes that the later stages of PCa evolution involves neuronal trans-differentiation, which would enable PCa cells to acquire independence from the neural axis, critical in primary tumors. Prostate 76:1312-1325, 2016. © 2016 Wiley Periodicals, Inc.

Theranostic hollow/mesoporous organosilica nanospheres enhance the therapeutic efficacy of anticancer drugs in metastatic hormone-resistant prostate cancer

Hollow mesoporous silica materials have received intensive interest in the field of cancer treatment owing to their large drug loading capacity, controlled release property and excellent biocompatibility.

Prostate-specific antigen doubling time and response to cabazitaxel in a hormone-resistant metastatic prostate cancer patient.

We report a case of metastatic castration-resistant prostate cancer, who received prior treatment with docetaxel and was then given cabazitaxel as salvage therapy. The patient was monitored by prostate-specific antigen doubling time and prostate-specific antigen absolute value. The prostate-specific antigen doubling time was found to be a good response predictor in the patient.

Phase II, multicenter, open-label, proof of concept study of tasquinimod in patients with advanced/metastatic hepatocellular (HCC), ovarian (OC), renal cell (RCC) and gastric (GC) carcinomas.

TPS2622 Background: Treatment resistance and disease progression are common in HCC, OC, RCC and GC. Tasquinimod is an oral, quinoline-3-carboxamide derivative that binds to S100A9, resulting in immunomodulatory, anti-angiogenic and anti-metastatic effects involving downregulation of chemokine receptor type 4 and hypoxia-inducible factor. Tasquinimod significantly improves PFS (7.6 v 3.3 mo) in patients with metastatic hormone-resistant prostate cancer (Pili, R. et al. 2011. JCO 29:4022-8) and is in an ongoing phase III program. Its unique mode of action (MOA) makes tasquinimod attractive for other indications. The primary study objective is to determine the clinical activity of tasquinimod in advanced/metastatic HCC, OC, RCC and GC. Tasquinimod has been shown to delay disease progression with limited tumor shrinkage, therefore an innovative design was proposed, with PFS rate as the main endpoint. Methods: Design: Phase II, multinational, exploratory proof of concept study to evaluate tasquinimod activity in 4 independent cohorts of patients (HCC, OC, RCC and GC) with progressive disease after standard therapy. An innovative design (Litwin S. 2007. Stat Med 26:4400-15) based on the proportion of patients who have not progressed nor died at predefined timepoints (PFS rate) will be used in each cohort independently. Patients: 110–200 patients (dependent on outcome of futility analyses) aged ≥18 yr, ECOG performance status 0 or 1 will be enrolled. Patients must have histologically confirmed and documented HCC, OC, RCC or GC and demonstrable disease progression on standard therapy. Recruitment is ongoing. Dosage: Tasquinimod will be administered as a starting dose of 0.5 mg/day, in each cohort. After 2 wks, the dose will be increased to 1 mg/day based on individual safety and tolerability. Primary endpoint: PFS rate, defined as the proportion of patients who have neither progressed nor died at 12 wks (GC), 16 wks (HCC, RCC) or 24 wks (OC). Secondary endpoints: Include OS, response rate, safety, pharmacokinetics, inflammatory and specific target biomarkers to explore comprehensively the MOA according to each disease type. Clinical trial information: NCT01743469.

Investigator-initiated pilot study of bicalutamide and raloxifene in hormone-resistant prostate cancer.

e16065 Background: Estrogens, in addition to androgen may contribute to the progression of prostate cancer.The combination of bicalutamide, a non-steroidal anti-androgen, and raloxifene, a selective estrogen receptor modulator, has a synergistic effect on cell death of prostate cancer cell lines such as DU145 and PC3. We investigated the safety of combined treatment of bicalutamide and raloxifene on quality of life in patients affected by hormone-resistant prostate cancer. Methods: Eligibility requirements included metastatic hormone-resistant prostate cancer, Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received the combination of bicalutamide, 50 mg, and raloxifene, 60 mg, daily in 28 day cycles for a maximum of 6 cycles. The primary endpoint was to describe the adverse event profile of combined treatment with bicalutamide and raloxifene. The secondary endpoint was to describe the quality of life of patients receiving the combination. Adverse events were graded by the investigator using the NCI Common Terminology Criteria for Adverse Events version 4.0 and the quality of life was assessed by the patient using aLinear Analog Scale Assessment (scale of 0-100). Serum levels of estradiol and testosterone were monitored during treatment. Results: Eighteen evaluable patients were included in the statistical analysis after an initial run-in safety cohort of six patients. Two patients completed 6 cycles per protocol, the remaining sixteen patients were taken off protocol after disease progression. Patients completed a median of 2 cycles. There were no grade 4 events and grade 3 adverse events consisted of hypertension (5.6%) and back pain (5.6%). Erectile dysfunction (grade 1) was the most common adverse event (77.8%). Patient assessment of quality of life (mental, physical, social, emotional, spiritual) did not reveal any statistically different changes after 2 cycles of treatment. An analysis of testosterone and estradiol levels will be reported. Conclusions: We conclude that combination of bicalutamide and raloxifene is well-tolerated. The combination of androgen and estrogen receptor blockade warrants further study for efficacy in hormone-resistant prostate cancer. Clinical trial information: NCT01050842.

Alpha Particle Radiobiology for Radium-223 (“Alpharadin”): The Fortuitous “Goldilocks” Effect Observed for Hormone-resistant Metastatic Prostate Cancer

Purpose/Objectives: The ALSYMPCA Trial of 223 Ra (“Alpharadin”) for men with metastatic castrate-resistant prostate cancer was a Phase III randomized trial comparing 223 Ra plus SOC vs best SOC. This trial was stopped early after 921 patients enrolled at over 100 centers achieved highly significant improvements in primary (overall survival) and all secondary endpoints.These extremely positive results prompted us to review some of the unique aspects of alpha particle radiobiology and ultra-short range molecular targeting capabilities resulting from endosteal surface new bone localization. The anatomic relationships between endosteal surfaces where isotope localization occurs and the positions of metastatic target cells and nearby marrow reserves were especially considered. Materials and Methods: Literature analysis and review of published radium autoradiographs Results: Highly energetic alpha particles such as those released during decay of 223 Ra (T 1/2 = 11.4 days) display unique radiobiologic and dosimetric aspects which may make them ideal for treating bony metastatic disease. The nuclear dose required in vitro for approximately 90% target cell kill by alpha particles is estimated to be less than 1 Gy and electron micrographs of various cell types obtained shortly after exposure confirm bizarre blebbing and condensation of chromosomal material characteristic of apoptosis. These radiobiologic effects may depend heavily on cell culture condition with more nonuniform DNA strand break damage observed in isolated detached cells. The 20-100 micron alpha particle path length (2-10 cells) appears to allow specific target cell populations to be killed within bony stroma without excessive damage to nearby sensitive hematopoietic cells. There may also be advantageous secondary cytokine signals produced as bystander effects. Calculated dosimetry models suggest bone surface to nearby marrow dose ratios of >10:1. 223 Ra treatment in rodent models showed that this family of Ca ++ analogs delivers extremely high doses to stromal elements such as bone-resorbing osteoclasts and this selectivity may aid in decreasing SREs and in pain relief. Conclusions: We highlight the fact that some basic radiobiologic and cell compartment-specific stromal localization principles known to be important in alpha particle radiopharmaceutical therapy may contribute to the very positive clinical outcomes observed while allowing minimal damage accumulation to nontarget cell groups. The highly localized cytotoxicity and fortuitous endosteal uptake patterns oberved (close enough to target cells and destructive osteoclasts for treatment efficacy but far enough away from marrow reserves to limit hemotoxicity) may serve to produce a salubrious Goldilocks effect and thereby aid in the observed treatment success. #3304

Can immuno-oncology offer a truly pan-tumour approach to therapy?

Increased understanding of cellular and molecular tumour immunology over the past two decades has enabled the identification of new and innovative ways to manipulate the immune response to cancer, with recent phase III trials in patients with metastatic melanoma and hormone-resistant prostate cancer providing proof-of-principle that immunotherapies can improve survival. Based on these successes, many new immunotherapies are being developed, including vaccines and other agents that prime or boost the immune system, T-cell modulatory agents, agents that enhance innate immunity and agents designed to inhibit immunosuppression within the tumour microenvironment. Current experience suggests that immunotherapies are a promising foundation to build treatment regimens for a variety of tumour types. Because many approaches target the immune system and not the cancer, immunotherapies are being evaluated in almost every tumour type, including those that were not previously considered likely to respond to immune manipulation. Immunotherapies also have potential for durable and adaptable cancer control at different stages of disease, including those with early-stage disease and low tumour burdens. To maximise benefits, however, it is likely that combination regimens with conventional cancer treatments or other immunotherapies will be necessary. In addition, the identification of biomarkers will allow further optimisation from a mechanistic and a patient selection perspective. Further advances in research will necessitate multidisciplinary collaboration among physicians, basic and translational researchers and the pharmaceutical industry to ensure that immuno-oncology becomes a cornerstone element in the development of cancer therapy.

Experience with sunitinib in hormone-resistant metastatic prostate cancer that is unresponsive to docetaxel

IntroductionSystemic treatment options for patients with hormone-refractory prostate cancer (HRPC) that progress despite the use of Docetaxel are very limited. One of the options of compassionate use currently available is the use of Sunitinib. We present a joint preliminary experience with the use of Sunitinib in this clinical case. Patients and methodsA series of eight cases is presented, which sets forth a prospective multicentre experience with Sunitinib in patients with hormone-refractory metastatic and progressive prostate cancer, previously treated with at least a regimen of Docetaxelbased chemotherapy. Other alternative chemotherapy regimes had already been tried in some patients. The primary objective of our study was the PSA response rate and our secondary objective was the progression-free period. We administered a dosage of 50 mg/day for four-week cycles, followed by a two-week rest per cycle, until we reached a total of eight cycles or up to clinical progression or intolerable toxicity. ResultsIn four cases, the PSA dropped to below 50% of the baseline level at the beginning of the treatment, and five patients presented some decrease in PSA. The progression-free time was 16.4 weeks. Toxicity arising from the treatment was moderate and manageable. ConclusionsDespite the limits of this experience, we can say that Sunitinib appears to be an active and safe option in patients with hormone-refractory prostate cancer that is resistant to chemotherapy with Docetaxel.

Health-related quality of life in pain-free or mildly symptomatic patients with metastatic hormone-resistant prostate cancer following treatment with the specific endothelin A receptor antagonist zibotentan (ZD4054)

Zibotentan (ZD4054) is a specific endothelin A receptor antagonist in clinical development for the treatment of hormone-resistant prostate cancer (HRPC). In a Phase II trial in patients with pain-free or mildly symptomatic metastatic HRPC, zibotentan was well tolerated with a promising signal for prolonged overall survival compared with placebo. As part of this trial, the impact of zibotentan compared with placebo on health-related quality of life (HRQoL) was assessed. Patients were randomized to receive once-daily oral zibotentan 10or 15mg, or matching placebo. Patients were allocated to one of two questionnaires; the Functional Assessment of Cancer Therapy-Prostate (FACT-P) or the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), supplemented by PR25, specific for prostate cancer. Questionnaires were completed at baseline and every 4weeks until disease progression when study treatment was discontinued. Compliance with questionnaire completion was >90% (286 of 312 patients) of the intention-to-treat population at baseline. Of baseline completers who were available for assessment (i.e., had not clinically progressed), 89% (164 of 184) and 83% (73 of 88) completed questionnaires at 12 and 24weeks, respectively. HRQoL scores from both questionnaires were high at baseline and remained high throughout the study, with scores being similar in the zibotentan and placebo groups. However, some floor and ceiling effects were seen in the EORTC QLQ-C30 questionnaire. High-baseline HRQoL scores were maintained throughout treatment with zibotentan. The FACT-P instrument was selected to further assess the impact of zibotentan on HRQoL in the Phase III clinical trial program.