Trials In Prostate Cancer Research Articles

Editorial introductions

Editorial introductions

An investigation of metronomic photodynamic therapies for local prostate cancer: supplementary fluorescent photography and proteomic studies, as measurable parameters of this treatment.

Aim: To investigate the clinical effects of metronomic Photodynamic therapy in prostate cancer patients, using different chlorophyll based photosensitisers. Methods and materials: The patients who enrolled in this ethics approved Phase 1 prostate cancer trial were treated with a variable combination of targeted photo-dynamic therapies and coupled ultrasound energies, mediated through orally/sub-lingually administered chlorophyll based photosensitisers. The metronomic technique involves the repeated administration of both the photosensitiser(s) and energies over set time intervals. As scientific assessment of the prostate cancer effects, intra-treatment fluorescent photography of the prostate gland /prostatic fossa, together with proteomic based urine specimen studies were performed. Results: The clinical data involved 666 treatment episodes, 333 photosensitiser dosages and includes 3-5 years patient follow-up. The effects on the prostate symptoms and cancer are documented, prostate size reduction being a serendipitous finding. Real time fluorescent photography has documented qualitative reproducible data. The quantitative urinary proteomic studies demonstrated statistically significant results, as documentation of the known pathological effects, attributable to this treatment. Conclusion: This study has been shown to be safe and to meet the criteria required of a TGA Phase 1 trial and reports the clinical and investigational prostate cancer responses to the metronomic therapy, involving the three different photosensitisers. The scientific bases for this therapy have been validated with the real-time fluorescent photographic and proteomic analyses data, of particular interest and importance are the immune system results. The new word metapoptosis is suggested as the description for PDT induced malignant cell death in association with immune stimulation, as described in this study.

Evolving Intersection Between Inherited Cancer Genetics and Therapeutic Clinical Trials in Prostate Cancer: A White Paper From the Germline Genetics Working Group of the Prostate Cancer Clinical Trials Consortium.

Advances in germline genetics, and related therapeutic opportunities, present new opportunities and challenges in prostate cancer. The Prostate Cancer Clinical Trials Consortium Germline Genetics Working Group was established to address genetic testing for men with prostate cancer, especially those with advanced disease undergoing testing for treatment-related objectives and clinical trials. The Prostate Cancer Clinical Trials Consortium Germline Genetics Working Group met monthly to discuss the current state of genetic testing of men with prostate cancer for therapeutic or clinical trial purposes. We assessed current institutional practices, developed a framework to address unique challenges in this population, and identified areas of future research. Genetic testing practices in men with prostate cancer vary across institutions; however, there were several areas of agreement. The group recognized the clinical benefits of expanding germline genetic testing, beyond cancer risk assessment, for the goal of treatment selection or clinical trial eligibility determination. Genetic testing for treatment selection should ensure patients receive appropriate pretest education and consent and occur under auspices of a research study whenever feasible. Providers offering genetic testing should be able to interpret results and recommend post-test genetic counseling for patients. When performing tumor (somatic) genomic profiling, providers should discuss the potential for uncovering germline mutations and recommend appropriate genetic counseling. In addition, family members may benefit from cascade testing and early cancer screening and prevention strategies. As germline genetic testing is incorporated into practice, further development is needed in establishing prompt testing for time-sensitive treatment decisions, integrating cascade testing for family, ensuring equitable access to testing, and elucidating the role of less-characterized germline DNA damage repair genes, individual gene-level biologic consequences, and treatment response prediction in advanced disease.

Abstract B013: Combined molecular targeting Src and mTOR pathways to impair prostate cancer cell survival

Abstract Overexpression of oncoproteins Src and mTOR has been shown to be highly associated with prostate cancer progression and poor clinical outcomes; therefore, small-molecule Src or mTOR inhibitors are being extensively evaluated in clinical trials for advanced prostate cancer. However, clinical data suggest that single treatment with any of these inhibitors only yields limited effects in patients. One possibility is that redundant signaling pathways in tumor cells exist that allow tumor cell uninterrupted upon blockade of purely one pathway. We hypothesize that Src and mTOR are two compensatory pathways that may cooperate to promote prostate cancer survival. Here we studied treatment effects of combining inhibitors targeting Src (saracatinib) and mTOR (rapamycin) on functional behaviors associated with tumor growth in prostate cancer cells with high level expression of both kinases. Combination of both inhibitors was found to inhibit cell proliferation and clonogenic survival more strongly than either single agent, as assessed by MTT and colony formation assay, respectively. Western blot analysis demonstrated that co-targeting Src and mTOR kinases leads to not only inhibition on phosphorylation of these oncoproteins but also greater blockade of multiple downstream pathways such as focal adhesion kinase (FAK), Akt, ERK, S6K, and 4E-BP1. These data indicate that combined application of small-molecule inhibitors targeting two different key pathways may cause significant impairment of phenotypes associated with prostate cancer growth and survival, suggesting that this combinative intervention modality may serve as a potential anticancer strategy that could be further tested in advanced prostate cancer models in vivo. Citation Format: Yao Dai, Dietmar W. Siemann. Combined molecular targeting Src and mTOR pathways to impair prostate cancer cell survival [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B013.

Therapeutic Vaccines for Genitourinary Malignancies.

The field of genitourinary malignancies has been a showcase for therapeutic cancer vaccine success since the application of intravesicular Bacillus Calmette-Guerin (BCG) for bladder cancer in the 1970s and enjoyed a renaissance in 2010 with the US Food and Drug Administration (FDA) approval of sipuleucel-T for prostate cancer. Several vaccine strategies have emerged, such as autologous or allogeneic whole-tumor vaccines, DNA vaccines, use of viral vectors, and peptides as immunostimulatory adjuvants. Despite impressive early trials, vaccine monotherapy has achieved limited success in the clinical world; however, combinations of vaccine and immune checkpoint inhibition or vaccine and cytokine stimulation are expected to move the field forward. This article reviews pivotal trials of cancer vaccines in prostate, renal, and bladder cancer and ongoing trials combining vaccines with other immune therapy agents.

Abstract IA26: Clinical development of PI3K/AKT pathway inhibitors in breast cancer

Abstract Targeting the PI3K/AKT/mTOR pathway has been a focus for drug development since the discovery of PI3K-activating mutations in p110α over 10 years ago. Breast cancer has been a primary indication for development of this class of drugs because of the high prevalence of these mutations, up to 45% in hormone receptor-positive breast cancer, and the synergy observed in combinations with endocrine therapies. An mTOR inhibitor, everolimus, was approved in breast cancer in combination with exemestane in 2012, indicating the synergy between ER and PI3K pathway translates to the clinic. Apitolisib, a dual PI3K pan-isoform and mTOR inhibitor, has discontinued development due to toxicities, despite compelling preclinical activity across multiple tumor types regardless of PI3K and PTEN status. Pictilisib, a pan-isoform PI3K inhibitor, has shown some evidence of activity, but in phase II studies has demonstrated that the activity is limited by dose intensity. Buparlisib, a pan-isoform PI3K inhibitor, has demonstrated efficacy in a large phase III study, but was not deemed sufficiently active relative to the toxicity in HR+ breast cancer to be submitted for regulatory approval. Second-generation PI3K and AKT inhibitors with higher selectivity and mutant specificity are in clinical development and hope to thread a better therapeutic index by dosing higher for more profound inhibition, and/or selectively inhibiting mutated forms of PI3K. Taselisib (GDC-0032) is a beta-sparing and PI3K-mutant selective inhibitor that leads to degradation of only the mutant form of PI3K and is currently in phase III. More recently, taselisib met the primary endpoint of improved response rates in a randomized, neoadjuvant phase II trial, LORELEI. Alpelisib is an alpha-selective PI3K inhibitor that is also in phase III. Recent data with ipatasertib, an AKT inhibitor, has demonstrated better tolerability and efficacy in randomized phase II trials of both prostate cancer and triple-negative breast cancer, where the PI3K/AKT signaling pathway is activated by either loss of PTEN or PI3K mutations, and may offer a better therapeutic index given its unique mechanism of action and place in the PI3K signaling pathway. Overall, the PI3K/AKT pathway is still considered an important pathway to target for certain cancers; however, target selectivity, dosing, and the right combination are critical to find a therapeutic index to provide a good option for patients. Citation Format: Mika Derynck. Clinical development of PI3K/AKT pathway inhibitors in breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr IA26.

Abstract CT066: Dendritic cell based cryoimmunotherapy associates with clinical variables and changes in T-cell receptor expression in a prospective phase I trial of metastatic castration resistant prostate cancer

Abstract Interim analysis data are presented for 13 patients with metastatic castration resistant prostate cancer treated with dendritic cell based cryoimmunotherapy (CryoIT) and at least three months follow-up (FU). In CryoIT autologous immature dendritic cells (iDCs) mature in cryoablated tumor tissue and engulf tumor associated antigens and thereafter migrate to lymph nodes to instruct systemic immune attacks on heterogenous cancer cells. Primary endpoint of the trial is to investigate safety of CryoIT while secondary aims include clinical, radiological and immunological responses to treatment. Adverse events (AEs) and blood analyses were registered at all visits and imaging performed before and three months post-treatment. Norwegian regulatory authorities have approved the study. CryoIT of the prostate was performed as a freeze-thaw process under anesthesia and autologous iDCs injected after last thawing cycle. Radiologic responses according to RECISTv1.1 could categorize participants into either Group 1; stable disease (n=5) or Group 2; progressive cancer (n=4). Three patients showed mixed response and one had no follow-up imaging. Hematologic and immunologic values were evaluated according to response group. To identify peripheral blood leukocyte subsets and circulating tumor cells (CTCs), ultradeep T-cell receptor (TCR) β-chain sequences of complementarity-determining region 3, we utilized flow / mass cytometry, Cellsearch System, and TCRSafe Technology, respectively. At inclusion median age was 69 (62-73) years, BMI 25.9 (25-35), ECOG score 0 (0-1) and median PSA 8 (5-11). Group 2 demonstrated higher PSA (p=0.03), median 3.9 (IQR 2.7-6.8) and 74.6 (IQR 47.4-99.0) for Group 1 and Group 2, respectively. In total, 13 possible iDC-related AEs were reported by 10 individuals, whereof one severe and 12 mild-to-moderate, with urinary retention in seven subjects. All but one resolved by use of indwelling urinary catheter for median 8 (1-40) days. Participants with high CTC numbers (>5) before therapy had higher rates of progression, moderate pre-treatment CTC counts (3-5) decreased and no patient acquired CTCs after therapy. Ultradeep TCR-sequencing showed more prevalent and higher expression (>5-fold) of new TCR clonotypes 2-6 weeks after treatment in Group 1. The treatment seems safe and well tolerated. Higher PSA indicates more advanced disease at baseline for Group 2. The data indicate immune responses to treatment with higher increases in TCR clonotypes in radiologic stable disease. Clinical trial ID: NCT02423928. Citation Format: Liv Cecilie V. Thomsen, Alfred Honorè, Bjarte Almås, Lars A. Reisæter, Jannicke Frugård, Einar K. Kristoffersen, Guro Melve, Torjan Haslerud, Jarle Rørvik, Martin Biermann, Svein Inge Helle, Gunnar Kvalheim, Waqas Azeem, Jan Roger Olsen, Ole Johan Halvorsen, Lars Akslen, Duke K. Bahn, Klaus Pantel, Sabine Riethdorf, Haakon Ragde, Bjørn Tore Gjertsen, Anne M. Øyan, Karl-Henning Kalland, Christian Beisland. Dendritic cell based cryoimmunotherapy associates with clinical variables and changes in T-cell receptor expression in a prospective phase I trial of metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT066.

Abstract LB-212: IMAAGEN study biomarker analysis in patients with long term response to abiraterone acetate with prednisone for non-metastatic castrate resistant prostate cancer

Abstract IMAAGEN is a phase 2, multicenter study evaluating 1000 mg abiraterone acetate + 5 mg prednisone (AAP) for the treatment of patients (pts) with high risk non-metastatic castration-resistant prostate cancer (nmCPRC). This study has been ongoing since 2010 and biomarker samples were obtained in 2016 from 30 pts who remained on study and were considered long-term responders (LTRs) with no evidence of progression. To investigate potential biomarkers associated with long-term response, RNA was extracted from whole blood and used for microarray analysis (Clariom D Genechip Expression Array) and Fluidigm qRT-PCR based 38 prostate cancer specific gene expression assay. The gene expression levels for these pts before treatment are not available for comparison. Microarray analysis showed expression of genes crucial for T cell effector function and anti-tumor immune response such as GZMB, GZMK, PRF1, CD3e are expressed at high levels. Pro-inflammatory cytokine expression such as IFNγ and IL-6 is low in these pts, possibly due to prednisone treatment. Expression of known checkpoint molecules that are expressed on T cells such as LAG-3 and PD-1 is uniformly low. Together, high T cell effector gene expression and low T cell checkpoint molecule expression suggests that these pts have T cells capable of enhanced immune surveillance which could prevent metastases. Genes that are crucial for tumor-induced immune-suppression by MDSC or macrophages such PD-L1, A2A receptor, IDO1, iNOS, Arginase, TIGIT and xCT are expressed at low levels in all 30 pts. Furthermore, known markers for granulocytic MDSC (G-MDSC) such as CD15, Arginase are expressed at a low level suggesting that there may be few G-MDSC in the blood of these pts. Accumulation of G-MDSC in the blood of prostate cancer pts has been shown to correlate with disease progression. Altogether, low levels of tumor-induced immune suppression concomitant with overall fitness and enhanced effector function of T cells may lead to enhanced immune surveillance and thus prevent metastases. Our qRT-PCR data showed that all LTRs have lower expression of 38 prostate cancer specific genes compared to historical control of pts with metastatic CRPC. No AR-V7, KLK2, KLK3, PITX2, and TMP.ERG expression is detected in any responder. NPY, cortical related gene, shows increased expression in LTRs compared with pts who have confirmed disease progression. This report presents a preliminary novel panel of immune and prostate-cancer specific biomarkers in pts with high-risk nmCPRC and should be further evaluated to see if they can be used for monitoring and predicting clinical response in prostate cancer trials. Citation Format: Olesya Chornoguz, Dong Shen, Gurpreet Kapoor, Weimin Li, Jennifer Phillips, Charles J. Ryan, E David Crawford, Neal D. Shore, Willie Underwood, Mary-Ellen Taplin, Philip W. Kantoff, Tracy McGowan. IMAAGEN study biomarker analysis in patients with long term response to abiraterone acetate with prednisone for non-metastatic castrate resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-212.

Abstract LB-309: Evaluation of ERG as a biomarker of responsiveness in a randomized trial of enzalutamide in combination with androgen deprivation in metastatic hormone sensitive prostate cancer

Abstract Background: TMPRSS2-ERG fusions are highly prevalent in prostate cancer patients, where androgen responsive TMPRSS2 gene promoter fused with coding sequence of ERG transcription factor resulting in androgen mediated expression of ERG factor. Metastatic cancer patients harbor the TMPRSS2-ERG fusions and presence of fusions associate with poor overall survival. The association between ERG transcription factor and anti-androgen therapy (enzalutamide (arm A) vs. bicalutamide (arm B)) responsiveness was evaluated in a randomized trial in metastatic hormone sensitive prostate cancer (mHSPC). Methods: 40 of 71 patients had evaluable tissue from metastatic biopsy. 18 patients were on enzalutamide arm (A) and 22 patients were on bicalutamide arm (B). PSA was monitored monthly for first 7 months and then every 3 months. Total RNA was isolated from biopsy specimens, QPCR analysis was performed for ERG gene. A standard curve was developed with ERG expressing plasmid in QPCR experiment and the copy number of ERG was determined in the metastatic biopsies. Seven month PSA Response (SMPR) rates were calculated for the high and low subset categories of median-dichotomized ERG copy number. The odds of SMPR was modeled as a function of continuous ungrouped correlative via univariable logistic regression. Results: 15/40 patients had both pre and post treatment biopsies available. The mean ERG copy number was increased in post treatment biopsy in both arms (enzalutamide, n=10 and bicalutamide, n=5). The mean copy increased (pre= 8541 and post =9789) upon enzalutamide treatment and also increased (pre=17186 and post = 23368) upon bicalutamide treatment. SMPR rates show that low copy number patients responded better (19/20) compared to high copy number patients (14/20). In arm A response rate is 100% (18/18), whereas in arm B, low ERG copy number patients responded better (8/11) compared to high copy number patients (7/11). Finally, the SMPR odds ratio remained close to 1.000 even for large copy number increase. Selective ERG responsive gene expression levels were determined in metastatic biopsies and will be associated with clinical endpoints. Conclusions: Enzalutamide improved the likelihood of PSA remission in mHSPC and follow up is ongoing. Metastatic biopsy specimen analysis show that higher ERG copy number had a lower likelihood of PSA response with ADT and may serve as a prognostic or predictive marker, but further analysis is warranted. Citation Format: Sreenivasa R. Chinni, Ulka N. Vaishampayan, Lance K. Heilbrun, Louie Semaan, Daryn Smith, Dipenkumar Modi, Paul Monk, Shiela Tejwani, Guru Sonpavde, Kimberlee Dobson, Brenda Dickow, Elisabeth Heath, Joseph Fontana, Micheal L. Cher. Evaluation of ERG as a biomarker of responsiveness in a randomized trial of enzalutamide in combination with androgen deprivation in metastatic hormone sensitive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-309.

Late Stage Prostate Cancer

Prostate cancer remains the second leading cause of cancer death in men and encapsulates a wide spectrum of disease. This review describes recent advances in genomic sciences and summarizes the impact of emerging molecular profiling–based clinical applications in the diagnosis and management of early and advanced prostate cancer. It addresses the controversial guidelines surrounding prostate-specific antigen–based screening for prostate cancer and summarizes the recommendations from six different agencies. This review highlights landmark clinical trials in metastatic prostate cancer, focusing on developments within the last 5 years. It also summarizes the rationale for earlier use of chemotherapy for newly diagnosed prostate cancer (chemohormonal therapy) and gives an overview of ongoing research into the development of novel genome-based therapeutics. This review contains 4 figures, 8 tables, and 74 references. Key words: castration resistant, molecular profiling, prostate cancer, screening guidelines, treatment options

Quality of radiotherapy reporting in randomized controlled trials of prostate cancer

BackgroundGood radiotherapy reporting in clinical trials of prostate radiotherapy is important because it will allow accurate reproducibility of radiotherapy treatment and minimize treatment variations that can affect patient outcomes. The aim of our study is to assess the quality of prostate radiotherapy (RT) treatment reporting in randomized controlled trials in prostate cancer.MethodsWe searched MEDLINE for randomized trials of prostate cancer, published from 1996 to 2016 and included prostate RT as one of the intervention arms. We assessed if the investigators reported the ten criteria adequately in the trial reports: RT dose prescription method; RT dose-planning procedures; organs at risk (OAR) dose constraints; target volume definition, simulation procedures; treatment verification procedures; total RT dose; fractionation schedule; conduct of quality assurance (QA) as well as presence or absence of deviations in RT treatment planning and delivery. We performed multivariate logistic regression to determine the factors that may influence the quality of reporting.ResultsWe found 59 eligible trials. There was significant variability in the quality of reporting. Target volume definition, total RT dose and fractionation schedule were reported adequately in 97% of included trials. OAR constraints, simulation procedures and presence or absence of deviations in RT treatment planning and delivery were reported adequately in 30% of included trials. Twenty-four trials (40%) reported seven criteria or more adequately. Multivariable logistic analysis showed that trials that published their quality assurance results and cooperative group trials were more likely to have adequate quality in reporting in at least seven criteria.ConclusionThere is significant variability in the quality of reporting on prostate radiotherapy treatment in randomized trials of prostate cancer. We need to have consensus guidelines to standardize the reporting of radiotherapy treatment in randomized trials.

Late toxicity in the randomized multicenter HYPRO trial for prostate cancer analyzed with automated treatment planning

Purpose/objectiveAssess to what extent the use of automated treatment planning would have reduced organ-at-risk dose delivery observed in the randomized HYPRO trial for prostate cancer, and estimate related toxicity reductions. Investigate to what extent improved plan quality for hypofractionation scheme as achieved with automated planning can potentially reduce observed enhanced toxicity for the investigated hypofractionation scheme to levels observed for conventional fractionation scheme. Material/methodsFor 725 trial patients, VMAT plans were generated with an algorithm for automated multi-criterial plan generation (autoVMAT). All clinically delivered plans (CLINICAL), generated with commonly applied interactive trial-and-error planning were also available for the investigations. Analyses were based on dose-volume histograms (DVH) and predicted normal tissue complication probabilities (NTCP) for late gastrointestinal (GI) toxicity. ResultsCompared to CLINICAL, autoVMAT plans had similar or higher PTV coverage, while large and statistically significant OAR sparing was achieved. Mean doses in the rectum, anus and bladder were reduced by 7.8 ± 4.7 Gy, 7.9 ± 6.0 Gy and 4.2 ± 2.9 Gy, respectively (p < 0.001). NTCPs for late grade ≥2 GI toxicity, rectal bleeding and stool incontinence were reduced from 23.3 ± 9.1% to 19.7 ± 8.9%, from 9.7 ± 2.8% to 8.2 ± 2.8%, and from 16.8 ± 8.5% to 13.1 ± 7.2%, respectively (p < 0.001). Reductions in rectal bleeding NTCP were observed for all published Equivalent Uniform Dose volume parameters, n. AutoVMAT allowed hypofractionation with predicted toxicity similar to conventional fractionation with CLINICAL plans. ConclusionCompared to CLINICAL, autoVMAT had superior plan quality, with meaningful NTCP reductions for both conventional fractionation and hypofractionation schemes. AutoVMAT plans might reduce toxicity for hypofractionation to levels that were clinically observed (and accepted) for conventional fractionation. This may be relevant when considering clinical use of the investigated hypofractionation schedule with relatively high fraction dose (3.4 Gy).

Risk factors for late bowel and bladder toxicities in NRG Oncology prostate cancer trials of high-risk patients: A meta-analysis of physician-rated toxicities

PurposeA meta-analysis of sociodemographic variables and their association with late (>180 days from start of radiation therapy[RT]) bowel, bladder, and clustered bowel and bladder toxicities was conducted in patients with high-risk (clinical stages T2c-T4b or Gleason score 8-10 or prostate-specific antigen level >20) prostate cancer. Methods and materialsThree NRG trials (RTOG 9202, RTOG 9413, and RTOG 9406) that accrued from 1992 to 2000 were used. Late toxicities were measured with the Radiation Therapy Oncology Group Late Radiation Morbidity Scale. After controlling for study, age, Karnofsky Performance Status, and year of accrual, sociodemographic variables were added to the model for each outcome variable of interest in a stepwise fashion using the Fine-Gray regression models with an entry criterion of 0.05. ResultsA total of 2432 patients were analyzed of whom most were Caucasian (76%), had a KPS score of 90 to 100 (92%), and received whole-pelvic RT+HT (67%). Of these patients, 13 % and 16% experienced late grade ≥2 bowel and bladder toxicities, respectively, and 2% and 3% experienced late grade ≥3 bowel and bladder toxicities, respectively. Late grade ≥2 clustered bowel and bladder toxicities were seen in approximately 1% of patients and late grade ≥3 clustered toxicities were seen in 2 patients (<1%). The multivariate analysis showed that patients who received prostate-only RT+HT had a lower risk of experiencing grade ≥2 bowel toxicities than those who received whole-pelvic RT+long-term (LT) HT (hazard ratio: 0.36; 95% confidence interval, 0.18-0.73; P = .0046 and hazard ratio: 0.43; 95% confidence interval, 0.23-0.80; P = .008, respectively). Patients who received whole-pelvic RT had similar chances of having grade ≥2 bowel or bladder toxicities no matter whether they received LT or short-term HT. ConclusionsPatients with high-risk prostate cancer who receive whole-pelvic RT+LT HT are more likely to have a grade ≥2 bowel toxicity than those who receive prostate-only RT. LT bowel and bladder toxicities were infrequent. Future studies will need to confirm these findings utilizing current radiation technology and patient-reported outcomes.

Chemotherapy and radiation for prostate cancer.

Over the past few decades there is growing appreciation for the role of chemotherapy in treatment of prostate cancer. Initial successful phase III randomized trials in castration resistant prostate cancer (CRPC) have led to additional successful trials in earlier presentations of disease. Given the established role of radiation in management of locally advanced disease and demonstrated efficacy of taxanes in treatment of prostate cancer, optimal combination of radiation and chemotherapy in this patient population has garnered increased attention. Successful phase III trials in this space have given additional stimulus to further exploring combination therapy with radiation. New directions include assessment of additional chemotherapeutic agents including cabazitaxel and PARP inhibitors as well as personalization of therapy with use of genomic testing and other emerging markers to guide therapeutic decisions.

Dendritic cell (DC) based cryoimmunotherapy (CryoIT) in a prospective phase I trial of metastatic castration resistant prostate cancer (mCRPC): Interim analysis.

e17014Background: Interim analysis data are presented for 13 pts with mCRPC treated with DC based CryoIT and at least 3 months follow-up (FU). CryoIT exposes tumor antigens in cryoablated tissue to...

PRM89 - Review of Frequently Implemented Patient Reported Outcomes in Current Prostate Cancer Clinical Trials

It is currently estimated that worldwide, prostate cancer will affect around 1 in 7 men during their lifetime. After lung cancer, it is the second highest cause of cancer deaths in men. This presents a widespread need for effective treatments. Patient reported outcomes (PROs) data provide useful insights into the symptoms and impacts experienced by patients, which can add supporting value to clinical trial endpoints when evaluating interventions. A number of PRO measures have been designed specifically for prostate cancer populations. This study provides a brief evaluation of the PROs most commonly used in current prostate cancer clinical trials. Clinicaltrials.gov was used to identify prostate cancer trials that include PROs as primary, secondary or exploratory endpoints. Search criteria were set to ensure that only interventional trials, currently recruiting and without results were included. From the search, 188 trials were identified. These included both generic and prostate cancer specific PROs. The five most common PROs were reviewed in accordance with regulatory guidelines. These were; the EPIC (n=38), the EORTC QLQ-C30 (n=31), the FACT-P (n=26), the IPSS (n=16) and the EORTC QLQ PR-25 (n=9). A review of these identified key features regarding their use. For example, although the EPIC is the most frequently used PRO, the recall period of four weeks may not always be appropriate depending on illness progression. Furthermore, the IPSS is just eight-items long, this can be beneficial as it reduces patient burden and thus increases compliance. However, it is important to evaluate whether this brief measure has sufficient conceptual coverage to assess total patient experience. Several validated measures exist in prostate cancer populations. Comparisons have been made between those most commonly used; their benefits and drawbacks have been summarized in this study. These findings should be considered when selecting an appropriate PRO to include in clinical trials.

Emerging Therapies in Metastatic Prostate Cancer.

In the last decade, there have been multiple landmark therapeutic advances for the treatment of metastatic prostate cancer, both in the castration-resistant and hormone-sensitive setting. In this review, we highlight recent progress and ongoing trials for metastatic prostate cancer, including advances in chemotherapy, androgen receptor-directed therapy, targeted therapies, and immunotherapy. Several landmark studies for men with metastatic hormone-sensitive prostate cancer demonstrated improvement in overall survival with the addition of docetaxel chemotherapy or abiraterone acetate to standard androgen deprivation therapy. A single-arm phase 2 study of the PARP inhibitor olaparib demonstrated high response rates and more favorable progression-free and overall survival for men with metastatic castration-resistant prostate cancer and DNA repair defects treated with olaparib compared with men without DNA repair defects. Multiple ongoing clinical trials are investigating novel hormonal therapies and combinations of chemotherapy, targeted small molecules, immunotherapy, and radiopharmaceuticals. Progress continues to be made in the treatment of metastatic prostate cancer, and ongoing clinical trials continue to investigate novel agents and approaches to treatment.

Impact of Radiation Therapy Dose Escalation on Prostate Cancer Outcomes and Toxicities.

Freedom from biochemical failure (FFBF) is a common primary outcome of randomized-controlled trials of prostate cancer (PCa). We aimed to determine how increasing the PCa biologically equivalent dose (BED) of external radiation therapy (RT) is correlated with FFBF and overall patient outcomes: overall survival (OS), distant metastasis (DM), and cancer-specific mortality (CSM); as well as genitourinary (GU), and gastrointestinal toxicities. We performed a meta-analysis of 6884 PCa patients from 12 randomized-controlled trials of external beam RT. Mixed effects regression models were used to estimate weighted linear relationships between BED and observed percentages of 5- and 10-year outcomes. For toxicities, a subset analysis of using 3-dimensional conformal RT (3D-CRT) versus intensity-modulated RT (IMRT) was performed. Increasing BED correlated with improved FFBF: 10-year absolute improvement of 9.6% and 7.2% for low-risk and intermediate-risk patients, respectively (P<0.05); but not with improvement of OS, DM, or CSM at either time point. BED escalation was not correlated with increased acute toxicities; it was correlated with increased late gastrointestinal toxicities in patients treated with 3D-CRT (1.5% increase over BED range, P<0.01). IMRT patients had significantly fewer late toxicities, despite being treated at higher BED. RT BED escalation has resulted in significantly improved PCa FFBF at up to 10 years; but not with improvement in OS, DM, or CSM. Thus, FFBF is a poor surrogate of overall patient outcomes for trials of RT. Late toxicities were less frequent with IMRT than with 3D-CRT, even at higher BED.

Pair-matched patient-reported quality of life and early oncological control following focal irreversible electroporation versus robot-assisted radical prostatectomy

PurposeThe design, conduct and completion of randomized trials for curative prostate cancer (PCa) treatments are challenging. To evaluate the effect of robot-assisted radical prostatectomy (RARP) versus focal irreversible electroporation (IRE) on patient-reported quality of life (QoL) and early oncological control using propensity-scored matching.MethodsPatients with T1c–cT2b significant PCa (high-volume ISUP 1 or any 2/3) who received unifocal IRE were pair-matched to patients who received nerve-sparing RARP. Patient-reported outcomes were prospectively assessed using the Expanded Prostate Cancer Index Composite (EPIC), AUA symptom score and Short Form of Health Survey (SF-12) physical and mental components. Oncological failure was defined as biochemical recurrence (RARP) or positive follow-up biopsies (IRE). Generalized mixed-effect models were used to compare IRE and RARP.Results50 IRE patients were matched to 50 RARP patients by propensity score. IRE was significantly superior to RARP in preserving pad-free continence (UC) and erections sufficient for intercourse (ESI). The absolute differences were 44, 21, 13, 14% for UC and 32, 46, 27, 22% for ESI at 1.5, 3, 6, and 12 months, respectively. The EPIC summary scores showed no statistically significant differences. Urinary symptoms were reduced for IRE and RARP patients at 12 months, although IRE patient initially had more complaints. IRE patients experienced more early oncological failure than RARP patients.ConclusionsThese data demonstrated the superior preservation of UC and ESI with IRE compared to RARP up to 12 months after treatment. Long-term oncological data are warranted to provide ultimate proof for or against focal therapy.

Patient-centered recruitment and retention for a randomized controlled study

BackgroundRecruitment and retention strategies for patient-centered outcomes research are evolving and research on the subject is limited. In this work, we present a conceptual model of patient-centered recruitment and retention, and describe the recruitment and retention activities and related challenges in a patient-centered comparative effectiveness trial.MethodsThis is a multicenter, longitudinal randomized controlled trial in localized prostate cancer patients.ResultsWe recruited 743 participants from three sites over 15 months period (January 2014 to March 2015), and followed them for 24 months. At site 1, of the 773 eligible participants, 551 (72%) were enrolled. At site 2, 34 participants were eligible and 23 (68%) enrolled. Of the 434 eligible participants at site 3, 169 (39%) enrolled. We observed that strategies related to the concepts of trust (e.g., physician involvement, ensuring protection of information), communication (e.g., brochures and pamphlets in physicians’ offices, continued contact during regular clinic visits and calling/emailing assessment), attitude (e.g., emphasizing the altruistic value of research, positive attitude of providers and research staff), and expectations (e.g., full disclosure of study requirements and time commitment, update letters) facilitated successful patient recruitment and retention. A stakeholders’ advisory board provided important input for the recruitment and retention activities. Active engagement, reminders at the offices, and personalized update letters helped retention during follow-up. Usefulness of telephone recruitment was site specific and, at one site, the time requirement for telephone recruitment was a challenge.ConclusionsWe have presented multilevel strategies for successful recruitment and retention in a clinical trial using a patient-centered approach. Our strategies were flexible to accommodate site-level requirements. These strategies as well as the challenges can aid recruitment and retention efforts of future large-scale, patient-centered research studies.Trial registrationClinicaltrials.gov, ID: NCT02032550. Registered on 22 November 2013.