Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol

Background: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival. Methods: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0–2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544). Findings: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86–107) in the abiraterone trial and 72 months (61–74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8–86·9) in the abiraterone group versus 45·7 months (41·6–52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53–0·73]; p<0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9–81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3–59·0) in the standard of care group (HR 0·65 [0·55–0·77]; p<0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83–1·32]; pinteraction=0·71) or between-trial heterogeneity (I2 p=0·70). In the first 5 years of treatment, grade 3–5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (<1%) with standard of care in the abiraterone trial). Interpretation: Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years. Funding: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

One dose of immunotherapy leading to an exceptional and durable response in a patient with metastatic renal cell carcinoma

ABSTRACT A 72-year-old man with metastatic clear cell renal carcinoma, who had progressed after previous treatment with Sunitinib and Axitinib, was given one dose of immunotherapy. He was initially unwell after treatment with fever, shortness of breath, chest pain and raised inflammatory markers. Following this he elected not to have any further immunotherapy. Before the treatment he had multiple pulmonary metastases and hilar and mediastinal lymph nodes on chest X-ray and suffered with a persistent cough. Chest X-ray 10 months after treatment showed normal appearances and his cough had largely resolved. The patient initially declined repeat computed tomography imaging but agreed to it 2 years after the immunotherapy, the results showed a maintained response. Some patients with renal cell carcinoma show a durable response to immunotherapy but we are not aware of other published cases where a patient has shown such a dramatic and sustained response to one dose.</jats:p

Second line axitinib in metastatic renal cell carcinoma: Evaluation of prognostic factors influencing outcome.

495 Background: Axitinib has been approved for 2nd line treatment in the UK for patients with advanced renal cell carcinoma on the basis of the AXIS study, which showed improved progression free survival (PFS) and a trend towards overall survival (OS) benefit. There is no randomised data to support the use of Axitinib after first line Pazopanib. Hence, we compared the efficacy of Axitinib after first line Pazopanib or Sunitinib. The influence of Heng prognostic risk score (HPRS) at initiation of Axitinib, previous nephrectomy, and haemoglobin (Hb) rise during Axitinib treatment on outcome was also evaluated. Methods: Thirty one patients were commenced on Axitinib between May 2013-May 2016. Patient demographics, laboratory parameters, and survival data were collected retrospectively. Data were analysed in October 2016, which served as a censor date for patients who were alive. Analysis of PFS and OS was performed by Kaplan-Meier estimates and log-rank test. Results: All 31 patients received axitinib as 2nd line treatment. At the time of analysis, 14 patients were alive and 7 remained on axitinib. The prognostic factors influencing outcome are shown in the table. Conclusions: There was no significant difference in PFS or OS regardless of first line treatment, supporting the use of axitinib post pazopanib or sunitinib. Prior nephrectomy, and favourable HPRS significantly predict better PFS and OS. The impact of Hb rise needs further validation in a larger cohort.[Table: see text] </jats:p

Transperineal ultrasound for aiding target volume delineation and monitoring during prostate cancer radiotherapy in men with bilateral hip prostheses

AbstractAims:To investigate the use of co-registration of the computerised tomography (CT) planning scan with transperineal ultrasound (TPUS) as an aid to the delineation of the clinical target volume (CTV), and the use of TPUS as a tool for inter- and intra-fractional monitoring in men with bilateral hip prostheses (b-P) undergoing prostate radiotherapy.Materials and methods:We marked the CTV of three patients with and without the co-registered TPUS images. A metal artefact reduction algorithm was utilised. Two patients were treated with intensity-modulated radiotherapy (IMRT) and one with volumetric-modulated arc therapy (VMAT). The inter- and intra-fractional monitoring details were reviewed retrospectively.Results:Clinician marking with TPUS/CT fusion improved the confidence of prostate CTV delineation leading to a consistent change in volumes across two observers. Inter- and intra-fractional monitoring was possible using TPUS as image guidance, as it is for those patients with non-prosthetic hips.Findings:Using TPUS in the radiotherapy workflow has enabled us to more confidently plan, treat and monitor patients with b-HP. Due to transperineal image acquisition, the ultrasound images are not affected by the presence of hip prostheses, which are outside the field of view.</jats:sec

A randomized controlled trial to determine the effect of triptorelin on reduction of prostate volume preradiotherapy compared with standard therapy (goserelin).

30 Background: Hormone therapy in combination with radiotherapy is a curative treatment option for prostate cancer (CaP). Neoadjuvant goserelin is known to reduce prostate gland volume by about 26%, such that radiotherapy treatment volumes are smaller, reducing the risk of damage to bladder and rectum. Triptorelin is 100 times more potent than native LHRH and has a longer half life than both native LHRH and goserelin. This study evaluated the equivalence of cytoreductive efficacy of neoadjuvant triptorelin and goserelin. Methods: Seventy-onepatients with localized CaP who have chosen radical radiotherapy had been randomized by stratified block design, toreceive either triptorelin (n=37) or goserelin (n=34) with bicalutamide cover. Prostate volume was measured at baseline and 14 weeks after start of therapy on transrectal ultrasound (TRUS). PSA, testosterone levels, and EQ5D, QLQ-PR25, QLQ-C30 questionnaires were completed at baseline, 6, 10, and 14 weeks after start of therapy. All the patients had subsequent radical radiotherapy and followed up as per departmental protocol. Changes in TRUS volume and time to castrate levels of testosterone were evaluated. Results: The mean (±S.D) baseline prostate volume in the goserelin and triptorelin groups was 38.1(±12.8) cc and 39.4(±17.5) cc, respectively. The mean (±S.D) reduction in the prostate volume after 14 weeks of goserelin and triptorelin was 36.8(±18.4)% and 32.5(±20.9)%, respectively (p=0.36: Analysis of Covariance). Twenty-nine out of 34 in the goserelin group and 33 out of 37 patients in the triptorelin group achieved castrate levels of testosterone (£0.5nmol/L). The median time to castration was 6.1 (95% CI: 5.8-6.5) and 6.4 (95% CI: 5.9-10.0) weeks for goserelin and triptorelin, respectively (p=0.72: log rank). Conclusions: Goserelin and triptorelin both caused a reduction inprostate volume and achieved castrate levels of testosterone. The cytoreductive efficacy of neoadjuvant triptorelin was equivalent (non-inferior) to that of goserelin. To our knowledge, this is the first reported prospective randomized data demonstrating the equivalence of goserelin and triptorelin in the neoadjuvant setting. Clinical trial information: 2008-007028-25. </jats:p

A study of the clinical, treatment planning and dosimetric feasibility of dose painting in external beam radiotherapy of prostate cancer

Background and purpose: Radiotherapy dose painting is a promising technique which enables dose escalation to areas of higher tumour cell density within the prostate which are associated with radioresistance, known as dominant intraprostatic lesions (DILs). The aim of this study was to determine factors affecting the feasibility of radiotherapy dose painting in patients with high and intermediate risk prostate cancer. Materials &amp; Methods: Twenty patients were recruited into the study for imaging using a 3 T magnetic resonance imaging (MRI) scanner. Identified DILs were outlined and the scan registered with the planning computed tomography (CT) dataset. Intensity-modulated plans were produced and evaluated to determine the effect of the organ-at-risk constraints on the dose that could be delivered to the DILs. Measurements were made to verify that the distribution could be safely delivered. Results: MRI scans were obtained for nineteen patients. Fourteen patients had one to two DILs with ten overlapping the urethra and/or rectum. The target boost of 86 Gy was achieved in seven plans but was limited to 80 Gy for five patients whose boost volume overlapped or abutted the urethra. Dosimetric measurements gave a satisfactory gamma pass rate at 3%/3 mm. Conclusions: It was feasible to produce dose-painted plans for a boost of 86 Gy for approximately half the patients with DILs. The main limiting factor was the proximity of the urethra to the boost volumes. For a small proportion of patients, rigid registration between CT and MRI images was not adequate for planning purposes

Predictors of improved biochemical progression free survival for salvage prostate bed radiotherapy after radical prostatectomy.

38 Predictors of improved biochemical progression free survival for salvage prostate bed radiotherapy after radical prostatectomy Background: About a third of patients undergoing radical prostatectomy (RP) develop biochemical recurrence, the rate of which increases to ~50% in high risk patients, with adverse features such as positive margins &amp; seminal vesicle invasion. Postop salvage radiotherapy (SRT) to the prostate bed improves biochemical progression free survival (bPFS). We sought to evaluate the benefit of SRT and predictors of bPFS. Methods: Patients who received SRT from Jan11 to Dec15 were retrospectively analysed. All patients had prostate bed radiotherapy (66Gy/33#/6.5wks). Hormone therapy (HT), when used was for a short duration of 3-6 months. PSA relapse after SRT was defined as serum PSA rising above the posttreatment nadir to a level of ≥0.2 ng/mL or by the initiation of HT after completion of SRT. The bPFS was calculated as the time from start of SRT till date of undetectable PSA, analysed by Kaplan-Meier estimates and log-rank test. Results: Overall, 111 patients were analysed. Median follow-up was 46 (range; 6-80) months. 46% (51/111) patients received HT. The median pre-SRT PSA was 0.4 ng/mL (range, 0.07 to 4.9). The bPFS rate was 60.4% overall, 65%for those with a pre-SRT PSA (ng/mL) level of ≤0.5 (n = 74), 53.6% for those with a PSA of &gt; 0.5 to ≤1.5 (n = 28), 44.4% for those with a PSA of &gt; 1.5 (n = 9); (p = 0.33). There was no significant difference in bPFS rates for pre-SRT PSA of ≤0.2 compared to PSA ≤0.5. Significantly improved bPFS rates were seen with an interval of &gt; 6m from detectable PSA to start of SRT (69% vs. 46.5%: p = 0.026), and a trend towards better bPFS rates when the time interval was &gt; 24m from RP to first detectable PSA (73% vs. 53%: p = 0.08). However, bPFS was similar in the proportion of patients (46%) who had HT compared to those (54%) who did not have HT. Conclusions: We have shown that there was no significant difference in bPFS rates between early (detectable PSA at 0.2) and deferred SRT and our data supports the practice of deferred SRT prior to PSA going above 0.5. Short course of HT was not shown to improve bPFS. The ongoing RADICALS and RAVE trials will further clarify these aspects. </jats:p