Capivasertib in combination with enzalutamide for metastatic castration resistant prostate cancer after docetaxel and abiraterone: Results from the randomized phase II RE-AKT trial.

BACKGROUND: PTEN loss and aberrations in PI3K/AKT signaling kinases associate with poorer response to abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC). In this study, we assessed antitumor activity of the AKT inhibitor capivasertib combined with enzalutamide in mCRPC with prior progression on AA and docetaxel. METHODS: This double-blind, placebo-controlled, randomized phase 2 trial, recruited men ≥ 18 years with progressing mCRPC and performance status 0-2 from 15 UK centers. Randomized participants (1:1) received enzalutamide (160 mg orally, once daily) with capivasertib (400 mg)/ placebo orally, twice daily on an intermittent (4 days on, 3 days off) schedule. Primary endpoint was composite response rate (RR): RECIST 1.1 objective response, ≥ 50 % PSA decrease from baseline, or circulating tumor cell count conversion (from ≥ 5 at baseline to < 5 cells/7.5 mL). Subgroup analyses by PTENIHC status were pre-planned. RESULTS: Overall, 100 participants were randomized (50:50); 95 were evaluable for primary endpoint (47:48); median follow-up was 43 months. RR were 9/47 (19.1 %) enzalutamide/capivasertib and 9/48 (18.8 %) enzalutamide/placebo (absolute difference 0.4 % 90 %CI -12.8 to 13.6, p = 0.58), with similar results in the PTENIHC loss subgroup. Irrespective of treatment, OS was significantly worse for PTENIHC loss (10.1 months [95 %CI: 4.6-13.9] vs 14.8 months [95 %CI: 10.8-18]; p = 0.02). Most common treatment-emergent grade ≥ 3 adverse events for the combination were diarrhea (13 % vs 2 %) and fatigue (10 % vs 6 %). CONCLUSIONS: Combined capivasertib/enzalutamide was well tolerated but didn't significantly improve outcomes from abiraterone pre-treated mCRPC.

Planned organ preservation for elderly patients with rectal cancer using short course radiotherapy and a contact brachytherapy boost-an International multi-institution analysis.

Background and purpose: The use of external beam radiotherapy (EBRT) and contact X-Ray brachytherapy (CXB) is emerging as an effective alternative in patients with early stage rectal cancer with the intent of organ preservation (OP). Short course radiotherapy (SCRT) is an alternative EBRT schedule for patients not fit for chemotherapy or for longer courses of EBRT. There are no multicentre studies that have reported on the outcomes of SCRT with a CXB boost, therefore we present these from patients from centres from the UK and Sweden. Materials and methods: From the Guildford Colorectal Database or local databases, 258 patients who underwent SCRT and CXB with the intent of OP from five centres treated between 2007 and 2019 were identified. Response and survival data was analysed and presented. Results: With a median age of 81, 226 patients were treated with radiotherapy alone (RTA) and 32 immediately after local excision (ILE). Median follow-up was 24 months. 70% and 97% of patients in the RTA and ILE groups respectively had a complete clinical response (cCR) after SCRT with CXB. Of those, local relapse was seen in 16% of the RTA and 3% of the ILE group. Median survival was 40 months after CXB in the RTA and 52 months in the ILE group. 94% of patients remained stoma-free to the point of latest follow-up. Conclusion: This data suggests that CXB when combined with SCRT, in a mainly elderly and comorbid population, provides good palliation with stoma-avoidance. Oncological outcomes compare with previously published work. A greater focus is required on quality of life outcomes after OP.

An international Delphi consensus for pelvic stereotactic ablative radiotherapy re-irradiation.

INTRODUCTION: Stereotactic Ablative Radiotherapy (SABR) is increasingly used to treat metastatic oligorecurrence and locoregional recurrences but limited evidence/guidance exists in the setting of pelvic re-irradiation. An international Delphi study was performed to develop statements to guide practice regarding patient selection, pre-treatment investigations, treatment planning, delivery and cumulative organs at risk (OARs) constraints. MATERIALS AND METHODS: Forty-one radiation oncologists were invited to participate in three online surveys. In Round 1, information and opinion was sought regarding participants' practice. Guidance statements were developed using this information and in Round 2 participants were asked to indicate their level of agreement with each statement. Consensus was defined as ≥75% agreement. In Round 3, any statements without consensus were re-presented unmodified, alongside a summary of comments from Round 2. RESULTS: Twenty-three radiation oncologists participated in Round 1 and, of these, 21 (91%) and 22 (96%) completed Rounds 2 and 3 respectively. Twenty-nine of 44 statements (66%) achieved consensus in Round 2. The remaining 15 statements (34%) did not achieve further consensus in Round 3. Consensus was achieved for 10 of 17 statements (59%) regarding patient selection/pre-treatment investigations; 12 of 13 statements (92%) concerning treatment planning and delivery; and 7 of 14 statements (50%) relating to OARs. Lack of agreement remained regarding the minimum time interval between irradiation courses, the number/size of pelvic lesions that can be treated and the most appropriate cumulative OAR constraints. CONCLUSIONS: This study has established consensus, where possible, in areas of patient selection, pre-treatment investigations, treatment planning and delivery for pelvic SABR re-irradiation for metastatic oligorecurrence and locoregional recurrences. Further research into this technique is required, especially regarding aspects of practice where consensus was not achieved.

Does prostate HistoScanning™ play a role in detecting prostate cancer in routine clinical practice? Results from three independent studies.

OBJECTIVES: To evaluate the ability of prostate HistoScanning™ (PHS; Advanced Medical Diagnostics, Waterloo, Belgium) to detect, characterize and locally stage prostate cancer, by comparing it with transrectal ultrasonography (TRUS)-guided prostate biopsies, transperineal template prostate biopsies (TTBs) and whole-mount radical prostatectomy specimens. SUBJECTS AND METHODS: Study 1. We recruited 24 patients awaiting standard 12-core TRUS-guided biopsies of the prostate to undergo PHS immediately beforehand. We compared PHS with the TRUS-guided biopsy results in terms of their ability to detect cancer within the whole prostate and to localize it to the correct side and to the correct region of the prostate. Lesions that were suspicious on PHS were biopsied separately. Study 2. We recruited 57 patients awaiting TTB to have PHS beforehand. We compared PHS with the TTB pathology results in terms of their ability to detect prostate cancer within the whole gland and to localize it to the correct side and to the correct sextant of the prostate. Study 3. We recruited 24 patients awaiting radical prostatectomy for localized prostate cancer to undergo preoperative PHS. We compared PHS with standardized pathological analysis of the whole-mount prostatectomy specimens in terms of their measurement of total tumour volume within the prostate, tumour volume within prostate sextants and volume of index lesions identified by PHS. RESULTS: The PHS-targeted biopsies had an overall cancer detection rate of 38.1%, compared with 62.5% with standard TRUS-guided biopsies. The sensitivity and specificity of PHS for localizing tumour to the correct prostate sextant, compared with standard TRUS-guided biopsies, were 100 and 5.9%, respectively. The PHS-targeted biopsies had an overall cancer detection rate of 13.4% compared with 54.4% for standard TTB. PHS had a sensitivity and specificity for cancer detection in the posterior gland of 100 and 13%, respectively, and for the anterior gland, 6 and 82%, respectively. We found no correlation between total tumour volume estimates from PHS and radical prostatectomy pathology (Pearson correlation coefficient -0.096). Sensitivity and specificity of PHS for detecting tumour foci ≥0.2 mL in volume were 63 and 53%. CONCLUSIONS: These three independent studies in 105 patients suggest that PHS does not reliably identify and characterize prostate cancer in the routine clinical setting.

Correlation between prostate brachytherapy-related urethral stricture and peri-apical urethral dosimetry: a matched case-control study.

BACKGROUND AND PURPOSE: Radiation dose to the bulbomembranous urethra has been shown to correlate with urethral stricture formation. This retrospective case-control study was designed to explore the relationship between dose to the apical/peri-apical regions of the urethra and development of brachytherapy (BXT)-related urethral stricture. MATERIALS AND METHODS: Cases were patients who developed urethral stricture after treatment with BXT as monotherapy and who had urethral dosimetry post-implant. Each case was matched with a control that had not developed urethral stricture. Dosimetry was compared between cases and controls. RESULTS: Twenty-three cases were pair matched with 23 controls. There were no significant differences between the two groups in terms of age, presenting Prostate Specific Antigen (PSA), International Prostate Symptom Score (IPSS) or Gleason score. The dose delivered to the peri-apical and apical urethra was significantly higher for cases when compared with controls (peri-apical urethra: mean V(150) 1.1 Vs 0.8 cc [p=0.02]; apical urethra: mean dose 200 Vs 174 Gy [p=0.01]). The distance from the prostate apex to isodose lines was also found to be significant in predicting stricture formation. CONCLUSION: There was evidence to suggest that the development of BXT-related stricture was associated with radiation dose at the apical and peri-apical urethra. Attention to the dose delivered to those areas may minimise the risk of developing such morbidity.

Long-term toxicity and quality of life up to 10 years after low-dose rate brachytherapy for prostate cancer.

OBJECTIVE: To report on the long-term toxicity outcome for patients with prostate cancer treated by low-dose rate (LDR) brachytherapy (BXT). PATIENTS AND METHODS: The study population comprised a cohort of men treated in our centre between March 1999 and April 2004 with LDR BXT for prostate cancer who had at least 5 years of follow-up post-implant. Patients who had died or experienced biochemical failure were excluded. We contacted eligible patients and asked them to complete a questionnaire to assess current urinary, erectile and bowel function. Urinary and erectile function was compared pre- and post-treatment and outcomes were assessed by treatment modality. RESULTS: Of the 226 LDR BXT-treated patients with >5 years of follow-up, 174 (77.0%) responded to the questionnaire. The mean International Prostate Symptom Score (IPSS) increased from 6.70 pre-BXT to 7.91 at follow-up (P = 0.003). Of the patients with mild symptoms pre-BXT (IPSS, 0-7), 64.2% retained mild symptoms at follow-up, 31.2% developed moderate symptoms (IPSS, 8-9) and 4.6% reported severe symptoms (IPSS, 20-35). A good or acceptable quality of life (QoL) secondary to urinary symptoms (IPSS QoL, 0-4) was reported by 98.0% of respondents. Of those patients potent (International Index of Erectile Function-5 ≥11) pre-BXT, 62.9% remained potent at follow-up. There were no differences in the proportion of patients who were potent when analyzed by the number of years post-implant. At follow-up, 51.7% and 45.4% of patients, respectively, had normal or mild bowel symptoms as indicated by the European Organisation for the Research and Treatment of Cancer questionnaire (QLQ-C30/PR25 scores, 4-8). Moderate bowel symptoms (QLQ-C30/PR25 scores, 9-12) were reported by 2.9% of respondents; none reported severe symptoms. CONCLUSION: The present study shows low morbidity after LDR BXT over the long-term for a large cohort of patients.