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PURPOSE Capivasertib is a pan-AKT inhibitor. Preclinical data indicate activity in metastatic castration-resistant prostate cancer (mCRPC) and synergism with docetaxel. PATIENTS AND METHODS ProCAID was a placebo controlled randomized phase II trial in mCRPC. Patients received up to ten 21-day cycles of docetaxel (75 mg/m2 intravenous, day 1) and prednisolone (5 mg twice daily, oral, day 1-21) and were randomly assigned (1:1) to oral capivasertib (320 mg twice daily, 4 days on/3 days off, from day 2 each cycle), or placebo, until disease progression. Treatment allocation used minimization factors: bone metastases; visceral metastases; investigational site; and prior abiraterone or enzalutamide. The primary objective, by intention to treat, determined if the addition of capivasertib prolonged a composite progression-free survival (cPFS) end point that included prostate-specific antigen progression events. cPFS and overall survival (OS) were also assessed by composite biomarker subgroup for PI3K/AKT/PTEN pathway activation status. RESULTS One hundred and fifty patients were enrolled. Median cPFS was 7.03 (95% CI, 6.28 to 8.25) and 6.70 months (95% CI, 5.52 to 7.36) with capivasertib and placebo respectively (hazard ratio [HR], 0.92; 80% CI, 0.73 to 1.16; one-sided P = .32). Median OS was 31.15 (95% CI, 20.07 to not reached) and 20.27 months (95% CI, 17.51 to 24.18), respectively (HR, 0.54; 95% CI, 0.34 to 0.88; two-sided P = .01). cPFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway activation status. Grade III-IV adverse events were equivalent between arms (62.2%). The most common adverse events of any grade deemed related to capivasertib were diarrhea, fatigue, nausea, and rash. CONCLUSION The addition of capivasertib to chemotherapy did not extend cPFS in mCRPC irrespective of PI3K/AKT/PTEN pathway activation status. The observed OS result (a secondary end point) will require prospective validation in future studies to address potential for bias.

436 Background: A subset of mUC exhibits a DNA repair deficiency (DRD) phenotype predicting benefit from platinum based chemotherapy (PBC). We hypothesised that switch maintenance therapy with the PARP inhibitor rucaparib, in patients who have derived clinical benefit from PBC, would improve outcomes for patients with mUC harbouring a DRD biomarker. Methods: ATLANTIS is an adaptive, multi-comparison, phase II trial platform. It tests multiple biomarker selected maintenance therapies for mUC after 4 to 8 PBC cycles without disease progression. Biomarker allocation to the rucaparib comparison was based on ≥10% genomic loss of heterozygosity (%LOH) and/or somatic alteration in defined DRD associated genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD54L) and/or germline BRCA1 or BRCA2 alteration. Biomarker positive patients were randomised (1:1) to maintenance rucaparib 600 mg BID PO, or matched placebo, within 10 weeks of completing PBC, until disease progression. The primary endpoint was progression free survival (PFS). Statistical analysis (data cut 17/Nov/2021) was pre-planned to target a hazard ratio of 0.5. We selected a 20% 1-sided alpha for this signal seeking phase II trial with 85.4% power (requiring 30 PFS events in 40 patients). PFS (RECIST 1.1) was compared between trial arms, by intention to treat, within a Cox model incorporating baseline minimisation factors. Adverse events (AE) were assessed by CTCAE v4.03. Results: 74 of 279 (26.5%) screened patients were biomarker positive. 40 were randomised within the rucaparib comparison (Dec 2017-Dec 2020). Biomarker positive status was by high %LOH in 22 (55%), DRD gene alteration in 11 (27.5%) and both in 7 (17.5%). Patient characteristics (median age 70.5; 82.5% male; 87.5% bladder primary; 52.5% ECOG PS 0; 62.5% prior cisplatin; 45% visceral metastases) were balanced by treatment arm. 12 (60%) and 20 (100%) PFS events have occurred in the rucaparib and placebo arms respectively (median duration follow up 94.6 weeks in those still alive). Median PFS was 35.3 weeks (80% confidence interval (CI) 11.7-35.6) with rucaparib and 15.1 weeks (80% CI 11.9-22.6) with placebo (hazard ratio 0.53, 80% CI 0.30-0.92, 1 sided p = 0.07). In the safety population (n = 39) treatment related adverse events were mostly low grade. Rucaparib was tolerable with a median duration of 10 rucaparib or 6 placebo cycles on treatment. The most frequent treatment related AEs (all grades) of fatigue (63.2% vs 30.0%, p = 0.03), nausea (36.9% vs 5.0%, p = 0.03) and rash (21.1% vs 0%, p = 0.04) were more common with rucaparib respectively. Conclusions: Maintenance rucaparib, following PBC, extended PFS in DRD biomarker selected patients with mUC and is tolerable. Further investigation of PARP inhibition for mUC is warranted. Clinical trial information: 25859465.

Purpose Up to 30% of patients who undergo radiation for intermediate- or high-risk localized prostate cancer relapse biochemically within 5 years. We assessed if biochemical disease-free survival (DFS) is improved by adding 6 months of androgen suppression (AS; two injections of every-3-months depot of luteinizing hormone–releasing hormone agonist) to primary radiotherapy (RT) for intermediate- or high-risk localized prostate cancer. Patients and Methods A total of 819 patients staged: (1) cT1b-c, with prostate-specific antigen (PSA) ≥ 10 ng/mL or Gleason ≥ 7, or (2) cT2a (International Union Against Cancer TNM 1997), with no involvement of pelvic lymph nodes and no clinical evidence of metastatic spread, with PSA ≤ 50 ng/mL, were centrally randomized 1:1 to either RT or RT plus AS started on day 1 of RT. Centers opted for one dose (70, 74, or 78 Gy). Biochemical DFS, the primary end point, was defined from entry until PSA relapse (Phoenix criteria) and clinical relapse by imaging or death of any cause. The trial had 80% power to detect hazard ratio (HR), 0.714 by intent-to-treat analysis stratified by dose of RT at the two-sided α = 5%. Results The median patient age was 70 years. Among patients, 74.8% were intermediate risk and 24.8% were high risk. In the RT arm, 407 of 409 patients received RT; in the RT plus AS arm, 403 patients received RT plus AS and three patients received RT only. At 7.2 years median follow-up, RT plus AS significantly improved biochemical DFS (HR, 0.52; 95% CI, 0.41 to 0.66; P < .001, with 319 events), as well as clinical progression-free survival (205 events, HR, 0.63; 95% CI, 0.48 to 0.84; P = .001). In exploratory analysis, no statistically significant interaction between treatment effect and dose of RT could be evidenced (heterogeneity P = .79 and P = .66, for biochemical DFS and progression-free survival, respectively). Overall survival data are not mature yet. Conclusion Six months of concomitant and adjuvant AS improves biochemical and clinical DFS of intermediate- and high-risk cT1b-c to cT2a (with no involvement of pelvic lymph nodes and no clinical evidence of metastatic spread) prostatic carcinoma, treated by radiation.

5520 Background: DP extends survival in mCRPC, but clinical benefit is modest. PI3K/AKT/PTEN pathway activation is common in mCRPC contributing to disease progression and DP resistance. C is a pan-AKT inhibitor. Pre-clinical data indicate activity in prostate cancer and synergism with DP. This phase II trial combined C with DP in mCRPC. Methods: Key eligibility criteria: histologically or cytologically proven measurable or evaluable mCRPC, suitable for treatment with DP for PSA and/or radiographic disease progression, ECOG performance status 0-1, no prior chemotherapy for mCRPC, not requiring insulin or > 2 oral hypoglycaemic drugs for diabetes mellitus. Treatment: up to 10 cycles of DP (D: 75 mg/m2 IV, day 1; P: 5 mg bd oral, day 1 – 21) and random assignment (1:1, double blind) to oral C (320 mg twice daily, 4 days on/3 days off, from cycle 1, day 2) or matched placebo to disease progression. Primary endpoint: progression free survival (PFS; comprising PSA, radiographic or clinical progression, new cancer therapy or death; PCWG2 criteria) in the intent to treat (ITT) population. Secondary endpoints included overall survival (OS) and safety. PFS and OS were also assessed by composite biomarker (B) subgroup for PI3K/AKT/PTEN pathway activation status (NGS/IHC on archival tumour, contemporaneous ctDNA). Statistics: designed to detect a 50% increase in median PFS (6 to 9 months (mo)) between the placebo and C arms (90% power, 20% 1-sided alpha) by Cox proportional hazards model. Registration: ISRCTN 69139368. Results: 150 patients were randomised to 01/2019. Median follow up 16.77 months (IQR 12.0-26.5). PFS and OS by ITT and B status, are shown in the table (NR, not reached; CI confidence interval). Grade 3–4 adverse events (AE) were equally common between arms (62.2%). The most common AEs were diarrhoea, fatigue and nausea. Conclusions: Adding C to DP did not extend PFS. The OS secondary endpoint was significantly increased. PFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway activation status. Clinical trial information: 69139368 . [Table: see text]

e23087 Background: The evidence for effect of anxiety and depression on cancer survival rates is contradictory (Ref : Prostate-JCO 2014.32:2471, Breast-JCO 1987. 5:768, Lung-JPSM 2017.53:1057). We assessed the effect of prospectively collected HADS score (Hospital Anxiety and Depression Scale) on subsequent long term survival. Methods: After ethics approval & informed consent, 145 prostate cancer patients (pts) were enrolled, onto a QOL study. HADS questionnaire was prospectively completed at baseline & at 3 mths after start of androgen deprivation therapy (ADT). Survival data collected in Jan 2019. PATIENT CHARACTERISTICS: Median age 69 (range 50 to 78); T stage T2:63.5%, T3:28.4%. Gleason 7 in 53.4% and 8-10 in 39.2%; Median PSA 10.2 (0.3 to 102); Median testosterone 11.6 (0.6 to 26.7); ADT duration median 6 mths (2 to 60 mths); Median overall survival 10.11 yrs Results: At baseline, HADS anxiety scores normal (0-7) in 78%; abnormality mild (8-10) in 12%; moderate (11-14) in 6% and severe (15-21) in 2%.. At > 3 mths, respective anxiety scores (%) were 71.3, 17.5, 7.7 and 3.5. At baseline, HADS depression scores (%) were 91.2, 5.2, 1.4 and 0.7. At > 3 mths, respective depression scores were (%) 83.9, 11.2, 3.5 and 1.4 Although median survival was numerically lower in pts scoring high on HADS at baseline, the survival rates were not statistically significant on Log rank test. Moreover, on Cox regression analysis with Age, Gleason Score, T Stage, baseline PSA as co-variates, there was no increased hazard from higher HADS scores (Table). Conclusions: Biological factors probably outweigh the influence of psychological factors on overall survival. [Table: see text]

63 Background: Androgen deprivation therapy (ADT) plays an important role in the management of non-metastatic prostate cancer (NMPC). We prospectively assessed the performance of a symptom rating scale, the aging men’s symptoms score (AMS) in relation to other validated QOL tools. Methods: Following ethics approval, 145 patients with a diagnosis of NMPC receiving ADT as part of radical treatment were enrolled after informed consent. Data was collected using the EORTC QLQ-C30, the AMS and the International Index of Erectile Function score (IIEF-5) questionnaires at baseline, 3 months (post ADT) and after ADT was stopped. Results: Eighty six (58.1%) patients had ADT for

10111 Background: Single fraction radiotherapy (RT) is standard of care for palliation of pain from bone metastases (ASTRO IJROBP 2011 79:965). But costly, complex, multi-fraction RT is quite often used for palliation of symptoms from various organs. Health care costs are burgeoning (ASCO JCO 2012 30: 1715). Costs can be constrained by judiciously reducing use of unnecessary multi-fraction RT in pts with limited life expectancy. But radiation oncologists’ ability to predict survival is inaccurate. (Chow IJROBP 2005 61:870). Hence we assessed clinical utility of Neutrophil Lymphocyte ratio (NLR) - a routinely available biomarker. Methods: 233 patients (pts) undergoing palliative RT over a 3 month at Nottingham University Hospital. Predominant Tumour SITES: Lung 28% Breast 13% Prostate 13% Colorectal 9% Gastro-Oesophageal 5% Myeloma 5% Bladder 5%. Predominant HISTOLOGY: Adenocarcinoma 61% Squamous Cell 14%. NLR available for 158 pts. Results: A NLR of 4.5 was highly predictive of 90-day mortality & overall survival in an unselected real world population. (Table). No survival benefit seen for multi-fraction RT over single fraction RT across all tumour sites. On survival analysis by Cox regression, increased NLR was significant with a hazard ratio of 2.2 (95% CI 1.3 to 3.7) whereas total radiation dose, use of multiple fractions , age, serum haemoglobin, serum albumin & histology were not significant. Conclusions: In palliative care of advanced cancer, for pts with high NLR (>4.5), Single fraction RT should be the standard of care for palliation of symptoms. [Table: see text]

e16615Background: The CHHiP trial, (ISRCTN 97182923), supports the hypothesis that alpha-beta ratio is low for prostate cancer & larger fractions (3Gy/#) of radiation have better cell kill. Paradox...

e21507Background: CPR can be a highly successful, lifesaving, medical intervention following an acute or reversible cardiorespiratory/metabolic dysfunction. However, CPR is futile in patients with ...

e16545Background: The FDA approved dose of Cabazitaxel for CRPC is 25mg/m2. In the pivotal TROPIC trial, Cabazitaxel was highly active and overall well tolerated. But in TROPIC trial, grade 3 or hi...

22 Background: Up to 30% patients irradiated for intermediate- or high-risk localized prostate cancer experience relapse biochemically within 5 years. We assessed if biochemical disease-free survival (BDFS) is improved by adding 6 months of androgen suppression (AS) – twice 3-month depot LHRH-agonist to primary irradiation (RT) for intermediate or high risk localized T1b-cT2a N0M0 prostate cancer. Methods: 819 patients staged cT1b-c with PSA ≥ 10 ng/ml or Gleason ≥ 7 or cT2a (UICC TNM 1997) N0 M0 with PSA ≤ 50 ng/ml were randomized between RT or RT+ADT. Centers elected one dose of prostate irradiation: 70, 74, or 78 Gy. Irradiation of pelvic nodes was left to the discretion of each institution. The trial aimed to show an increase of +7.5% in 5-year BPFS (HR=0.714) with 80% power. This requires 274 events in intent-to-treat analysis. HRQoL was assessed by EORTC QLQ-C30+PR25 (ClinicalTrials.gov NCT00021450). Results: Patients were 70 y old in median, 88% had WHO PS 0, 74.8% were intermediate risk, and 24.8% high risk. In the RT arm, 407/409 received RT, in the RT+ADT, 403/410 received RT+ AS and 3 RT. Six patients refused treatment. After a median follow-up of 7.2 years, 201 and 118 events for BPFS were observed in the RT and RT+ AS arm. RT+ AS improved BPFS compared to RT (HR=0.53, CI: 0.42-0.67, P0.1). The 5-y BPFS increased from 69.3% to 82.5%. Clinical PFS was also statistically significantly improved (205 events, HR=0.63, CI: 0.48-0.84, P=0.001, +7.9% at 5 years). Late genitourinary toxicity was reported by 5.9% vs. 3.6% of the patients, on RT+ AS and RT, respectively (p=0.14), whereas 27.0% vs 19.4% reported severe impairment of sexual function (p=0.010). Overall HRQoL did not differ between the groups. Hormonal treatment symptoms, sexual activity and functioning scales are clinically significantly impaired by AS at month 6 and year 1; from year 2 no marked difference is seen. Conclusions: The addition of 6 months of medical castration to primary irradiation improves BPFS and PFS in intermediate- and high-risk localized T1b-cT2a N0M0 prostatic carcinoma with no persistent detriment on HRQoL or sexual function. Clinical trial information: NCT00021450.

430 Background: Two previous single arm trials have drawn conflicting conclusions regarding pazopanib in urothelial bladder cancers (UBC) after failure of platinum-based chemotherapy. PLUTO is a randomized phase II trial to compare the efficacy of pazopanib with paclitaxel in this setting. Methods: It was planned for 140 patients with progressive, advanced UBC (with at least a component of transitional cell carcinoma) who had previously received a single prior platinum containing chemotherapy regimen for advanced UBC to be randomised(1:1). Patients in arm A received weekly paclitaxel 80mg/m2 and those in arm B received pazopanib (800mg once daily) until progression. The primary endpoint was overall survival analysis of which would occur after 110 events. The efficacy was assessed by an independent data monitoring committee during the trial. Results: Between Aug 2012- Oct 2014, 131 patients were randomised. 74.0% of patients had visceral metastases. The study was terminated early by the IDMC due to futility of pazopanib. Final analysis after 110 deaths occurred in July 2015. The median number of cycles of paclitaxel received was 4 (12 weeks). The median time on pazopanib was 11 weeks. Median overall survival was 8.0 months for paclitaxel [80% confidence interval (CI) 6.9 to 9.7 months] and 4.7 months for pazopanib [80% CI 4.2 to 6.4 months]. The hazard ratio (HR) adjusted for baseline stratification factors was 1.25 [80% CI 0.96 to 1.63; 1-sided p = 0.86] in favour of paclitaxel. Median progression free survival was 3.2 months for paclitaxel [80% CI 2.9 to 5.0 months] and 3.1 months for pazopanib [80% CI 2.7 to 3.8 months]. The adjusted HR for PFS was 1.06 [80% CI 0.83 to 1.36; 1-sided p = 0.62] (in favour of paclitaxel). Discontinuations for toxicity occurred in 6.3% and 20.0% for paclitaxel and pazopanib respectively. VHL, HIF1alpha, VEGFR2 and PD-L1 expression were measured from archived tissue and correlated with outcome. Conclusions: Pazopanib does not have greater efficacy than paclitaxel in the second line treatment of UBC. There is a trend towards superior OS with paclitaxel. Clinical trial information: NCT00949455.

Purpose: The purpose of this trial was to establish if maintenance lapatinib after first-line chemotherapy is beneficial in HER1/HER2 positive metastatic urothelial bladder cancer (UBC) patients. Method: Patients with metastatic UBC were screened centrally for HER1/HER2 over expression. HER1/2 positive screened patients, who did not have progressive disease during chemotherapy (4-8 cycles) were randomised (1:1) to lapatinib (L) or placebo (P) after completion of first line/initial chemotherapy for metastatic disease. The primary endpoint was progression free survival (PFS). Results: Between 2007-2013, 446 UBC patients were screened and 232 HER 1 or 2 positive patients were randomised. The median PFS for L and P were 4.5 months (95% CI: 2.8 – 5.4) and 5.1 months (95% CI: 3.0 – 5.8) respectively [HR: 1.07 (95% CI: 0.81 - 1.43) p = 0.63]. The overall survival for L and P were 12.6 months (95% CI: 9.0 – 16.2) and 12.0 months (95% CI: 10.5 – 14.9) respectively [HR = 0.96 (95% CI: 0.7 - 1.31) p = 0.80]. Discontinuation due to AEs were similar in both arms (6% lapatinib and 5% placebo). The rate of grade 3-4 AEs for L and P was 8.6% vs. 8.1% (p = 0.82). Pre-planned subset analysis of i) HER1/HER2 strongly positive patients (3+ on immunohistochemistry: n= 111) ii) HER1 only positive patients (n= 102) iii) HER2 only positive patients (n= 42) showed no significant benefit with lapatinib in terms of PFS and OS (p>0.05 for each). Conclusion: This trial failed to find significant improvements in outcome by the addition of maintenance lapatinib to standard of care.

409 Background: Dual TORC1 and 2 inhibitors such as AZD2014 have theoretical advantages over isolated TORC1 inhibitors such as everolimus in the treatment of mRCC. In this study we compare the activity of these drugs in patients with vascular endothelial growth factor (VEFG) refractory mRCC. Methods: Patients with measurable VEGF refractory mRCC were randomised (1:1) to AZD2014 or everolimus stratified by MSKCC prognostic score and 1st line targeted therapy. Progression free survival (PFS) measured by RECIST v1.1 was the primary endpoint. Adverse events (AE) (CTCAE v4.03), response rates (RR) and overall survival (OS) were reported. This was an investigator led study and had appropriate ethical approval. Results: The study was stopped early (May 2014) with the recommendation of the IDMC. At this point 48 patients were recruited and 40 (AZD2014 23 :everolimus 17) patients were assessable for efficacy. Patient’s demographics were similar in the 2 groups. The median PFS was shorter for AZD2014 than everolimus (2.0 [95% CI 1.6-3.2] months vs. 5.8 [95% CI 2.8-11.2] months: stratified HR [2.4 95% CI:1.0-5.7; p

91 Background: Several drugs can now improve survival in mCRPC after docetaxel, including cabazitaxel, a next generation taxane. TROPIC (NCT00417079) showed an overall survival benefit of 2.4 months for cabazitaxel compared with mitoxantrone for mCRPC. The UK EAP provided patients access to cabazitaxel; detailed QOL and safety data were recorded. Interim analysis suggested improvements in QOL, particularly pain scores and a good safety profile. We report final QOL and updated safety data. Methods: 108 patients recruited at 12 centres received cabazitaxel 25mg/m2intravenously every 3 weeks with oral prednisolone 10mg daily. EQ-5D questionnaires and health state visual analogue scale (VAS) were completed at baseline, at alternate cycles and at 30 days post treatment. Safety assessments followed each cycle. Results: According to EQ-5D and VAS scores, QOL was stable with an overall trend towards improvement in patients who continued treatment. Paired ‘within patient’ analyses also support this trend. Improved pain was noted more frequently than deterioration at all time points and pain scores were at least stable in 96% of patients at cycle 10. A median of 6 cycles were given. 34 patients (31%) received 10 or more cycles. Grade 3/4 adverse events were uncommon, the most frequent being fatigue (9.3%), diarrhoea (2.8%) and neutropenic sepsis (1.9%). 85% received prophylactic granulocyte colony stimulating factor. Conclusions: Almost 1/3 of patients completed 10 or more cycles in the UK EAP. QOL was stable with trends to improved EQ-5D and VAS scores. Improved or stable pain was observed in the majority of patients continuing therapy. The UK EAP provides the first data on QOL benefit with cabazitaxel in mCRPC post docetaxel and demonstrates manageable toxicity. Final safety data will be available for presentation. Clinical trial information: NCT01254279. [Table: see text]

44 Background: Cabazitaxel, a tubulin-binding taxane, improved survival in mCRPC in the TROPIC trial. Notable toxicities were neutropenia and diarrhoea. We report interim safety and QOL data from a single arm multicentre open label study providing early access to cabazitaxel in the UK. Methods: Patients recruited from 12 centres received cabazitaxel 25mg/m2 intravenously every 3 weeks and prednisolone 10mg daily. Safety assessments were performed before each cycle. Patients completed the EQ-5D questionnaire and health state visual analogue scale (VAS) at baseline and at alternate cycles. Patients recruited before March 31st 2011 are included in the safety analysis. QOL data collected before July 31st 2011 at baseline (n=62), cycle 2 (n=50) and cycle 4 (n=26) are included. Results: Median age was 68 years; 24% were aged over 75 years. 93% had bone metastases. 50% had experienced disease progression during or within 3 months of docetaxel and the remaining 50% within 3-6 months. A median of 3 cycles of cabazitaxel were completed with 99% relative dose intensity. 83% continued cabazitaxel at the time of safety analysis. 7 patients stopped before completing the full course, 5 of these were due to disease progression. One treatment related death occurred within 30 days of the last cabazitaxel infusion (2.4%). 85% of patients received granulocyte-colony stimulating factor prophylaxis from cycle 1. The proportion of patients reporting no pain or discomfort increased between baseline, cycle 2 and cycle 4 (22.6% to 38% to 50%). Anxiety and depression, mobility and self-care scores from EQ-5D were stable. Median VAS health state increased from baseline (75%) to cycle 4 (79%). Conclusions: Improvements in pain control and health states were reported during early stages of cabazitaxel treatment. Other EQ-5D QOL measures were stable. Severe toxicity was rare. Results will be updated from final analysis in late 2011. [Table: see text]