Simon Chowdhury

Anti-angiogenic agents, such as vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors and anti-VEGF antibodies, and immune checkpoint inhibitors (CPIs) are standard treatments for advanced renal cell carcinoma (aRCC). In the past, these agents were administered as sequential monotherapies. Recently, combinations of anti-angiogenic agents and CPIs have been approved for the treatment of aRCC, based on evidence that they provide superior efficacy when compared with sunitinib monotherapy. Here we explore the possible mechanisms of action of these combinations, including a review of relevant preclinical data and clinical evidence in patients with aRCC. We also ask whether the benefit is additive or synergistic, and, thus, whether concomitant administration is preferred over sequential monotherapy. Further research is needed to understand how combinations of anti-angiogenic agents with CPIs compare with CPI monotherapy or combination therapy (e.g., nivolumab and ipilimumab), and whether the long-term benefit observed in a subset of patients treated with CPI combinations will also be realised in patients treated with an anti-angiogenic therapy and a CPI. Additional research is also needed to establish whether other elements of the tumour microenvironment also need to be targeted to optimise treatment efficacy, and to identify biomarkers of response to inform personalised treatment using combination therapies.

Introduction Apalutamide and darolutamide are next-generation androgen receptor inhibitors that have demonstrated superior efficacy compared to placebo in men with non-metastatic castration-resistant prostate cancer (nmCRPC) receiving androgen deprivation therapy (ADT). In the absence of head-to-head studies, the present study sought to indirectly compare the efficacy and tolerability between these two treatments. Methods This anchored matching-adjusted indirect comparison (MAIC) used patient-level data from the phase 3, randomized, controlled SPARTAN study (apalutamide + ADT), weighted to match aggregate published data from the ARAMIS study (darolutamide + ADT) for clinically relevant baseline measures. Hazard ratios (HR) and 95% credible intervals (CrI) were estimated for efficacy endpoints: metastasis-free survival (MFS), prostate-specific antigen (PSA) progression, progression-free survival (PFS), and overall survival (OS). Odds ratios were estimated for tolerability outcomes: adverse events and serious adverse events. Results Before weighting, baseline characteristics from SPARTAN versus ARAMIS were different for median PSA (7.8 vs. 9.2 ng/mL), Eastern Cooperative Oncology Group performance status of 1 (23% vs. 31%), use of bone-targeted agents (10% vs. 4%), median time from initial diagnosis (94.9 vs. 85.4 months), and proportion of patients from North America (35% vs. 12%) and Europe (50% vs. 64%). After matching (n = 455), our analysis demonstrated that apalutamide + ADT had a Bayesian probability of being more effective than darolutamide + ADT for MFS [98.3%; HR 0.70 (95% CrI 0.51, 0.98)], PSA progression [~ 100%; HR 0.46 (95% CrI 0.33, 0.64)], and PFS [93.2%; HR 0.79 (95% CrI 0.59, 1.08)]. Results for OS and tolerability were similar between apalutamide + ADT and darolutamide + ADT. Conclusion This anchored MAIC analysis of pivotal phase 3 studies in patients with nmCRPC suggests that apalutamide + ADT is more effective than darolutamide + ADT for MFS, progression-free survival (PFS), and prostate-specific antigen (PSA) progression, with a similar OS benefit and tolerability profile. Trial Registration ARAMIS ClinicalTrials.gov number: NCT02200614; SPARTAN ClinicalTrials.gov number: NCT01946204.

Background: Using progression-free survival (PFS)2, time from randomization to 2nd disease progression or death, is proposed as a surrogate for overall survival (OS) in oncology clinical trials. We used published data from solid tumor trials to assess whether PFS2 and OS are correlated. Methods: A literature search identified studies that reported PFS, PFS2, and OS. Two reviewers screened for eligibility, and documented PFS2, PFS or time from 1st to 2nd disease progression or death and OS. Correlation between PFS2 and OS was assessed using: (1) Kendall's Tau + Pearson's correlation coefficient in randomized controlled trials (RCTs); (2) Meta-analysis with the random effects model to compute the pooled correlation of PFS2 and OS. Results: Overall, 133 studies met search criteria, 15 (28 arms) had complete PFS2 and OS data in ovarian, gastric, colorectal, prostate, lung, renal and breast cancers. A positive correlation for PFS2 and OS was found for all 15 studies (Kendall's Tau = 0.7 [95% CIs 0.54, 0.78]); 10 RCTs (Pearson's correlation coefficient = 0.86); and meta-analysis from 7 trials (pooled Spearman's correlation coefficient = 0.84 [p = 0.0001; 95% CIs 0.71, 0.96]). Conclusions: In this retrospective analysis PFS2 strongly correlates with OS supporting the use of PFS2 to measure long-term clinical benefit when OS cannot be assessed.

Background Metastatic prostate cancer has a 30% 5-year survival rate despite recent therapeutic advances. There is a need to improve the clinical understanding and treatment of this disease, particularly in the real-world setting and among patients who are under-represented in clinical trials. Objective We aimed to evaluate the characteristics and clinical outcomes of patients who received their first treatment for metastatic castration-resistant prostate cancer (mCRPC) in routine clinical practice, independent of treatment used, including subgroups with baseline cardiac disease, diabetes mellitus, or visceral metastases. Patients and methods Prospective, noninterventional analysis of patient record data in the multicenter Prostate Cancer Registry (PCR) of men with mCRPC. The data were collected in 16 countries with the aim of recruiting more than 3000 patients between 2013 and 2016. The study end date was 9 July 2018. Data evaluated included baseline characteristics, treatment exposure, and efficacy outcomes [overall survival (OS) and time to progression (TTP)] of patients treated with abiraterone acetate plus prednisone or prednisolone (collectively, “abiraterone”), enzalutamide, or docetaxel. Descriptive outcomes are reported from the overall patient population and subgroups of patients with baseline cardiovascular disease, diabetes mellitus, or visceral metastases. The treatment effects for time to progression were compared for the overall patient population. Results The study enrollment period lasted 2.5 years, and each patient was followed for a maximum of 3 years. A total of 1874 patients in the PCR had not received previous mCRPC treatment at baseline, although they had received androgen-deprivation therapy. Prevalent co-morbidities included cardiovascular disease in 65.4% and diabetes mellitus in 17.4% of patients. Baseline characteristics suggested that patients with more advanced disease received docetaxel treatment. In the overall patient population, the median time to progression with abiraterone, enzalutamide, and docetaxel as first-line mCRPC therapy was 9.6, 10.3, and 7.6 months, respectively, and median OS was 27.1, 27.1, and 27.9 months, respectively. Outcomes in the subgroups of patients with cardiovascular disease or diabetes mellitus were similar to those of the whole population in the analysis. As expected, patients with visceral metastases had shorter TTP and OS than patients in the overall population. Conclusions This analysis shows, for the first time, the effectiveness in parallel of first-line abiraterone, enzalutamide, and docetaxel in mCRPC, including in patients with co-morbidities such as cardiovascular disease or diabetes mellitus or in patients with visceral metastases. These real-world findings from the PCR provide meaningful information to help manage mCRPC, particularly in patients under-represented in clinical studies. Trial Registration ClinicalTrials.gov identifier NCT02236637; registered September 2014.

Introduction Apalutamide and enzalutamide are next-generation androgen receptor inhibitors that demonstrated efficacy in placebo-controlled studies (SPARTAN for apalutamide; PROSPER for enzalutamide) when used in combination with androgen deprivation therapy (ADT) for treatment of non-metastatic castration-resistant prostate cancer (nmCRPC). In the absence of comparative studies between these agents, the present study sought to indirectly compare metastasis-free survival (MFS) and overall survival (OS) in patients with nmCRPC who received these therapies. Methods Individual patient-level data from SPARTAN (apalutamide plus ADT) and published data from PROSPER (enzalutamide plus ADT) were utilized. An anchored matching-adjusted indirect comparison (MAIC) was conducted by weighting the patients from the SPARTAN study to match baseline characteristics reported for PROSPER. Hazard ratios (HRs) for MFS and OS were re-estimated for SPARTAN using weighted Cox proportional hazards models and indirectly compared with those of PROSPER using a Bayesian network meta-analysis. Results From the SPARTAN population (N = 1207), a total of 1171 patients were matched to the PROSPER population (N = 1401). The recalculated HRs (95% confidence interval) for apalutamide versus ADT based on the reweighted SPARTAN data to mimic the PROSPER patient population were 0.26 (0.21; 0.33) for MFS and 0.62 (0.41; 0.94) for OS. MAIC-based HRs (95% credible interval) for apalutamide versus enzalutamide were 0.91 (0.68; 1.22) for MFS and 0.77 (0.46; 1.30) for OS. The Bayesian probabilities of apalutamide being more effective than enzalutamide were 73.6% for MFS and 83.5% for OS. Conclusions MAIC results suggest that nmCRPC patients treated with apalutamide have a higher probability of a more favorable MFS and OS compared with those treated with enzalutamide.

The present study aimed to indirectly compare apalutamide and enzalutamide with respect to tolerability and health-related quality of life (HRQoL) among men with non-metastatic castration-resistant prostate cancer (nmCRPC).

This analysis estimated the number needed to treat with enzalutamide versus bicalutamide to achieve one additional patient with chemotherapy-naïve metastatic castration-resistant prostate cancer who would obtain clinical benefit regarding progression-free survival, radiographic progression-free survival, or no prostate-specific antigen progression at 1 and 2 years following treatment initiation. Clinical event rates were obtained from the STRIVE (NCT01664923) and TERRAIN (NCT01288911) trials, and the number needed to treat was the inverse of the absolute rate difference between the event rates of enzalutamide and bicalutamide. The 95% Confidence Interval of the number needed to treat was derived from the 95% Confidence Interval of the event rate difference. Using STRIVE data (patients with metastatic disease: n = 128 enzalutamide; n = 129 bicalutamide) comparing enzalutamide with bicalutamide at 1 and 2 years, the numbers needed to treat to achieve one additional patient with chemotherapy-naïve metastatic castration-resistant prostate cancer with progression-free survival were 2.0 and 2.8, respectively; with radiographic progression-free survival, 2.6 and 3.0, respectively; and without prostate-specific antigen progression, 1.8 and 2.4, respectively. Using TERRAIN data (n = 184 enzalutamide; n = 191 bicalutamide) comparing enzalutamide with bicalutamide at 1 and 2 years, the numbers needed to treat to achieve one additional patient with progression-free survival were 4.3 and 3.7, respectively; with radiographic progression-free survival, 10.0 and 2.8, respectively; and without prostate-specific antigen progression, 2.1 and 3.2, respectively. The combined data from TERRAIN and STRIVE demonstrated that treating chemotherapy-naïve metastatic castration-resistant prostate cancer with enzalutamide leads to more patients without clinical progression at 1 and 2 years than with bicalutamide. STRIVE (NCT01664923; registration date: August 10, 2012) and TERRAIN (NCT01288911; registration date: February 1, 2011).

The KHP PCaBB was established in 2013 and recruits donors from the Urology or Oncology Departments at Guy’s Hospital in London (UK). Prostate cancer patients may be approached to give their consent for biobanking at any point in their treatment pathway, which allows residual material from their earlier diagnosis to be transferred and used by the Biobank. Currently, patients are specifically asked to donate samples of blood and surplus prostate tissue as well as permitting access to their clinical and pathological data that continues to be added throughout the course of their disease. Between 2013 and 2015, 549 prostate cancer patients gave their consent to the biobank and, the tissue repository collected 489 blood samples, 120 frozen prostate tissue samples and 1064 formalin fixed paraffin embedded diagnostic blocks. Prostate cancer has become a chronic disease in a large proportion of men, with many men receiving multiple subsequent treatments, and their treatment trajectory often spanning over decades. Therefore, this resource aims to provide an ideal research platform to explore potential variations in treatment response as well as disease markers in the different risk categories for prostate cancer. A recent audit of the KHP PCaBB revealed that between 2013 and 2015, 1796 patients were diagnosed with prostate cancer at King’s Health Partners (KHP), out of which 549 (30.6%) gave their consent to KHP PCaBB. Comparisons between demographic and clinical characteristics of patients who had consented compared to the total patient population revealed that the KHP PCaBB is demographically representative of the total prostate cancer patient population seen in Guy’s and St Thomas’ NHS Foundation Trust (GSTT). We observed no differences in distribution of ethnicity (p = 0.507) and socioeconomic status (p = 0.097). Some differences were observed in clinical characteristics, specifically with treatment type – which differed significantly between the patients who had given consent and total patient population. The KHP PCaBB has thereby amassed a rich data and tissue repository that is largely reflective of both the demographic and clinical diversity within the total prostate cancer patient population seen at KHP, making it an ideal platform for prostate cancer research.

LBA5003 Background: Abiraterone showed a survival advantage in men with castration-refractory prostate cancer. We assessed whether abiraterone would work earlier in the disease. STAMPEDE is a randomized controlled trial using a multi-arm multi-stage platform design. It recruits patients (pts) with high-risk locally advanced or metastatic PCa starting long-term ADT. We report the first comparative survival data. Methods: The standard-of-care (SOC) was ADT for 2+yrs; radiotherapy (RT) was mandated for men with N0M0 disease & encouraged for N+M0. Stratified randomization allocated pts 1:1 to SOC or SOC+abiraterone 1000mg + prednisolone 5mg daily. Treatment duration depended on stage & intent to give radical RT: pts not having RT or M1 disease, treatment continued until PSA, radiological & clinical progression; otherwise treatment continued until the earlier of 2 years or all types of progression. The primary outcome measure was death from any cause. Comparison to control for survival had 90% power at 2.5% 1-sided alpha for hazard ratio (HR) of 0.75, requiring ~267 control arm deaths, accounting for 3 intermediate lack-of-benefit analyses on failure-free survival (FFS). Analyses used Cox proportional hazards & flexible parametric models, adjusted for stratification factors. Results: 1,917 pts were contemporaneously randomized to these arms (Nov 2011- Jan 2014). Groups were balanced: median age 67yrs; 52% metastatic, 20% N+/X M0, 28% N0M0; 95% newly-diagnosed; median PSA 53ng/ml. Median follow-up was 40m. There were 262 control arm deaths (82% PCa). The adjusted HR = 0.63 (95% CI 0.52-0.76; p=0.115x10^-7; 184 deaths) for SOC+Abi vs SOC, with 3yr OS improved from 76% to 83%. There were 535 control arm FFS events; the adjusted HR = 0.29 (95% CI 0.25-0.34; p = 0.377x10^-63, 248 FFS events) for SOC+Abi vs SOC. Grade 3 & 4 adverse events were seen in 29% & 3% SOC, 41% & 5% SOC+Abi; Grade 5: 3 & 9 (1 & 2 related). Conclusions: The results show a clinically & statistically significant effect on overall survival & failure-free survival from adding abiraterone at start of ADT with a manageable increase in toxicity. ADT (+/- RT) + abiraterone is a new standard of care for this group. Clinical trial information: NCT00268476.

E16061 Background: Markers of the systemic inflammatory response have prognostic value in ccRCC prior to starting treatment. Dynamic changes during therapy and their role in predicting prognosis are not well characterised. Methods: A retrospective analysis was conducted of a randomised, double-blind phase II study evaluating cediranib vs cediranib and saracatinib in patients with relapsed metastatic ccRCC (COSAK). Haemoglobin (Hb), neutrophil count (N0) platelet count (Plt), lactate dehydrogenase (LDH) and C-reactive protein (CRP) were recorded at randomisation, 8-weeks and progression (PD). Change in mean values at each time point were compared. Baseline prognostic values for overall survival (OS) were assessed using Cox regression. Absolute changes in parameters were calculated at 8 weeks and PD, patients were grouped around the upper or lower quartile. Prognostic value of dynamic changes was assessed at 8 weeks and PD using the Kaplan-Meier method. Results: 138 patients were assessed; median OS was 12.0 months (IQR 8.1-15.6 months). Outcomes in the combination arm were similar to single agent arm (HR 1.28 (1.00–1.63)). On multivariate analysis at baseline, MSKCC score (0/1-2/≥3) (HR 2.52 (1.60 -3.96)), CRP ( < 10/≥10mg/L) (HR 1.72 (1.04 – 2.86)) and N0 ( < 7.5/≥7.5x109) (HR 2.38 (1.43 – 3.96)) were independent predictors of OS. Mean CRP was significantly different at baseline, 8 weeks and PD (64.9, 42.3 and 85.7 mg/L respectively, p < 0.001). Mean N0 count at baseline was 5.3 x109/L and was significantly higher 6.3x 109/L at PD (p < 0.001). Mean Hb at baseline, 8 weeks and PD was 11.5, 13.0 and 12.9g/L respectively (P < 0.001). A rise in CRP or N0 at 8 weeks was predictive of poor outcome ((HR 1.62 (1.10-2.56) and (HR 1.77 (1.19-2.61) respectively). A fall in Hb was predictive of poor outcome at 8 weeks (HR 1.75 (1.18-2.60)) and PD (HR 1.80 (1.20-2.76)). Conclusions: Dynamic changes occur in prognostic markers in patients receiving VEGF-targeted therapy in ccRCC and may predict OS.