Prostate cancer prognosis after initiation of androgen deprivation therapy among statin users. A population-based cohort study

Purpose Statins’ cholesterol-lowering efficacy is well-known. Recent epidemiological studies have found that inhibition of cholesterol synthesis may have beneficial effects on prostate cancer (PCa) patients, especially patients treated with androgen deprivation therapy (ADT). We evaluated statins’ effect on prostate cancer prognosis among patients treated with ADT. Materials and methods Our study population consisted of 8253 PCa patients detected among the study population of the Finnish randomized study of screening for prostate cancer. These were limited to 4428 men who initiated ADT during the follow-up. Cox proportional regression model adjusted for tumor clinical characteristics and comorbidities was used to estimate hazard ratios for risk of PSA relapse after ADT initiation and prostate cancer death. Results During the median follow-up of 6.3 years after the ADT initiation, there were 834 PCa deaths and 1565 PSA relapses in a study cohort. Statin use after ADT was associated with a decreased risk of PSA relapse (HR 0.73, 95% CI 0.65–0.82) and prostate cancer death (HR 0.82; 95% CI 0.69–0.96). In contrast, statin use defined with a one-year lag (HR 0.89, 95% CI 0.76–1.04), statin use before ADT initiation (HR 1.12, 95% CI 0.96–1.31), and use in the first year on ADT (HR 1.02, 95% CI 0.85–1.24) were not associated with prostate cancer death, without dose dependency. Conclusion Statin use after initiation of ADT, but not before, was associated with improved prostate cancer prognosis.

68Ga-PSMA PET/CT for Patients with PSA Relapse after Radical Prostatectomy or External Beam Radiotherapy

The study aimed to summarize clinical characteristics associated with Gallium-68-prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (68Ga-PSMA PET/CT) scans as patients were restaged for prostate-specific antigen (PSA) relapse after radical prostatectomy (RP) or external beam radiotherapy (EBRT). Our analyses included multiple cox regression analyses. The study evaluated 95 patients with rising values of PSAs after RP and after EBRT. Sixty 63% of patients had a positive 68Ga-PSMA PET/CT scan. Twelve patients (13%) had a positive site in the prostate bed, 29 patients (30%) had a positive site in the regional lymph nodes, and 19 (20%) had positive sites in distant organs. After four years follow-up, 21 patients (22%) died. Using multiple Cox regression analyses, the number of positive sites on the 68Ga-PSMA PET/CT scan significantly predicted overall survival (OS) (p = 0.0001), whereas risk score and regional locations of the positive sites were not significant in the multiple Cox regression analyses. Our study indicates that the specific findings of 68Ga-PSMA PET/CT scans are important because detailed findings of the scans predict the outcome after salvage treatment of patients with PSA relapse examined with 68Ga-PSMA PET/CT scans.

Comparison of 68Ga-PSMA-11 PET/CT with 11C-acetate PET/CT in re-staging of prostate cancer relapse

Positron emission tomography (PET) imaging is used to localize recurrent disease in prostate cancer (PCa). The tracer 68Ga-PSMA-11 visualizes lesions overexpressing prostate-specific membrane antigen (PSMA), while 11C-acetate visualizes lesions with increased anabolic metabolism. The aim of this study was to compare the performance of PSMA-PET and acetate-PET in re-staging patients with biochemical relapse. Thirty PCa patients with prostate-specific antigen (PSA) relapse after primary curative therapy were prospectively evaluated. PET/CT examinations using 11C-acetate and 68Ga-PSMA-11 were performed. Identified lesions were categorized according to anatomical location and PET measurements were correlated with PSA at time of scan. Tumour lesions showed higher semi-quantitative uptake values on PSMA-PET than acetate-PET. PSMA-PET identified more lesions in 11 patients, fewer lesions in eight patients, and identical number of lesions in 11 patients. This study indicates better diagnostic performance of PSMA-PET, particularly in detecting lymph node (81% vs 60%, p = 0.02) and bone metastasis (95% vs 61%, p = 0.0001) compared to acetate-PET. However, 38% of PSMA-expressing metastases appear to be metabolically inactive and 15% of metabolically active metastases lack PSMA expression. Addition of PET with a metabolic tracer, such as 11C-acetate, might be beneficial before making treatment decisions.

A randomized phase III trial between adjuvant docetaxel and surveillance after radical radiotherapy (RT) for intermediate and high-risk prostate cancer (PC): Quality-of-life results (QoL) in SPCG-13 trial.

313 Background: Six docetaxel cycles did not improve PSA relapse free survival as an adjuvant treatment after radical RT (Kellokumpu-Lehtinen EURURO-8532). Here we report SPCG-13 trials QoL results. Methods: A total of 376 PC patients (T2 with Gleason score (GS) 4+3, PSA>10; T2, GS 8-10 any PSA; or any T3) were randomised to receive either 6 cycles of docetaxel 75mg/m2 every 3 weeks (Arm A, n=188) or surveillance (Arm B, n=188) after radical RT NTC006653848. Neoadjuvant/adjuvant ADT was mandatory. Primary end-point was a rising PSA > 2 ng/ml above the nadir. Patients were followed for 5 years with PSA every 3 months for two years and thereafter every 6 month. FACT-P QoL questionnaires were used at baseline, during and after docetaxel treatment and in the follow-ups (at 1 year, 2 years and 4 years after treatment) in both groups, and analysed using analysis of variance (ANOVA) models. Results: Median follow-up was 59.4 months (range 1 to 111 months). 147 (78.2%) patients completed all six cycles in arm A. Mean age was 66.2 years in Arm A and 66.4 years in Arm B. The total QoL scores at baseline did not differ between the Arms (mean 119.0, SD±18.9, n=177 vs 118.2, SD±18.1, n=180). In Arm A the total score declined to 116.3 (SD+15.2), at 24 weeks and was 118.5 (SD±21.3) after chemotherapy. In Arm B at 24 weeks the QoL score had increased to 123.3 (SD±19.2) and was significantly higher than in Arm A (estimated difference of 8.2 with p<0.0001, ANOVA model adjusted for baseline). However, in the first follow-up (1 year) the QoL score was same in both Arms (123.7 vs 123.6, respectively, p=0.344, ANOVA model adjusted for baseline) and remained at the same level during further follow-ups. The decline in QoL scores during the docetaxel treatment were seen only in two sub-scores; functional and physical. Conclusions: Adjuvant docetaxel did decrease the QoL of patients during the treatment. However, in the later follow-ups it increased to the same level as those patients without docetaxel treatment. These results further support our conclusions of showing no benefit from docetaxel as adjuvant treatment in this patient group after radical curative treatment. Clinical trial information: RT NTC006653848.

A phase II Salvage Trial of AR Inhibition with ADT and Apalutamide with Radiation therapy followed by docetaxel in men with PSA recurrent prostate cancer (PC) after radical prostatectomy (STARTAR).

TPS5097 Background: Androgen deprivation combined with salvage external beam radiation therapy (RT) have improved survival for patients (pts) with non-metastatic hormone naïve PC and PSA recurrence after radical prostatectomy (RP). Our recent STREAM trial showed addition of enzalutamide to RT and ADT had a 3-year progression free survival (PFS) of 53%. Adding effective PC treatments in this setting may further improve 3-year PFS. Methods: STARTAR is an investigator-initiated phase 2 trial for salvage treatment of biochemically recurrent PC following prostatectomy. Key inclusion criteria include histologic prostate adenocarcinoma, either Gleason 7 with T3/positive margin/1-4 positive lymph nodes or Gleason 8-10 disease, PSA relapse within 4 years of prostatectomy (minimum PSA 0.2 ng/mL to maximum PSA 4 ng/mL). Treatment involves ADT with apalutamide for 9 months, continue with with prostate bed +/- nodal RT at month 3, followed by 6 cycles of docetaxel 75mg/m2 IV every 3 weeks for 6 cycles. The primary endpoint of the study is 3-year PFS. With a one-sided alpha of 0.05 to improve 3-year PFS from 50% to 75%, we will have 92% power by enrolling 42 pts (including 10% dropout rate) based on the binomial test. Key secondary endpoints include 1, 2, and 3-year PSA recurrence rates with testosterone recovery, PSA PFS, PSA nadir, time to testosterone recovery, and safety of combination therapy. Quality of life will be assessed by EPIC questionnaire. As of February 2019, we have enrolled and treated 12 pts in this PCCTC trial. Accrual to the STARTAR trial is ongoing (NCT03311555). Clinical trial information: NCT03311555.

A randomized phase Ib/II study of nivolumab with or without BMS-986253 in combination with a short course of ADT in men with castration-sensitive prostate cancer (MAGIC-8).

TPS329 Background: Androgen deprivation therapy (ADT) is highly effective in castration-sensitive prostate cancer (CSPC) but is associated with significant side effects. Novel strategies to reduce ADT exposure and prolong disease control are needed. ADT initially induces a complex immune infiltrate within prostate tumors, suggesting that immunologic intervention may be more effective at the time of castration. Emerging data suggests that the cytokine interleukin-8 (IL-8) recruits immunosuppressive polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment (TME) of many malignancies, including prostate cancer and serum IL-8 levels correlate with lack of response to anti-PD-1 therapy. We hypothesize that immunotherapy with nivolumab (a PD-1 inhibitor) with or without BMS-986253 (an IL-8 inhibitor) combined with degarelix (an LHRH antagonist) will be safe and promote an anti-tumor immune response that can prolong time to disease relapse in CSPC. Methods: This is a randomized, multicenter, two-arm, phase 1b/2 trial of patients with biochemically-recurrent or low volume metastatic CSPC and a rapidly rising PSA (≤12 months). 60 patients will receive immunotherapy with nivolumab or nivolumab plus BMS-986253 for 24 weeks. 16 weeks of ADT with degarelix will be added after 8 weeks of immunotherapy alone. The primary endpoints are safety and PSA relapse rate 10 months after the initiation of therapy. Secondary endpoints include relapse-free survival (RFS), time to testosterone recovery, rate of metastatic progression and change in PSA with immunotherapy alone. Correlative studies will quantify the systemic immune response through cytokine analysis and peripheral T cell profiling using serum and whole blood specimens collected from all enrolled patients. Pre- and on-treatment biopsies will also be obtained from the subgroup of patients with metastatic disease to further define changes in the TME using RNA-sequencing and quantitative multiplex immunofluorescence. The study is open with 1 patient currently enrolled at the time of submission. Clinical trial information: NCT03689699.

Stereotactic body radiation therapy for clinically localized prostate cancer

Background. In the last decade, we observed a significant increase in the number of patients undergoing radiotherapy for prostate cancer (PC). It became possible with the development of new equipment that can significantly increase radiation efficiency and reduce the frequency and severity of side effects. Active investigation of new fractionation regimens led to the development of stereotactic radiotherapy (StR) technique. In this article, we describe our own experience of using StR in patients with localized PC.Material and methods. The study included 48 patients treated with CyberKnife robotic radiosurgery system. The patients received a total dose of 36.25 Gy delivered in 5 fractions.Results. At a median follow-up of 24 months, the estimated four-year prostate-specific antigen (PSA) relapse-free survival rate was 95.8 %. The median PSA nadir was 0.48 ng/mL. We observed no grade III–IV side effects (either early or late).Conclusion. Our results suggest that the use of StR allows achieving good biochemical control comparable to that achieved by other methods and demonstrates comparable and sometimes even lower toxicity.