Citations

Abstract Purpose: Outcomes for resistant metastatic castration-resistant prostate cancer (CRPC) are poor. Stereotactic ablative radiotherapy (SABR) induces antitumor immunity in clinical and preclinical studies, but immunologic biomarkers are lacking. Patients and Methods: Eighty-nine patients with oligometastatic CRPC were identified by 11C-Choline-PET (Choline-PET) from August 2016 to December 2019 and treated with SABR. Prespecified coprimary endpoints were 2-year overall survival (OS) and PSA progression. Secondary endpoints included 2-year SABR-treated local failure and 6-month adverse events. Correlative studies included peripheral blood T-cell subpopulations before and after SABR. Results: 128 lesions in 89 patients were included in this analysis. Median OS was 29.3 months, and 1- and 2-year OS were 96% and 80%, respectively. PSA PFS was 40% at 1 year and 21% at 2 years. Local PFS was 84.4% and 75.3% at 1 and 2 years, respectively, and no grade ≥3 AEs were observed. Baseline high levels of tumor-reactive T cells (TTR; CD8+CD11ahigh) predicted superior local, PSA, and distant PFS. Baseline high levels of effector memory T cells (TEM; CCR7−CD45RA−) were associated with improved PSA PFS. An increase in TTR at day 14 from baseline was associated with superior OS. Conclusions: This is the first comprehensive effector T-cell immunophenotype analysis in a phase II trial before and after SABR in CRPC. Results are favorable and support the incorporation of immune-based markers in the design of future randomized trials in patients with oligometastatic CRPC treated with SABR.

AbstractPurposeTo prospectively assess acute differences in patient‐reported outcomes in bowel and urinary domains between intensity‐modulated radiotherapy (IMRT) and proton beam therapy (PBT) for prostate cancer.Methods and MaterialsBowel function (BF), urinary irritative/obstructive symptoms (UO), and urinary incontinence (UI) domains of EPIC‐26 were collected in patients with T1‐T2 prostate cancer receiving IMRT or PBT at a tertiary cancer center (2015‐2018). Mean changes in domain scores were analyzed from pretreatment to the end of and 3 months post‐radiotherapy for each modality. A clinically meaningful change was defined as a score change >50% of the baseline standard deviation.ResultsA total of 157 patients receiving IMRT and 105 receiving PBT were included. There were no baseline differences in domain scores between cohorts. At the end of radiotherapy, there was significant and clinically meaningful worsening of BF and UO scores for patients receiving either modality. In the BF domain, the IMRT cohort experienced greater decrement (−13.0 vs −6.7, P < .01), and had a higher proportion of patients with clinically meaningful reduction (58.4% vs 39.5%, P = .01), compared to PBT. At 3 months post‐radiotherapy, the IMRT group had significant and clinically meaningful worsening of BF (−9.3, P < .001), whereas the change in BF score of the PBT cohort was no longer significant or clinically meaningful (−1.2, P = .25). There were no significant or clinically meaningful changes in UO or UI 3 months post‐radiotherapy.ConclusionsPBT had less acute decrement in BF than IMRT following radiotherapy. There was no difference between the two modalities in UO and UI.

e17587 Background: Radium (Ra)-223 has become the cornerstone treatment in patients with metastatic castrate-resistant prostate cancer (mCRPC) with bone metastases. Ra-223 has been shown to suppress abnormal bone formation by inducing DNA double-strand breaks in tumor cells. This can reduce skeletal-related events, as well as improve survival and quality of life. Studies have indicated mutations that regulate DNA damage response in prostate cancer as susceptible to PARP inhibitors and platinum-based therapies. This study aims to evaluate mCRPC response to Ra-223 stratified by tumor genomics. Methods: This is a retrospective study of mCRPC patients who received Ra-223 and genetic testing within the Mayo Clinic database (Arizona, Florida, and Minnesota). Patient demographics, genetic mutations, treatment responses in terms of alkaline phosphatase (ALP) and prostate-specific antigen (PSA), and survival were assessed. Primary end points were progression-free survival (PFS) and overall survival (OS) from time of first radium treatment. Results: 239 mCRPC patients treated with Ra-223 were identified. Germline and/or somatic genetic sequencing was available in 50 patients, who had a median age of 61 years at time of diagnosis and 68 years at time of Ra-223 treatment. Median Gleason score at time of diagnosis was 8.0. 100% of patients received prior androgen deprivation therapy. 72% received prior docetaxel, and 18% received prior cabazitaxel. Notable mutations included TP53 (45.2%), TMPRSS2-ERG (28.6%), PTEN (26.2%), BRCA1/2 (14.3%), ATM (9.3%), CDK12 (7.1%), and Rb (4.9%). TMPRSS2-ERG was the second most commonly found mutation, with median OS 12.7 mo versus 15.4 mo in patients without TMPRSS2-ERG mutations (p = 0.099). In patients with CDK12 mutations (2 of 28 tested positive), PFS was 10.4 mo versus 5.6 mo in patients without CDK12 mutations (p = 0.157). The assessment of ALP and PSA response to radium treatment stratified by genetic mutation did not reach statistical significance. Conclusions: Among mCRPC patients treated with Ra-223 at Mayo Clinic, TMPRSS2-ERG was the second most commonly found genetic mutation and had observed worse survival outcomes that approached statistical significance. Prospective studies and increased sample sizes are needed to determine the impact of genetic mutations in response to Ra-223.

4595 Background: For stage I-II testicular seminoma, RT is highly effective at eradicating disease in the abdominopelvic lymph nodes, but results in unnecessary exposure to normal tissues including the GI tract. The purpose of this study was to define the incidence and risk factors for late GI complications in this patient population. Methods: A retrospective review was performed of 251 patients with stage I-II testicular seminoma treated with curative intent RT at our institution from 1974-2009. All patients underwent orchiectomy and postoperative external beam RT to the involved and/or at-risk nodal basins. Potential late GI complications that were assessed included endoscopically-confirmed gastric or duodenal ulceration, small bowel obstruction (SBO), and biopsy-confirmed malignancy of the GI tract. Risks were estimated using the Kaplan-Meier (KM) technique and univariate/multivariate analyses were performed using the Cox proportional hazards model. Results: Median age at diagnosis was 36 years (range 18 – 80). Clinical stage was I (n=199) or II (n=52). Median abdominopelvic RT dose was 26 Gy (interquartile range 25 – 30). Median follow-up was 15 years (range 0.1 – 38). KM estimates for any GI complication (ulcer, SBO, or GI malignancy) at 10, 20, and 30 years were 7, 10 and 24%, respectively. Four patients died as result of a GI complication. KM estimates for ulcer at 10, 20, and 30 years were 4, 7, and 9%, respectively. Age at RT (Hazard Ratio [HR] 1.05, 95% Confidence Interval [CI] 1.00 – 1.10, p=0.03) and RT total dose (per Gy, HR 1.20, 95% CI 1.09 – 1.31, p<0.01) were associated with risk of ulcer. KM estimates for SBO at 10, 20, and 30 years were 2%, 2%, and 3%, respectively. History of inflammatory bowel disease was associated with risk of SBO (HR 43, 95% CI 7-325, p<0.01). KM estimates for GI malignancy at 10, 20, and 30 years were 0.5, 3 and 16%, respectively. Age at RT was associated with risk of GI malignancy (HR 1.07, 95% CI 1.02-1.14, p=0.01). Conclusions: In patients with stage I-II testicular seminoma treated with RT, late GI complications were a relatively uncommon, but clinically significant source of late morbidity. Use of low dose, limited field, and/or proton RT may reduce these risks.

14046 Background: LDM CTX is a minimally toxic anti-angiogenic therapy that has demonstrated activity in multiple tumour types including HRPC. Increased Cyclooxygenase 2 (COX 2, a prostaglandin synthase enzyme) expression appears to be a consistent feature of a variety of human tumours, including prostate cancer. COX 2 inhibitors like CEL exhibit anti-tumour activity in pre-clinical studies, at least in part due to their anti-angiogenic activity. Pre-clinical work supports the concept that the combination of selective angiogenesis inhibitors like CEL with metronomic chemotherapy can enhance the effects of these agents on tumour angiogenesis. Methods: Men with asymptomatic HRPC at a single Canadian centre received celecoxib 400 mg po BID and cyclophosphamide 50 mg po daily. The primary efficacy endpoint of this 2 stage phase II study is disease control rate (DCR): 50% PSA response, tumour response or prolonged (=6 mos) PSA or stable measurable disease. This study is also assessing the safety of LDM CTX and CEL as well as potential anti-angiogenic biomarkers in these patients including circulating endothelial cells and their precursors (CEC/P), plasma levels of thrombospondin-1 (TSP-1) and vascular endothelial growth factor (VEGF). Results: Enrollment for the first stage of this study (10 men) has been completed. There were 2 patients with disease control by the a priori criteria: one patient with a partial tumour response (PR) (PR duration 13 mos with PSA stabilization for 12 mos) and one patient that had both prolonged stable PSA (7 mos) and prolonged stable measurable disease (8 mos). In addition, another patient had an unconfirmed PR. The therapy was well tolerated. One patient had angina that responded well to medical therapy but there were no serious arterial-thromboembolic events. One patient developed grade 3 hypertension. All other toxicities were grade 1/2. Data on CEC/P, TSP-1 and VEGF levels will be presented at the meeting. Conclusions: LDM CTX + CEL is a well tolerated therapy in men with asymptomatic HRPC. 2/10 patients achieved disease control in the first stage of the trial, meeting the criteria to proceed to the second stage. [Table: see text]

5144 Background: The time course of testosterone (TST) recovery after prolonged androgen suppression (AS) is not well established. We examined TST recovery prospectively in prostate cancer (PCa) patients treated with 2 years of AS. Methods: 153 PCa men with pT3N0 or positive margins after radical prostatectomy (RP), or with PSA relapse (persistently detectable postoperative PSA [= 0.2 ng/mL], delayed detectable PSA = 6 months after surgery, or palpable/biopsy proven local recurrence after RP), were treated with radiation (RT) to the prostate bed (60 - 70 Gy in 30 - 35 fractions) plus 2 years of AS as part of a phase II study. AS consisted of nilutamide 100 mg PO tid for 4 weeks, starting within 1 week after completing RT, and busereline acetate 6.6 mg SC every 2 months for 2 years, starting within 2 weeks of nilutamide. The primary endpoint was PSA relapse-free survival. Serum TST levels were measured at baseline, every 4 months during AS, and every 6 months after completing AS. The planned sample size was 150 patients. Time to TST recovery was analyzed using the Kaplan-Meier method. Cox Proportional Hazards regression was used for a multivariate analysis of predictive factors for TST recovery. Results: 122 men completed the planned AS. Median follow up after finishing AS was 36.4 months (range 9.4 - 76.2). A castrate TST level was defined as =1.7 nmol/L (50 ng/dL), with normal levels being 10 - 40 nmol/L. All men achieved castrate TST levels on AS. Table 1 shows TST recovery at 36 months after completing AS and median times to recovery. Median recovery time to normal TST was 27 months, although 8% of men did not recover to above castrate levels by 3 years. On multivariate analysis, younger age (<60 vs. =60) predicted for a significantly shorter recovery time to normal TST (P = <0.0001), while baseline TST (<10 nmol/L vs. =10.0 nmol/L) was of borderline significance (P = 0.06). Conclusions: TST recovery after 2 years of AS is protracted. Older men have significantly longer recovery times. [Table: see text] [Table: see text]

305 Background: Toxicity due to radiotherapy (RT) may differ in patients (pts) with prostate cancer who receive intensity-modulated radiotherapy (IMRT) or proton beam therapy (PBT). Methods: Patient-reported bowel function (BF), urinary incontinence (UI), and urinary irritative/obstructive symptoms (UO) domains of the Expanded Prostate Index Composite Questionnaire (EPIC-26) were prospectively collected in pts with localized prostate cancer receiving either IMRT (n=157) or PBT (n=105) to the prostate +/- proximal seminal vesicles for clinical stage T1-T2 N0 prostate cancer at a single tertiary cancer center between 2015 and 2018. Changes in domain scores were analyzed from pretreatment to the end of RT and 3 months post-RT, assessing the acute effects of each modality. A clinically relevant change was defined as a score change that exceeded 50% of the standard deviation of a baseline value. Results: At baseline there was no difference in the scores of BF, UI, and UO domains between IMRT and PBT cohorts. At the end of RT, pts treated with either modality had a statistically significant and clinically relevant worsening of BF and UO compared to baseline. Pts treated with IMRT experienced a significantly greater decrement in BF compared to the PBT cohort (-13 vs -9, p<0.01), including significantly more IMRT pts having a clinically relevant deterioration in BF compared to PBT pts (58% vs 40%, p=0.01). Though there was a statistically significant deterioration in UI in the IMRT cohort (-4, p<0.001), this did not reach the predefined threshold for clinical relevance. Three months following RT, the IMRT group continued to have statistically significant and clinically relevant worsening of BF (-9, p<0.001), whereas the change in BF domain score of the PBT cohort was no longer statistically significant or clinically relevant compared to baseline (-1, p=0.25). There were no statistically significant or clinically relevant changes in UO or UI in either cohort at three months when compared to baseline. Conclusions: Pts who received IMRT or PBT reported unique patterns of toxicity, and pts treated with IMRT had worse decrement in BF immediately after and three months following RT, compared to those treated with PBT.

75 Background: Combined radiotherapy (RT) and long-term hormonal therapy (HT) is a standard treatment option for high-risk prostate cancer. Dose escalated RT alone has been shown to improve disease free survival. Increased sensitivity of prostate cancer to high doses per fraction has led to hypofractionation as a method to radiobiologically escalate dose.We report on the quality of life of patients treated with combined hypofractionated RT and HT. Methods: A prospective phase I/II study enrolling patients with any of: clinical T3, PSA ≥20, or Gleason 8-10. Forty-five Gy (1.8 Gy/fraction) was delivered to the pelvic nodes with a concomitant 22.5 Gy intensity-modulated RT boost to the prostate, for a total of 67.5 Gy (2.7 Gy/fraction) in 25 fractions over 5 weeks. Hormonal therapy was administered for 2-3 years. Patient reported outcomes were measured at baseline and every 6 months using the validated Expanded Prostate Cancer Index Composite (EPIC) questionnaire, which measures urinary, bowel, sexual, and hormonal domains. Results: Sixty patients with a minimum 24 months of patient-reported outcomes were analyzed. Mean scores comparing baseline to 24 month values are reported. There were no statistically significant changes in the urinary summary scores (86.3 vs. 86.0, p=0.45) or any of the urinary subscales (function, bother, incontinence, irritative/obstructive). Domain summary score decreases were observed in: bowel by 4.4% (94.7 vs. 90.3, p<0.01), sexual by 27% (44.5 vs. 17.5, p<0.01), and hormonal by 11.9% (93.1 vs. 81.2, p<0.01). Examining time trends in outcomes, most changes occurred within the first 6 months with smaller changes thereafter. Conclusions: Hypofractionated RT combined with long-term HT is associated with good patient-reported urinary and bowel outcomes at 24 months. Sexual and hormonal summary scores are affected, largely due to continued androgen deprivation therapy. Further follow-up is needed to document patient reported outcomes after testosterone recovery. No significant financial relationships to disclose.