Unfavorable Intermediate-risk Prostate Cancer Research Articles

Predictors of PSMA positivity at initial staging of prostate cancer.

283 Background: PSMA-based imaging improves detection of metastatic disease for initial staging of men diagnosed with prostate cancer (PCa) with higher accuracy compared to conventional imaging. PSMA imaging is now being increasingly adopted for initial local and distant metastatic staging. We sought to determine the contribution of clinical and pathological factors associated with PSMA positive nodal or metastatic disease. Methods: We retrospectively identified 404 men diagnosed with PCa who underwent initial staging with Gallium-68 or F-18 piflufolastat (DCFPyL) PSMA PET/CT across our eleven-hospital system from July 2021-December 2022. Patient characteristics, including demographic, clinical, pathologic, and imaging variables were obtained. PSMA positivity representing a suspicious nodal or distant lesion was determined based on radiology reports, histopathology, and other imaging modalities, and equivocal or likely benign lesions were counted as negative. Patients with prior diagnosis (>6 months) of PCa (n=42) or incomplete clinical history (n=22) were excluded. Clinical variables were compared with Wilcoxon Rank Test, Chi square, and Fishers’ exact test as well as univariable and multivariable logistic regression. Number of risk factors for patients with unfavorable intermediate or very high risk disease was also examined. PSA was log transformed. Statistical significance was defined as p<0.05. Results: 103/340 patients (30.3%) had PSMA imaging findings concerning for nodal or distant metastatic disease. Patients with positive finding were less likely to be Black, and had higher PSA, biopsy Gleason Grade Group, and higher presumptive NCCN risk. Stratifying by pre-scan NCCN risk group, PSMA positivity was observed in no patients with favorable intermediate risk PCa (n=17), 9.8% (12/123) with unfavorable intermediate risk PCa, 29% (25/86) with high risk PCa, and 58% (66/114) with very high risk PCa. Stratifying by number of risk factors, there were significant differences in scan positivity comparing unfavorable intermediate risk disease with 1 vs ≥2 risk factors (4.2% vs 17%, p=0.03) and very high risk disease with 1 risk vs ≥2 risk factors (49% vs 72%, p=0.01). On multivariable analysis, NCCN classification stratified by risk factors was associated with PSMA positivity while Black race was inversely associated (OR 0.32, 95% CI 0.11, 0.82, p=0.03). Conclusions: Initial staging with PSMA PET/CT identified local regional or metastatic disease in 30% of PCa patients. A substantial proportion of unfavorable intermediate risk men were N1 or M1 based on PSMA positivity, particularly those with multiple unfavorable intermediate risk features. The clinical benefit for PSMA PET/CT in patients with favorable intermediate risk PCa is low. Limitations include retrospective design (including possible selection bias for patients with equivocal lesions on conventional imaging) and a limited number of black men in the cohort.

Update from the PSMA-dRT trial: A randomized phase III trial of PSMA-PET prior to definitive radiation therapy for unfavorable intermediate-risk or high-risk prostate cancer.

291 Background: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) has superior diagnostic accuracy for detecting regional and distant metastases compared to conventional imaging (CT, bone scan, and MRI) in men with prostate cancer. This has the potential to guide definitive radiation therapy (dRT) patient selection and planning. Whether the use of improved diagnostic accuracy imaging improves patient outcomes remains to be demonstrated in clinical trials. Methods: This multi-institutional phase III randomized clinical trial (PSMA-dRT, NCT04457245) was designed to randomize 312 men with unfavorable intermediate-risk or high-risk prostate cancer 1.08:1 between receiving (n=162) and not receiving (n=150) a PSMA PET/CT prior to starting dRT. Treating radiation oncologists incorporated the PSMA PET/CT into radiotherapy planning. All other imaging modalities were allowed in the control arm. There were no prespecified androgen deprivation therapy (ADT) or dRT dose and volumes protocols. The primary endpoint was 5-year progression-free survival (PFS). Results: 54 patients were randomized between November 2020 and December 2021 (25 to PSMA PET/CT and 29 to control). The trial closed early following FDA approval and insurance coverage of PSMA PET/CT, since treatment without PSMA PET/CT in the control group was no longer acceptable for many patients and physicians. Among patients staged with PSMA PET/CT in the intervention group, 14 patients (58.3%) had localized miT2b-cN0M0 disease, 6 (25.0%) had locally advanced disease (miT3a-bN0M0), 3 (12.5%) had regional disease (miN1M0), and 1 (4.2%) had nodal and distant disease (miN1M1b). Four patients (16.7%) were upstaged relative to their staging at time of randomization. All three patients with miN1M0 disease received pelvic lymph node irradiation as part of their dRT course. The patient with miN1M1b disease received upfront ADT with abiraterone acetate and prednisone followed by consolidative radiotherapy to the prostate and pelvic lymph nodes. With a median follow-up of 21 months (interquartile range: 17.6-26.3 months), there were no cases of biochemical failure (PSA >2 ng/mL above nadir), radiographic or biopsy-proven recurrence, salvage therapy, or prostate cancer death in either arm. Two-year PFS was 93.8% in the PSMA PET/CT arm (due to 2 non prostate cancer deaths) and 100% in the control arm. There was no significant difference in PFS between the PSMA PET/CT and control arms ( P=0.13). Conclusions: PSMA PET/CT upstaged 17% of patients compared to prior baseline staging, which allowed for more accurate treatment planning. Due to early termination, this trial was underpowered to assess the effect of PSMA PET/CT on PFS. PSMA-dRT is currently under submission for complete enrollment and data pooling at German sites. Clinical trial information: NCT04457245 .

A randomized, non-comparative, phase II multicentric trial on short-term darolutamide (ODM-201) concomitant to radiation therapy for patients with unfavorable intermediate-risk prostate cancer: DARIUS (AFU-GETUG P15).

A randomized, non-comparative, phase II multicentric trial on short-term darolutamide (ODM-201) concomitant to radiation therapy for patients with unfavorable intermediate-risk prostate cancer: DARIUS (AFU-GETUG P15).

A phase 2 study of neoadjuvant PARP inhibition followed by radical prostatectomy (RP) in patients with unfavorable intermediate-risk or high-risk prostate cancer with BRCA1/2 gene alterations (NePtune).

TPS353 Background: Patients with localized high-risk prostate cancer have an increased risk of relapse following RP. Approximately 6% of patients with high-risk disease harbor germline alterations in the DNA repair pathway, of which BRCA1/2 alterations are the most common. Patients with germline BRCA1/2 mutations have higher rates of aggressive disease, distant metastases, and worse survival compared to non-carriers. Olaparib is a PARP inhibitor which demonstrates improved overall survival in patients with metastatic castration resistant prostate cancer with BRCA1/2 germline and somatic alterations. Additionally, olaparib has demonstrated improved invasive disease-free survival as adjuvant therapy in patients with germline BRCA1/2 HER-2 negative breast cancer. Novel, multimodal treatment strategies for patients with high-risk localized prostate cancer with germline or somatic BRCA1/2 may improve outcomes for these patients. Methods: We designed a multicenter phase 2 single arm study evaluating neoadjuvant olaparib in combination with a LHRH agonist for 6 months followed by RP. Eligible patients include those with a Gleason score ≥4+3=7, PSA >20 ng/mL or T3 disease (by DRE or prostate MRI) and lymph node <20 mm. Patients with intraductal carcinoma are eligible independent of Gleason score, PSA, or T stage. Patients must have a germline or somatic BRCA1/2 pathogenic or likely pathogenic alterations identified on standard of care molecular profiling. Eligible patients receive olaparib 300 mg by mouth twice daily and a LHRH agonist for 6 months followed by RP. The primary endpoint is the rate of a pathologic complete response (pCR) or minimum residual disease (MRD, tumor ≤5 mm) as determined by central pathology review. Secondary endpoints include PSA response, surgical staging at RP, positive margin rate, time to testosterone recovery, and safety. Exploratory endpoints include quality of life assessment, proportion of downstaging on multi-parametric MRI (mpMRI), correlation of mpMRI with pathologic response, and tissue based molecular predictors of response and resistance. The sample size was estimated based a Binomial Exact test to assess the null hypothesis of the pCR/MRD rate ≤10% with one-sided 5% significance level. If the observed rate from this study is ≥32.5%, to have 90% power to conclude that the pCR/MRD rate is above 10%, a total of 30 patients will be enrolled. We can reject the null hypothesis if there are at least 7 responses. This trial is enrolling patients through the Hoosier Cancer Research Network. The study is activated at the University of California San Diego and University of Pennsylvania. Sites pending activation include: Johns Hopkins Hospital, Memorial Sloan Kettering Cancer Center, Columbia University, and University of Buffalo. Clinical trial information: NCT05498272 .

Long-Term Outcomes Associated with Different High-Dose-Rate Brachytherapy Dose Regimens for Favorable and Unfavorable Intermediate Risk Prostate Cancer.

To present long-term efficacy outcomes of prostate high-dose-rate (HDR) brachytherapy monotherapy using 38 Gy in 4 fractions, 24 Gy in 2 fractions, and 27 Gy in 2 fractions for men with favorable and unfavorable intermediate risk prostate cancer. Patients treated with HDR brachytherapy monotherapy for NCCN favorable (FIR) or unfavorable (UIR) intermediate risk prostate cancer from 1999-2020 were identified in a prospectively maintained, single institution database. Patients with less than two years of follow-up and those treated with single fraction HDR brachytherapy were excluded. Biochemical failure was determined using Phoenix criteria. 10-year biochemical control (BC), local control (LC), and distant metastasis (DM) rates were estimated using the Kaplan-Meier method. Two hundred sixty-seven patients were included. One hundred eighty-nine had FIR and 78 had UIR prostate cancer, with median follow-up of 9.6 years and 7.2 years, respectively. Of the 189 patients with FIR prostate cancer, 59 (31.2%) received 38 Gy in 4 fractions, 26 (13.7%) received 24 Gy in 2 fractions, and 104 (55.0%) received 27 Gy in 2 fractions. Of the 78 patients with UIR prostate cancer, 20 (25.6%) received 38 Gy in 4 fractions, 11 (14.1%) received 24 Gy in 2 fractions, and 47 (60.2%) received 27 Gy in 2 fractions. Date ranges of treatment for the respective fractionation schedules were 1999-2010, 2007-2016, and 2009-2020. Upfront androgen deprivation therapy (ADT) was given to 12 (6.3%) patients with FIR and 10 (12.8%) patients with UIR. 10-year rates of BC for FIR and UIR patients were 90.1% and 78.8% (p = 0.004), respectively. 10-year rates of LC were 92.4% and 85.0% (p = 0.06), respectively. 10-year rates of DM were 1.9% and 4.7% (p = 0.12), respectively. For FIR patients, 10-year BC rates were 96.2% for patients receiving 38 Gy in 4 fractions vs. 86.3% (p = 0.07) for those treated with the 2-fraction regimens, while 10-year LC rates were 97.9% and 89.0% (p = 0.049), respectively. Within the UIR subset, the 10-year BC rates for patients receiving 38 Gy in 4 fractions and patients receiving treatment in 2 fractions were 95.0% and 70.6% (p = 0.038). 10-year LC rates were 100% and 77.8% (p = 0.045), respectively. 10-year BC rates by treatment schedule are shown in the table below. HDR brachytherapy monotherapy results in excellent long-term local control for intermediate risk prostate cancer. Improvements in biochemical and local disease control for patients treated with 38 Gy in 4 fractions warrants consideration of prospective study of optimal treatment dosing regimens.

High-Dose Rate Brachytherapy Alone for Treatment of Unfavorable Intermediate Risk Prostate Cancer: A Propensity-Score Matched Analysis.

To demonstrate the feasibility of high-dose rate brachytherapy (HDR BT) as monotherapy for unfavorable intermediate risk (UIR) prostate cancer by comparing survival outcomes of HDR BT alone against external beam radiation therapy (EBRT) + HDR BT boost, +/- androgen deprivation therapy (ADT) using propensity-score matched (PSM) data. This retrospective study queried two data registries collecting patient data from 1991 to present. 633 patients with UIR prostate cancer treated with HDR BT alone, HDR BT+EBRT or HDR+EBRT+ADT were included. HDR BT patients received 42-45Gy/6 fractions (fx) or 27 Gy/2 fx. For HDR BT+EBRT, the HDR dose was 20-24 Gy/2 fx, 24 Gy/4 fx, or 15 Gy/1 fx. EBRT patients received 45 Gy/25 fx to the prostate +/- pelvic nodes. GU/GI toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Time-to-event analyses were carried out to evaluate the relationship between treatments and five primary endpoints of interest: freedom from biochemical recurrence (FFBC), freedom from distant metastasis (FFDM), freedom from local failure (FFLF), cancer specific survival (CSS), and overall survival (OS) at 5 years. PSM was performed with one-to-n matching. Logistic regression was used to estimate the respective propensity scores. The five potential confounders identified were T-stage, Gleason score, pre-treatment PSA, age, and percent positive cores. Balance was checked using the standardized mean difference of covariates. Univariate and multivariate analyses were conducted on the matched data. Toxicity analysis was performed via association between a change in pre- and post-treatment GU/GI toxicity status and the treatment group, as well as incidence of post-treatment severe GI/GU toxicity (grade 3 or higher) and the treatment group. Univariate analysis with Kaplan-Meier method and log rank test comparison between the three cohorts demonstrated no significant difference in all survival outcomes FFBC, FFDM, FFLF, CSS, OS (p = 0.15, 0.19, 0.29, 0.57, 0.28, respectively). Multivariate analysis with Cox proportional hazard regression showed no differences in HR for FFBC and OS (p = 0.95, 0.11) with addition of EBRT, or with EBRT+ADT (p = 0.17, 0.24); no fit was obtainable for FFDM, CSS, FFLF. Toxicities between the three cohorts were not significantly different when comparing post-treatment and baseline GI/GU symptoms (p = 0.53/1). No Grade 2 or 3 GI toxicities were identified, while 8%/1% HDR patients, 10%/1% HDR+EBRT patients, and 12%/2% HDR+EBRT+ADT patients experienced Grade 2/3 GU toxicities. The incidence of grade 3 or higher GU toxicities between the three groups was not significantly different (p = 0.91). This propensity-score matched study demonstrates the feasibility of HDR BT alone for effective treatment of UIR prostate cancer when compared to HDR+EBRT or HDR+EBRT+ADT, while potentially minimizing the added toxicities of EBRT and the undesirable side effect profile of ADT.

Risk Factors Predicting Relapse 10 Years Following Extreme Dose-Escalated SBRT for Intermediate-Risk Prostate Cancer: Is De-Intensification Feasible in Unfavorable Subgroups?

Adding short-term androgen-deprivation therapy (ADT) to radiotherapy is recommended in unfavorable intermediate-risk (UIR) prostate cancer (PCa). Data supporting the addition of ADT to stereotactic body radiotherapy (SBRT) in intermediate-risk (IR) patients are limited. Given ADT has well-documented toxicities, we sought to identify the UIR prognostic factors that predict for relapse following SBRT without ADT. We combined results from two mature multicenter trials to determine if extreme dose-escalated SBRT yielded UIR subgroups in which the omission of ADT may be considered. Between 2008 and 2011, two prospective national trials enlisted 39 centers to enroll 285 patients with IR PCa: 182 had Memorial Sloan Kettering (MSK) favorable intermediate-risk (FIR) and 103 had MSK UIF PCa. All were treated with a non-coplanar robotic SBRT platform using real-time tracking of implanted fiducials. Two dose regimens were used: 40Gy in 5 fractions of 8Gy, and 38Gy in 4 fractions of 9.5Gy. ADT was not allowed. Univariate and multivariate analyses using a Cox proportional hazards model was performed for relapse free survival (RFS): relapse included pathologic or radiographic failure, initiation of salvage or systemic therapy, or biochemical relapse by the nadir + 2 definition. Insufficient events prevented similar analyses for local control, metastasis-free and PCa-specific survival. Examined risk factors included dose regimen, clinical T-stage, Gleason score, pre-treatment PSA, % positive biopsy cores, and number of unfavorable risk factors (URFs). All reported rates are actuarial, using Kaplan-Meier method. Median follow-up was 8.1 years. 71 patients were followed 10 years. There were no statistically significant differences in rates of toxicity, local failure, RFS, overall nor metastasis-free survival between the two dose regimens. For the entire group, 10-year overall survival was 82.9%, RFS was 83.2%, and the local failure rate was 3.6%. On univariate analysis, primary Gleason pattern 4 (PGP4) and >2 URFs predicted for RFS. On multivariate analysis, only PGP4 (hazard ratio: 3.71, p = 0.0053) was statistically significant. Examining the UIR subgroup, the only predictor for RFS was PGP4 (HR: 3.64, p = 0.0253). 10-year RFS was 88.4% for FIR and 89.1% for UIR without PGP4; this fell to 58.5% in patients with a PGP4. Following dose-escalated SBRT monotherapy, 10-year RFS rates were favorable in UIR patients without PGP4. Extreme dose escalation appeared to effectively address UIR factors correlating with tumor bulk (i.e., CS T2b, >50% cores+, PSA 10-20), but was less effective with biologically aggressive pathology (PGP4). A randomized trial, ideally including genomic classification, would be necessary to determine if dose-escalated SBRT allows de-intensification (omission of ADT) in such biologically less aggressive UIR subgroups. The high relapse rate observed in UIR patients with PGP4 affirms the need for adjuvant ADT in this subgroup.

Active Surveillance for Taiwanese Men with Localized Prostate Cancer: Intermediate-Term Outcomes and Predictive Factors.

Active surveillance (AS) is one of the management options for patients with low-risk and select intermediate-risk prostate cancer (PC). However, factors predicting disease reclassification and conversion to active treatment from a large population of pure Asian cohorts regarding AS are less evaluated. This study investigated the intermediate-term outcomes of patients with localized PC undergoing AS. This cohort study enrolled consecutive men with localized non-high-risk PC diagnosed in Taiwan between June 2012 and Jan 2023. The study endpoints were disease reclassification (either pathological or radiographic progression) and conversion to active treatment. The factors predicting endpoints were evaluated using the Cox proportional hazards model. A total of 405 patients (median age: 67.2 years) were consecutively enrolled and followed up with a median of 64.6 months. Based on the National Comprehensive Cancer Network (NCCN) risk grouping, 70 (17.3%), 164 (40.5%), 140 (34.6%), and 31 (7.7%) patients were classified as very low-risk, low-risk, favorable-intermediate risk, and unfavorable intermediate-risk PC, respectively. The 5-year reclassification rates were 24.8%, 27.0%, 18.6%, and 25.3%, respectively. The 5-year conversion rates were 20.4%, 28.8%, 43.6%, and 37.8%, respectively. A prostate-specific antigen density (PSAD) of ≥0.15 ng/mL² predicted reclassification (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.17-2.88) and conversion (HR 1.56, 95% CI 1.05-2.31). A maximal percentage of cancer in positive cores (MPCPC) of ≥15% predicted conversion (15% to <50%: HR 1.41, 95% CI 0.91-2.18; ≥50%: HR 1.97, 95% CI 1.1453-3.40) compared with that of <15%. A Gleason grade group (GGG) of 3 tumor also predicted conversion (HR 2.69, 95% CI 1.06-6.79; GGG 3 vs 1). One patient developed metastasis, but none died of PC during the study period (2,141 person-years). AS is a viable option for Taiwanese men with non-high-risk PC, in terms of reclassification and conversion. High PSAD predicted reclassification, whereas high PSAD, MPCPC, and GGG predicted conversion.

5-Years Analysis of Effectivity and Toxicity of Ultra-Hypofractionated Proton Radiotherapy in the Treatment of Low- and Intermediate-Risk Prostate Cancer-A Retrospective Analysis.

We retrospectively analyzed the 5-year biochemical disease-free survival (bDFS) and occurrence of late toxicity in prostate cancer patients treated with pencil beam scanning (PBS) proton radiotherapy. In the period from January 2013 to June 2018, 853 patients with prostate cancer were treated with an ultra-hypofractionated schedule (36.25 GyE/five fractions). The mean PSA value was 6.7 (0.7-19.7) µg/L. There were 318 (37.3%), 314 (36.8%), and 221 (25.9%) patients at low (LR), favorable intermediate (F-IR), and unfavorable intermediate risk (U-IR), respectively. Neoadjuvant hormonal therapy was administered to 197 (23.1%) patients, and 7 (0.8%) patients had adjuvant hormonal therapy. The whole group of patients reached median follow-up time at 62.7 months, and their mean age was 64.8 (40.0-85.7) years. The bDFS rates and late toxicity profile were evaluated. Median treatment time was 10 (7-38) days. Estimated 5-year bDFS rates were 96.5%, 93.7%, and 91.2% for low-, favorable intermediate-, and unfavorable intermediate-risk groups, respectively. Cumulative late toxicity (CTCAE v4.0) of G2+ was as follows: gastrointestinal (GI)-G2: 9.1%; G3: 0.5%; genitourinary (GU)-G2: 4.3%, and no G3 toxicity was observed. PSA relapse was observed in 58 (6.8%) patients: 16 local, 22 lymph node, 4 bone recurrences, and 10 combined sites of relapse were detected. Throughout the follow-up period, 40 patients (4.7%) died, though none due to prostate cancer. Ultra-hypofractionated proton beam radiotherapy is an effective treatment for low- and favorable intermediate-risk prostate cancer, with long-term bDFS rates comparable to other techniques. It is promising for unfavorable intermediate-risk prostate cancer and has acceptable long-term GI and favorable GU toxicity.

LDR-Brachytherapy monotherapy appears unsuited for NCCN unfavorable intermediate-risk prostate cancer patients

BackgroundTo validate the subdivision of intermediate-risk (IR) prostate cancer (PCa) into favorable intermediate-risk (FIR) and unfavorable intermediate-risk (UIR) PCa in a historical patient cohort and to compare 2 different radiotherapy regimens. MethodsPatients with intermediate-risk (IR) PCa, treated either by 125J-LDR-brachytherapy monotherapy (BT) or by combined-modality radiation therapy (CRT), were retrospectively subclassified into FIR and UIR and reanalyzed with regard to biochemical recurrence-free survival (BRFS), metastasis-free survival (MFS), and prostate cancer-specific survival (CSS). Kaplan-Meier product-limit method and log-rank tests were applied to estimate survival probabilities and compare survival, respectively. Uni- and multivariable analyses were performed using Cox proportional hazard regression. ResultsOf 490 IR patients, 252 had received BT (86.5% FIR, 13.5% UIR), and 238 had received CRT (30% FIR, 70% UIR). Retrospective analysis revealed that BRFS at 10 years was 81% for BT, and 94% for CRT in FIR patients. For UIR patients, BRFS at 10 years was 37% for BT, and 89% for CRT. MFS at 10 years for FIR patients was 87% for BT, and 94% for CRT. For UIR patients MFS at 10 years was 78% for BT, and 95% for CRT. In multivariable analysis treatment (BT vs. CRT) was the single associated factor for biochemical recurrence, and for metastases in the UIR group (BFRS, P < 0.001, HR 16.07 (CI 4.23–61.10); MFS, P = 0.011, HR 8.43 (CI 1.62–43.9). ConclusionsSubclassification of IR prostate cancer into FIR and UIR subcategories appears mandatory. For FIR patients, outcomes after BT monotherapy were acceptable. However, clinical failure after 125J-LDR-BT in UIR patients was notably increased, suggesting that BT monotherapy was less successful in this risk group. In contrast, the outcome in UIR patients after CRT was excellent.

PP04 Presentation Time: 9:47 AM: Outcomes of Patients with Unfavorable Intermediate Risk Prostate Cancer Treated with External Beam Radiotherapy and Brachytherapy with or without Androgen Deprivation Therapy

PP04 Presentation Time: 9:47 AM: Outcomes of Patients with Unfavorable Intermediate Risk Prostate Cancer Treated with External Beam Radiotherapy and Brachytherapy with or without Androgen Deprivation Therapy

PO65: A Potential Role for HDR Brachytherapy Alone in the Treatment of Unfavorable Intermediate Risk Prostate Cancer

PO65: A Potential Role for HDR Brachytherapy Alone in the Treatment of Unfavorable Intermediate Risk Prostate Cancer

The Diagnostic Value of PSMA PET/CT in Men with Newly Diagnosed Unfavorable Intermediate-Risk Prostate Cancer.

Our objective was to determine the diagnostic value of prostate-specific membrane antigen (PSMA) PET/CT in staging men with newly diagnosed unfavorable intermediate-risk prostate cancer (PCa). Methods: Patients with newly diagnosed unfavorable intermediate-risk PCa, in whom PSMA PET/CT was performed as a primary staging modality, were retrospectively studied. PSMA PET/CT was performed at several diagnostic centers and reported by expert nuclear medicine physicians within 2 high-volume PCa centers. A multivariate logistic regression analysis, taking into account clinical, biochemical, pathologic, and radiologic variables, was performed to identify potential independent predictors for metastatic disease on PSMA PET/CT. Results: In total, 396 men with newly diagnosed unfavorable intermediate-risk PCa were studied. Metastatic disease was observed in 37 (9.3%) men, of whom 29 (7.3%) had molecular imaging locoregional lymph node metastases (miN1) and 16 (4.0%) had distant metastases (miM1). A radiologic tumor stage of at least T3 on MRI (odds ratio, 2.72 [95% CI, 1.27-5.83]; P = 0.01) and more than 50% positive prostate biopsies (odds ratio, 3.87 [95% CI, 1.74-8.62]; P = 0.001) were found to be independently associated with metastatic disease on PSMA PET/CT. Conclusion: Given that metastatic disease was observed in nearly 1 in 10 men with newly diagnosed unfavorable intermediate-risk PCa, PSMA PET/CT is considered to be of diagnostic value within this population. Further stratification using the radiologic tumor stage and the percentage of positive prostate biopsies could aid in identifying those patients at risk of having metastatic disease on PSMA PET/CT.

High-dose-rate brachytherapy as monotherapy versus as boost in unfavorable intermediate-risk localized prostate cancer: A matched-pair analysis

PURPOSEHigh-dose-rate brachytherapy as monotherapy (HDR-M), or as a boost combined with external beam radiotherapy (HDR-B), are both suitable treatments for intermediate-risk prostate cancer. However, data directly comparing these two approaches for men with unfavorable intermediate-risk (UIR) patients are lacking. METHODS AND MATERIALSPatients with NCCN-defined UIR prostate cancer treated from 1997 to 2020 were identified in a prospectively maintained, single institution database. HDR-M and HDR-B patients were matched using three factors: age ±3 years; Gleason score (major and minor); and clinical T stage. Biochemical failure was defined as PSA nadir (nPSA) + 2. Available acute and chronic toxicities are additionally reported. RESULTSA total of 247 patients were identified (170 receiving HDR-B, 77 receiving HDR-M), ultimately yielding 70 matched pairs (140 patients) for inclusion. The median followup time was 5.2 years for HDR-M compared with 9.3 years for HDR-B (p < 0.001). The two cohorts had similar calculated prostate EQD2 (HDR-B 118 Gy vs. HDR-M 115 Gy, p = 0.977). No significant differences in OS, CSS, DM, LRR, or FFBF were identified. HDR-B had an increased rate of any acute grade 2+ gastrointestinal toxicity and worse acute dysuria and diarrhea. Chronic gastrointestinal and genitourinary toxicity was similar. CONCLUSIONSThese data suggest that HDR brachytherapy as monotherapy is an effective treatment option for selected patients with unfavorable intermediate-risk prostate cancer and provides a more favorable gastrointestinal toxicity profile than HDR-B. Prospective trials should be conducted to refine the selection process for this heterogeneous cohort of patients.

Combined radiotherapy and hormone therapy in unfavorable intermediate risk prostate cancer

Background. Currently, the group of intermediate risk prostate cancer (PC) includes 2 subgroups - favorable and unfavorable intermediate risk according to the National Comprehensive Cancer Network (NCCN) classification. The optimal scope of therapy is not defined for the unfavorable intermediate risk subgroup. In particular, the need for and duration of hormone therapy (HT) during combined radiotherapy (CRT) have not yet been determined.Aim. To perform a comparative analysis of the efficacy and toxicity of CRT in patients with unfavorable intermediate risk treated with and without HT.Materials and methods. Eighty-four (84) patients with unfavorable intermediate risk PC were treated with CRT at the clinic of the A.F. Tsyb Medical Radiological Research Center between May 2016 and December 2020. Patients were divided into two groups: external beam radiation therapy + brachytherapy (n = 40) and external beam radiation therapy + brachytherapy + HT (n = 44). Conformal external beam radiation therapy was delivered with conventional fractionation to a total dose of 44-46 Gy and the 192Ir high-dose rate brachytherapy was delivered with a single fraction of 15 Gy. Median duration of HT consisting of gonadotropin-releasing hormone agonist was 6 months. Median age was 65.2 years (range: 49-80 years). Median follow-up was 58.1 months (range: 18.6-83.7 months).Results. With a median follow-up of 4.8 years, progression-free survival was 95 % and 97.6 % in the external beam radiation therapy + brachytherapy group and external beam radiation therapy + brachytherapy + HT group, respectively (p = 0.578). The break between treatment stages of more than 28 days was associated with a statistically significant increase in the risk of PC recurrence (p = 0.007). Overall survival for the external beam radiation therapy + brachytherapy group versus external beam radiation therapy + brachytherapy + HT group was 97.5 and 93.2 % (p = 0.376), respectively.Late genitourinary toxicity was grade I in 8 (9.5 %) patients and grade II in 1 (1.2 %) patient. Urethral stricture developed in 3 (3.6 %) patients. Late gastrointestinal toxicity was grade I in 7 (8.3 %) patients and grade II in 1 (1.2 %) patient. There were no statistically significant differences in the incidence of late complications between groups with and without HT. There was a statistically significant (p = 0.049) effect of prostate volume on the incidence of late radiation proctitis.Conclusion. There were no statistically significant differences in progression-free survival and overall survival in patients with unfavorable intermediate risk PC who received external beam radiation therapy + brachytherapy with or without HT. The incidence and severity of adverse events were acceptable and allowed patients with PC to maintain high quality of life.

PO-2194 uLDR-BT in treating patients with unfavorable intermediate-risk group prostate cancer.

PO-2194 uLDR-BT in treating patients with unfavorable intermediate-risk group prostate cancer.

Late Toxicity of Moderately Hypofractionated Intensity-Modulated Proton Therapy Treating the Prostate and Pelvic Lymph Nodes for High-Risk Prostate Cancer

To evaluate late gastrointestinal (GI) and genitourinary (GU) toxicity of moderately hypofractionated intensity modulated proton therapy (IMPT) targeting the prostate and pelvic lymph nodes. A target accrual of 56 patients with high-risk or unfavorable intermediate risk prostate cancer were enrolled into a prospective study (ClinicalTrials.gov: NCT02874014)of moderately hypofractionated IMPT. IMPT with pencil beam scanning was used to deliver 6750 and 4500 cGy relative biological effectiveness in 25 dailyfractions simultaneously to the prostate and pelvic lymph nodes, respectively. All received androgen deprivation therapy. Late GI and GU toxicity was prospectively assessed using Common Terminology Criteria for Adverse Events version 4.0, at baseline, weekly during radiation therapy, 3-month postradiation therapy, and then every 6 months. Actuarial rates of late GI and GU toxicity were estimated using Kaplan-Meier method. Median age was 75.5 years. Fifty-four patientswere available for late toxicity evaluation. Median follow-up was 43.9 months (range, 16-66). The actuarial rate of late grade ≥2 GI toxicity at both 2 and 3 years was 7.4% (95% confidence interval [CI], 0.2%-14.2%). The actuarial rate of late grade 3 GI toxicity at both 2 and 3 years was 1.9% (95% CI, 0%-5.4%). One patient experienced grade 3 GI toxicity with proctitis. The actuarial rate of late grade ≥2 GU toxicity was 20.5% (95% CI, 8.9%-30.6%) at 2 years, and 29.2 % (95% CI, 15.5%-40.7%) at 3 years. None had grade 3 GU toxicity. The presence of baseline GU symptoms was associated with a higher likelihood of experiencing late grade 2 GU toxicity. A moderately hypofractionated IMPT targeting the prostate and regional pelvic lymph nodes was generally well tolerated. Patients with pre-existing GU symptoms had a higher rate of late grade 2 GU toxicity. A phase 3 study is needed to assess any therapeutic gain of IMPT, in comparison with photon-based radiation therapy.

Late Gastrointestinal and Genitourinary Toxicities of a Moderately Hypofractionated Regimen of Intensity-Modulated Proton Therapy Targeting the Prostate/Seminal Vesicles and Pelvic Lymph Nodes for High Risk or Unfavorable Intermediate Risk Prostate Cancer

<h3>Purpose/Objective(s)</h3> To assess late gastrointestinal (GI) and genitourinary (GU) toxicities of intensity-modulated proton therapy (IMPT) targeting the prostate/seminal vesicles and regional pelvic lymph nodes for high risk (HR) or unfavorable intermediate risk (UIR) prostate cancer (Pca). <h3>Materials/Methods</h3> A prospective study (ClinicalTrials.gov: NCTXXX) to evaluate a moderately hypofractionated regimen of IMPT for HR-Pca or UIR-Pca accrued a target sample size of 55 patients. The prostate/seminal vesicles and pelvic lymph nodes were treated simultaneously with 67.5 Gy (2.7 Gy/fraction) and 45 Gy (1.8 Gy/fraction), respectively, in 25 fractions over 5 weeks. IMPT plan was prepared with pre-defined dose-volume histogram objectives for target volumes and organs at risk. All received androgen deprivation therapy (ADT). GI and GU toxicities were prospectively assessed, using the CTCAEv.4, at baseline (before IMPT); 3-, 6-, and 12-month post-RT and then every 6 months thereafter. Late toxicity was defined as toxicity persisting for > 3 months, or developing > 3 months post-RT. Late GI and GU toxicity rates were computed using Kaplan-Meier estimates, and log-rank tests were utilized for comparisons of time-to-event distributions. <h3>Results</h3> Median age was 75 years (range: 55-87). Median PSA was 10.5 ng/mL (range: 0.65 -97.3). Fifty-three patients had HR-Pca; 2 had UIR-Pca. Median duration of ADT was 18 months. Fifty-four patients were available for late toxicity assessment. Median follow-up was 46 months (range: 16-66). 29% and 6% experienced late grade 1 and 2 GI toxicity, respectively. One patient (2%) had late grade 3 GI toxicity (proctitis). The actuarial rate of late grade ≥ 2 GI toxicity was 7% (95% CI: 0.2-14%) at both 2 and 3 years. The actuarial rate of late grade 3 GI toxicity was 2% (95% CI: 0-5%) at both 2 and 3 years. 76% and 24% experienced late grade 1 and 2 GU toxicity, respectively. None had late grade ≥ 3 GU toxicity. The actuarial rate of late grade 2 GU toxicity was 21% (95% CI: 9-31%) at 2 years, and 29% (95% CI: 15-40%) at 3 years. None had late grade ≥ 4 GI or GU toxicity. The presence of baseline GU symptom was associated with a greater likelihood of experiencing late grade 2 GU toxicity. Of 44 patients with baseline GU symptoms, late grade 2 GU toxicity rate at 3 years was 36% (95%: 19-49%), compared to 0% among 10 patients with no baseline GU symptoms (p=0.02). <h3>Conclusion</h3> A moderately hypofractionated regimen of IMPT targeting prostate/seminal vesicles and pelvic lymph nodes for HR-Pca or UIR-Pca yielded very acceptable late GI and GU toxicity.

PSOR9 Presentation Time: 12:10 PM: Utilization of Brachytherapy Boost in Men with Unfavorable Intermediate Risk Prostate Cancer Treated with Radiation Plus Androgen Deprivation Therapy

<h3>Purpose</h3> Randomized data has shown a lower risk of recurrence with the addition of a brachytherapy (BT) boost in men with intermediate- and high-risk prostate cancer treated with external beam radiotherapy (EBRT) and concomitant androgen deprivation therapy (ADT). The inclusion of ADT with BT-based dose escalation is controversial, and professional guidelines support adding or excluding ADT for men with unfavorable intermediate risk prostate cancer treated with EBRT plus a BT boost. However, inclusion of ADT in men with intermediate risk prostate cancer may become more routine after results from RTOG 0815, and its impact on BT utilization in this population is unclear. Herein, we investigate the landscape of BT boost utilization in men with unfavorable intermediate risk prostate treated with EBRT and ADT in the United States. <h3>Materials and Methods</h3> Men ≥ 18 years diagnosed with clinical stage T1-2N0M0, PSA < 20, and Gleason grade group 3 prostate cancer between 2004-2017 were analyzed from the National Cancer Database. Those missing risk-stratification or treatment data were excluded. Eligible patients were grouped into the following cohorts based on primary radiation treatment modality: (i) EBRT alone or (ii) EBRT plus BT boost. EBRT monotherapy group received conventionally fractionated (1.8-2.0 Gy per fraction) ≥ 74 Gy or moderately hypofractionated (2.5-3.0 Gy per fraction) ≥ 60 Gy. EBRT plus BT boost group received conventionally fractionated ≥ 45 Gy or moderately hypofractionated ≥ 37.5 Gy, and either LDR or HDR BT. All patients received concomitant ADT. Cochran-Armitage was used to evaluate radiation modality treatment trends over time, and multivariable logistic regression was used to identify sociodemographic predictors of treatment. <h3>Results</h3> Among the eligible cohort, 46,490 (82%) were treated with EBRT alone and 10,236 (18%) were treated with EBRT plus BT boost. Median (range) age was 70 years (38-90). Between 2004 to 2017, there was a significant decline in annual use of a BT boost, from 24.5% in 2004 to 16.4% in 2017 (p<0.001). On MVA, Black race (adjusted OR 0.85, 95% CI 0.79-0.90, P<.0001), Medicaid insurance (aOR 0.67, 95% CI 0.57-0.78, P<.0001), and Charlson-Deyo comorbidity index > 1 (aOR 0.78, 95% CI 0.61-0.99, P=0.04) were associated with decreased odds of receiving a BT boost. Private insurance (aOR 1.11, 95% CI 1.05-1.18, P=.001), treatment at an academic institution (aOR 1.25, 95% CI 1.12-1.39, p<.0001), and Charlson-Deyo comorbidity index 0 (aOR 1.07, 95% CI 1.00-1.15, P=.04) were associated with increased odds of receiving a BT boost. <h3>Conclusions</h3> For men with unfavorable intermediate risk prostate cancer, utilization of a BT boost has significantly declined in the United States over the past two decades. Black and uninsured men have been at particularly high risk of undertreatment. Future studies aimed at identifying which men with intermediate-risk prostate cancer (e.g. based on genomic classifier or magnetic resonance imaging) derive the greatest oncologic benefit from a BT boost with EBRT and ADT is warranted to appropriately identify those who may be at risk of undertreatment with its exclusion. Additionally, future initiatives are needed to close the disparity gap in access and/or delivery of this efficacious treatment for Black and uninsured men, an overall undertreated population.

Friday, June 17, 20229:00 AM - 10:00 AM PP01 Presentation Time: 9:00 AM: Propensity-Matched Analysis of High-Dose-Rate Brachytherapy in Intermediate Risk Prostate Cancer: Monotherapy or Boost?

<h3>Purpose</h3> High-Dose-Rate Brachytherapy (HDR BT) either as monotherapy or boost has excellent reported prostate cancer control outcomes. Monotherapy is more commonly used for those with favorable risk features, while HDR tends to be combined with external beam radiotherapy (EBRT) for those with higher risk disease. Patients with intermediate risk prostate cancer (IR-PCa) can be managed either with monotherapy or boost. In the absence of randomized data, our objective is to compare biochemical response and oncological outcomes for patients with intermediate risk prostate cancer treated with either HDR as monotherapy or as a boost in combination with EBRT. <h3>Materials and Methods</h3> A propensity score matching analysis was performed of IR-PCa patients treated with either HDR monotherapy (27 Gy in 2 fractions), or HDR boost (15 Gy followed by EBRT; 37.5 Gy in 15 fractions delivered with Intensity modulated radiotherapy). The former patients were included in a prospective clinical trial whereas the latter were selected from a retrospective institutional database. Matching was based on age, baseline PSA, T stage, grade group, perineural invasion, and percentage of positive cores. No patient received androgen deprivation therapy. The primary outcome was biochemical disease-free survival (bDFS) defined as time from treatment to PSA nadir +2 or death. Secondary outcomes included PSA nadir and incidence of grade (G) ≥3 genitourinary (GU) and gastrointestinal (GI) toxicities measured using CTCAE v.4. A General Linear Mixed Model and Analysis of Covariance was used to investigate changes in PSA over time. <h3>Results</h3> A total of 132 patients were matched, 66 in each cohort with a median age of 66 years (range: 48-80). Median follow up was 59 months (interquartile range (IQR) 54, 62) for the HDR monotherapy cohort and 63 months (IQR 42, 81) for the boost BT group. They were well matched with a Propensity Score of 0.4615 and 0.4612, respectively. Thirty-eight percent of patients had unfavorable intermediate risk disease. Patients treated with monotherapy had slightly higher PSA in the first 4 years, Figure 1 (p=0.034), although by 5-years median PSA was 0.14 ng/ml (IQR 0.06, 0.34) with monotherapy and 0.15 ng/ml (IQR 0.07, 0.51) with boost. At 4 years, 24 (36%) monotherapy patients and 26 (44%) boost patients had PSA <0.2 ng/ml. Among all patients, 7% (10 of 132) experienced biochemical failure: six patients in the HDR monotherapy group and four in the boost group, resulting in 5-year bDFS of 93.5% and 93.3%, respectively. Favorable and Unfavorable IR-PCa had similar risk of recurrence. Late G3 GU toxicity occurred in 2 out of 66 boost patients and was not seen in the monotherapy patients. <h3>Conclusions</h3> Although limited by small sample size, we report high efficacy of HDR brachytherapy as either monotherapy or boost for all patients with intermediate risk disease. Boost patients had a lower PSA value in the first 4 years, although with a suggestion of greater G3 urinary toxicity.