Adjuvant Androgen Deprivation Therapy Research Articles

Prevalence of variant of unknown significance (VUS) in men with prostate cancer who serve as a benchmark for enhanced screening and for personalized therapy.

342 Background: Pathogenic variants (PVs) in DNA repair genes (DRG), such as in BRCA1, BRCA2, ATM, CHEK2, etc., have implications for prostate cancer (PCa) family genetic counselling, testing and risk stratification in men. However, understanding how to counsel patients with variants of unknown significance (VUS) is an unmet clinical need. On the other hand, there is the necessity to cautiously interpret VUS findings and to bolster VUS evaluations with additional evidence for pathogenicity. In this study, we aim to investigate the prevalence of germline VUS in men with PCa and their association with outcomes after robot-assisted radical prostatectomy (RARP). Methods: This is a nested cohort case study from an ongoing PCa screening, set to identify and screen men in the Italian population with a genetic predisposition (AIRC - Fondazione AIRC per la Ricerca sul Cancro project IG 2020 ID 25027). Cases for the current analysis were selected by “Adam's rib strategy” searching for germline DRG variant in men with a diagnosis of high-risk PCa who were scheduled for RARP. After informed consent was signed, a blood sample was obtained. A previously validated multigene panel test was used to assess the presence of germline variants. PVs and VUS were classified according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology consensus criteria and International Agency for Research on Cancer guidelines. The primary endpoint was to describe the prevalence of VUS and the secondary to correlate VUS with pathological outcomes after RARP. Results: A total of 118 men with diagnosis of PCa who underwent RP were enrolled. The mean age at diagnosis of PCa was 65.9 (±6.42) years; pathological grade was ISUP 1-2 in 58.0% patients and 3-5 in 42.0%. Of the 76 men evaluated, 18 (23.7%) had a VUS and 1 (1.32%) a pathogenic germline variant in BRCA1 and PALB2. Among those with VUS younger men at diagnosis were more likely to carry a VUS than older at diagnosis mean (age 64 ± 6.41 vs. 66 ± 7.20 years). Additionally, 33.3% vs 16.2 % were carrier of VUS and N+ and required adjuvant androgen deprivation therapy. No difference between ISUP at final pathology and positive margin rate were found. Conclusions: Our findings showed a high prevalence of VUS germline mutations in PCa patients undergoing RARP. These mutations seem to be associated with worse pathological outcomes. Limitations includes short follow-up and absence of non-Caucasian patients.

Health-Related Quality of Life Assessment in Prostate Cancer Patient Undergoing Androgen Deprivation Therapy: Real-World Experience in the READT Study.

To investigate the effect of androgen deprivation therapy (ADT) on health-related quality of life (HRQOL) in Asian men with all stages of prostate cancer. READT (real-life evaluation of the effect of ADT in prostate cancer patients in Asia) was a multi-center, prospective observational study involving six sites across four Asian populations. We enrolled eligible prostate cancer patients, who opted for ADT alone or in combination without prior neoadjuvant or adjuvant ADT within 12 months. The EuroQoL-5 dimensions, 5 level scale (EQ-5D-5L) utility index scores and visual analog scale (VAS) were evaluated at baseline, month 6 and month 12. A total of 504 patients were recruited into READT between September 2016 and May 2020 with 52.9% diagnosed with metastatic prostate cancer. The EQ-5D-5L was evaluable in 442/504 (87.7%) of patients. Overall baseline EQ-5D-5L utility index score was 0.924 (interquartile range [IQR] 0.876-1.000). We observed a statistically significant difference in baseline EQ-5D-5L utility index score among different populations with a median EQ-5D-5L utility index score of 1 for Taiwan & Hong Kong, 0.897 for China and 0.838 for Malaysia. Similar trend was observed throughout multiple treatment time-points. Stage IV prostate cancer were significantly associated with a lower baseline EQ-5D-5L utility index score compared to stage I-III prostate cancer, producing a median disutility value of -0.080. Participants had a high median VAS (80, IQR 70-90), indicating good overall health on average during ADT initiation. The study highlights the differences in health state utility index scores among various Asian prostate cancer patients receiving ADT at real-world setting. Our findings will be informative and useful in cost-effectiveness evaluation and policy decision making.

Trimodality Therapy With Iodine-125 Brachytherapy, External Beam Radiation Therapy, and Short- or Long-Term Androgen Deprivation Therapy for High-Risk Localized Prostate Cancer: Results of a Multicenter, Randomized Phase 3 Trial (TRIP/TRIGU0907)

This phase 3 randomized investigation was designed to determine whether 30 months of androgen deprivation therapy (ADT) was superior to 6 months of ADT when combined with brachytherapy and external beam radiation therapy (EBRT) for localized high-risk prostate cancer. This study was conducted at 37 hospitals on men aged 40 to 79 years, with stage T2c-3a, prostate-specific antigen >20 ng/mL, or Gleason score >7, who received 6 months of ADT combined with iodine-125 brachytherapy followed by EBRT. After stratification, patients were randomly assigned to either no further treatment (short arm) or 24 months of adjuvant ADT (long arm). According to the Phoenix definition of failure, the primary endpoint was the cumulative incidence of biochemical progression. Secondary endpoints included clinical progression, metastasis, salvage treatment, disease-specific mortality, overall survival, and grade 3+ adverse events. An intention-to-treat analysis was conducted using survival estimates determined using competing risk analyses. Of 332 patients, 165 and 167 were randomly assigned to the short and long arms, respectively. The median follow-up period was 9.2 years. The cumulative incidence of biochemical progression at 7 years was 9.0% (95% CI, 5.5-14.5) and 8.0% (4.7-13.5) in the short and long arms, respectively (P=.65). The outcomes of secondary endpoints did not differ significantly between the arms. Incidence rates of endocrine- and radiation-related grade 3+ adverse events for the short versus long arms were 0.6 versus 1.8% (P=.62) and 1.2 versus 0.6% (P=.62), respectively. Both treatment arms showed similar efficacy among selected populations with high-risk features. The toxicity of the trimodal therapy was acceptable. The present investigation, designed as a superiority trial, failed to demonstrate that 30-month ADT yielded better biochemical control than 6-month ADT when combined with brachytherapy and EBRT. Therefore, a noninferiority study is warranted to obtain further evidence supporting these preliminary results.

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.

Health-Related Quality of Life at Five Years for a Randomized Trial of Tri-Modality Therapy with I-125 Brachytherapy, External Beam Radiation Therapy, and Short- vs. Long-Term Androgen Deprivation Therapy for High-Risk Localized Prostate Cancer (TRIP)

To describe the patient-reported health-related quality of life (HR-QoL) outcomes at five years for a multicenter randomized trial of tri-modality therapy with iodine-125 brachytherapy, external beam radiation therapy (EBRT), and short- versus long-term androgen deprivation therapy (ADT) for high-risk localized prostate cancer (TRIP/TRIGU0907). A total of 332 men with high-risk prostate cancer were randomized to either 6 months of ADT (n = 165) or 30 months of ADT (n = 167) in conjunction with combined modality radiation therapy. For the HR-QoL assessment, general HR-QoL and disease-specific HR-QoL were measured using the Japanese version of the Medical Outcomes Study 8-items Short-Form Health Survey (SF-8) and the Expanded Prostate Cancer Index Composite (EPIC). Patient-reported outcome questionnaires were filled out before ADT initiation, and five years after. Scores were reported as mean with the standard deviation. QoL end points were assessed as the change between pre and post treatment using paired student t-test. Changes in the International Prostate Symptom Scores (IPSS) score, including total score and subscores, were also evaluated. The study was powered according to the primary endpoint of biochemical progression free survival with HR-QoL as a secondary endpoint. In addition, recovery of testosterone level (300ng/dL or higher) was calculated as the cumulative incidence curve and compared between arms by log-rank test. The cumulative incidence of biochemical progression, and salvage ADT treatment were not different between the arms. Mean domain scores at baseline were well balanced between the two arms in all HR-QoL. There were no differences in the SF-8 assessment and the total and subscore EPIC assessments between the arms. The average sexual function score was lower in short arm versus long arm; 16.24 versus 20.24 at baseline, but not different at five years, 9.96 versus 7.78 (p = 0.164). There were no significant differences between the arms for the total and subscore IPSS. Significantly higher percentage of patients, 71.7% in the short arm recovered to a normal testosterone level at 6 years after the initiation of ADT compared to 43.2% in long arm (p<0.0001). At five years after ADT initiation, there were no significant differences in all score changes between the two arms with general HR-QoL and disease-specific HR-QoL. Most of HR-QoL returned to baseline level, and sexual function scores were low from baseline in this population. Two-years' adjuvant ADT did not affect HR-QoL at five years, although it significantly retarded testosterone recovery compared to 6 months of hormone therapy.

Final Analysis of a Phase III Controlled Randomized Study of Stereotactic Body Proton Therapy or Conventionally Fractionated Proton Therapy for Early Prostate Cancer: PCG GU002

To determine if stereotactic body proton therapy (SBPT) is non-inferior to conventionally fractionated proton therapy (CFPT) in patients with early prostate cancer. Multicenter, randomized, controlled, open-label, non-inferiority phase 3 trial that included patients with histologically confirmed low-risk prostate adenocarcinoma defined by Gleason score ≤6, PSA <10 ng/mL, and clinical stage T1-2a N0 M0 by AJCC 7th Ed. Eligible participants were randomly assigned (initially 1:1 and later 2:1 ratio) to CFPT (79.2 Gy in 44 fractions for 9 weeks) or SBPT (38 Gy in 5 fractions for 1 week). Concurrent or adjuvant androgen deprivation therapy was not allowed. The primary endpoint was freedom from failure (FFF) at 2 years, defined as the first occurrence of local, regional, or distant recurrence, biochemical failure by the Phoenix definition (increase of PSA ≥2 ng/mL over the nadir PSA), or the start of salvage therapy including ADT. Secondary endpoints included GI and GU grade ≥2 toxicity according to CTCAE v4 criteria, as well as health-related quality of life (HRQoL) metrics assessed by AUASI and EPIC scores. Non-inferiority would be declared if the 1-sided 95% confidence interval limit for the difference in 2-year FFF rate was below 4.2% between both groups by Clopper-Pearson exact method. Between November 2010 and September 2020, 133 patients were enrolled and randomly assigned to CFPT (n = 45) or SBPT (n = 88). Median follow-up was 5 years (IQ 3.9-5.2), with the last patient enrolled followed for at least 2 years. The 2-year FFF was 100% for both groups, fulfilling the pre-specified criteria for non-inferiority of SBPT compared to CFPT. By KM estimates, 5-year FFF was 97.4% and 100% (P = 0.1), and the 5-year OS was 97.1% and 95.5% (P = 0.46) for patients treated with CFPT and SBPT, respectively. The cumulative incidence of any grade ≥3 toxicities at 5 years was 0% and 5.7% (P = 0.14) for patients treated with CFPT and SBPT, respectively. The frequency of GI grade ≥2 toxicity at 6 months was of 0% and 2.3% (P = 0.55), and at 2 years was of 6.7% and 3.4% (P = 0.69) for patients treated with CFPT and SBPT, respectively. The frequency of GU grade ≥2 toxicity at 6 months was of 2.2% and 5.7% (P = 0.42), and at 2 years was of 8.9% and 5.7% (P = 0.54) for patients treated with CFPT and SBPT, respectively. Changes in HRQoL scores at 2 years were similar between groups (Table). SBPT is non-inferior to CFPT regarding FFF and associated with similar long-term toxicity rates and HRQoL metric scores.

Phase III Study of Hypofractionated, Dose Escalation Radiotherapy vs. Conventional Pelvic Radiation Therapy followed by High Dose Rate Brachytherapy Boost for High Risk Adenocarcinoma of the Prostate (PCS VI): Acute Toxicity Results

The low α\β ratio of 1.2-2 for prostate cancer (PCa) suggests high radiation-fraction sensitivity and predicts a therapeutic advantage of lager fraction size. We have recently shown (PCS5) that high risk prostate cancer patients can safely and effectively be treated with moderate hypofractionated radiation therapy (HF-RT). To date there has been no phase-III randomized clinical-trial comparing moderately HF-RT with EBRT and HDR boost (HDRB). We are reporting the acute safety of EBRT+HDRB compared to moderate HF-RT in this phase III Canadian trial. From January 2015-June 2022, 308 high-risk localized PCa patients were randomized to receive either HF-RT or EBRT+HDRB. All patients received neo-adjuvant, concurrent, and long-term adjuvant androgen deprivation therapy (ADT). EBRT+HDRB consisted of 46 Gy in 2 Gy per fraction to the pelvis and a 15 Gy in one fraction HDR boost within 3 weeks of EBRT. HF-RT include concomitant dose escalation of 68 Gy in 2.72 Gy per fraction to the prostate, and 45 Gy in 1.8 Gy per fraction to the pelvic lymph-nodes. Of the 308 patients, 148 received HF-RT and 144 EBRT+ HDRB. The remainder either withdrew from the study or were treated with standard (2 Gy per fraction) fractionation for technical reasons. In both intention to treat and as treated analysis, using log-Rank, there were more grade 1 or worse (G1+) acute GI and GU events and more G2+ acute GI events in the HF-RT than EBRT+HDRB. As treated analysis the acute G1+ and G2+ GI events were 92 vs 77 (60.1% vs. 53.5%; p < 0.017) and 21 vs 10 (13.7% vs. 6.9%; p = 0.052), respectively for HF-RT and EBRT + HDRB. Similarly, the G1+ acute GU events were 123 vs. 101 (80.4% vs.70.1%; p < 0.001) respectively for HF-RT and EBRT+HDRB. There were only four G3 GI and one G3 GU acute toxicities in both arms. No grade 4 toxicities were reported. This is the first study of EBRT+HDRB compared to moderate HF dose escalated RT in high-risk prostate cancer patients treated with long-term ADT and pelvic RT. Our results demonstrate that both treatment approaches are well-tolerated and that EBRT+HDRB carries less G2+ GI and G1+ GU acute toxicities.

Identification of Early Biochemical Recurrence Predictors in High-Risk Prostate Cancer Patients Treated with Carbon-Ion Radiotherapy and Androgen Deprivation Therapy.

The aim of this retrospective study was to identify clinical predictors of early biochemical recurrence (BCR) in patients with high-risk prostate cancer (PCa) treated with carbon-ion radiotherapy (CIRT) and androgen deprivation therapy (ADT). A total of 670 high-risk PCa patients treated with CIRT and ADT were included in the study. Early BCR was defined as recurrence occurring during adjuvant ADT after CIRT or within 2 years after completion of ADT. Univariate and multivariate analyses were performed to identify clinical predictors of early BCR. Patients were also classified according to the Systemic Therapy in Advancing or Metastatic Prostate cancer (STAMPEDE) PCa classification. Early BCR was observed in 5.4% of the patients. Multivariate analysis identified clinical T3b stage and ≥75% positive biopsy cores as clinical predictors of early BCR after CIRT and ADT. The STAMPEDE PCa classification was also significantly associated with early BCR based on univariate analysis. These predictors can help clinicians identify patients who are at risk of early BCR. In the future, combination therapy of ADT with abiraterone may be an option for high-risk PCa patients who are at risk of early BCR, based on the results of the STAMPEDE study.

Early Endpoints in High-risk Localized Prostate Cancer: Exploratory Analysis of Three Radiation Therapy Oncology Group Phase 3 Studies

BackgroundEarly endpoints in clinical trials of high-risk localized prostate cancer (HRLPC) that resemble those monitored in real-world practice could expedite clinical development. ObjectiveTo assess the association of prostate-specific antigen (PSA) recurrence (PSA-R)-based early endpoints with metastasis-free survival (MFS), overall survival (OS), and prostate cancer (PC)-specific survival (PCSS), and to identify clinically undetectable disease. Design, setting, and participantsA post hoc analysis of patients with HRLPC from Radiation Therapy Oncology Group studies 9202, 9902, and 0521 was performed. InterventionLong-term adjuvant androgen-deprivation therapy (ADT) and post-primary definitive radiotherapy. Outcome measurements and statistical analysisEvent-free survival (EFS; PSA-R, locoregional recurrence [LRR], distant metastasis [DM], or death), biochemical failure (PSA-R), general clinical failure (PSA-R, LRR, DM, ADT initiation, or death), and no evidence of disease (NED; alive patients without PSA-R, LRR, DM, and subsequent PC therapy, and with testosterone recovery) were assessed for association with MFS, OS, and PCSS using correlation and landmark analyses, Kaplan-Meier method, and Cox proportional-hazard model. PSA-R was defined as PSA nadir + 2 ng/ml; PSA nadir + 2 ng/ml and rising; PSA >5, 10, and 25 ng/ml; or PSA doubling time (PSADT) <6 mo. Results and limitationsAmong assessed early endpoints, EFS with PSA nadir + 2 ng/ml and rising, or with PSA >5 ng/ml was associated with MFS, OS, and PCSS. No development of EFS with PSADT <6 mo or ADT initiation event or achievement of NED at 3 yr was associated with prolonged OS, MFS, and PCSS (hazard ratio [95% confidence interval], 0.53 [0.45–0.64], 0.63 [0.52–0.76], and 0.26 [0.18–0.36], or 0.56 [0.48–0.66], 0.62 [0.52–0.74], and 0.26 [0.19–0.37]) after the landmark time. Older studies performed before the current guidance should be interpreted with caution. ConclusionsWe identified EFS with PSA nadir + 2 ng/ml and rising, PSA >5 ng/ml, or PSADT <6 mo ± ADT initiation and NED as potentially promising early endpoints in HRLPC that should be validated further. Patient summaryWe identified novel clinical measures that may expedite the development of new medicines for patients with localized prostate cancer at a high risk of progression. These measures, which took into account prostate-specific antigen assessments and other clinical characteristics, should be confirmed in future studies. We also defined a novel measure of no evidence of disease that can help treating physicians identify patients with clinically undetectable disease.

Replicating the timing of androgen deprivation therapy randomized trial (TROG 03.06 and VCOG PR 01-03 [TOAD]) for recurrent prostate cancer using real-world observational data.

e17090 Background: The landmark TOAD trial (Lancet Oncol 2016) demonstrated an overall survival benefit for immediate compared to delayed androgen deprivation therapy (ADT) for patients with recurrent prostate cancer or unsuitable for curative treatment. However, the extent to which TOAD trial results can be replicated in real-world population-based observational data is unknown. For these reasons, we used TOAD trial data and criteria to define a similar retrospective cohort of men with rising PSA after definitive treatment of localized prostate cancer to compare immediate versus delayed ADT for recurrent non-metastatic disease. Methods: We used two data sources to conduct this study: 1) TOAD trial data, and 2) national electronic health record, cancer registry, administrative, pharmacy, and laboratory data for men treated with radical prostatectomy or radiotherapy for localized prostate cancer and laboratory confirmed biochemical recurrence (BCR) between 2005- 2015 in the Veterans Health Administration. We defined BCR according to guidelines and used National Death Index data through 2019 for survival outcomes. We designated randomization to the ‘immediate’ and ‘delayed’ arms for men receiving ADT within (immediate) or after (delayed) 2 years of BCR in the observational data. We used Cox proportional hazards regression models adjusting for age, PSA at BCR, comorbidities, and Gleason score, stratified by prior ADT exposure, to compare survival outcomes for immediate versus delayed ADT. Results: We identified 9,866 men with BCR after radical prostatectomy, 3,431 after radiotherapy alone, and 2,703 after radiotherapy and adjuvant ADT. The mean age at randomization for the TOAD cohort was older (74.8 vs. 75.9 years, delayed vs. immediate) compared to our observational cohort (68.1 vs. 67.0 years, delayed vs. immediate). In unadjusted survival analyses, we found both overall and prostate cancer-specific survival were higher among patients with delayed ADT (log-rank p-value &lt; 0.001 for both). Our multivariable survival models among men with and without prior ADT exposure also demonstrated survival benefit associated with delayed ADT (prior ADT exposure, adjusted hazard ratio (aHR) 2.3, 95% confidence interval (CI) 1.7, 3.0, no prior ADT exposure 2.6, 95% CI 2.4, 2.8). Conclusions: The benefit of immediate ADT administration compared to delayed as reported within the TOAD study was not found in a comparable observational cohort of men with non-metastatic recurrent prostate cancer. Even after multivariable adjustment, we found clear association of delayed ADT administration with improved survival outcomes suggesting selection bias and unobserved confounding, or that delayed ADT may be warranted for selected patient populations necessitating further investigation. Source of Funding: NCI R01 CA242559.

Maintenance of castration with concomitant relugolix and apalutamide (Apa) in patients with high-risk localized prostate cancer (HR-LPC): 1 year update.

e17094 Background: Androgen deprivation therapy (ADT) is a mainstay in the management of prostate cancer (PC). We assessed the efficacy of achieving and maintaining castrate testosterone (T) levels when combining relugolix, an oral gonadotropin-releasing hormone antagonist, concomitantly with Apa, an androgen receptor inhibitor. The single-arm, open-label, multicenter, phase 2 Apa-RP study evaluates the biochemical recurrence-free rate in patients with HR-LPC following radical prostatectomy (RP) who received 12 months of adjuvant Apa and ADT (main study). A substudy was added to assess whether the approved maintenance dose of relugolix with concomitant Apa maintained castration. Study results of the 28-day coadministration of relugolix + Apa showed that all evaluable patients achieved and maintained castration at standard relugolix dose and were transitioned into the main study (Brown et al. Target Oncol. 2022). Herein, we report longer term data of T levels and safety findings in the substudy patients who received relugolix + Apa for 1 year. Methods: Patients (n = 12) with HR-LPC (PSA ≥20 ng/mL or Gleason score ≥8) received a loading dose of relugolix (360 mg) at substudy initiation (Day -14) followed by the standard, approved relugolix dose (120 mg/d) for 13 days. Starting on Day 1, patients received relugolix + Apa (240 mg/d) for 28 days, with substudy completion on Day 28. These patients transitioned to the main study and received relugolix + Apa for a total of 1 year. T levels (castrate level defined as &lt; 50 ng/dL) were measured at baseline (Day -14), Day 1, Day 28, and then every 3 months. Results: Of the 12 patients who continued onto the main study, 1 withdrew and another was noncompliant with therapy and subsequently withdrew but maintained castration while on therapy. Of the 10 patients who successfully completed therapy, 100% maintained castration during 1 year of concomitant therapy with relugolix + Apa . No patient required dose modification of relugolix. Median T level was 10.0 ng/dL after 1 year of treatment. One month after treatment discontinuation, 8/10 (80%) patients saw recovery of their T (T ≥50 ng/dL). Treatment-emergent adverse events (TEAEs) occurred in all 12 patients (100%). TEAEs were consistent with known safety profiles for each drug administered separately. Conclusions: During the 12 months of concomitant relugolix + Apa administration, all patients who completed therapy maintained castrate T levels without relugolix dose modification. All but 2 patients had T recovery within 30 days of therapy discontinuation. These data support long-term T suppression with relugolix + Apa at standard doses. Subsequent T levels will be reported upon final analysis of the main study. Clinical trial information: NCT04523207 .

Extended versus standard pelvic lymph node dissection yields no difference in 3-year biochemical recurrence rates.

extended pelvic lymph node dissection (ePLND) increases the detection rate of lymph node positive prostate cancer compared to a standard pelvic lymph node dissection (sPLND). However, improvement of patient outcomes remains questionable. Here we report and compare 3-year postoperative PSA recurrence rates between patients that underwent sPLND versus ePLND at the time of prostatectomy. 162 patients received a sPLND (which involvedremoval of periprostatic, external iliac, and obturator lymph nodes bilaterally), and 142 patients received an ePLND (which involved removal of periprostatic, external iliac, obturator, hypogastric, and common iliac nodes bilaterally). Decision to undergo ePLND versus sPLND at our institution was changed in 2016 based on the National Comprehensive Cancer Network guideline. The median follow-up time was 7 and 3years for sPLND and ePLND patients, respectively. All node-positive patients were offered adjuvant radiotherapy. Kaplan-Meier analysis was carried out to assess the impact of a PLND on early postoperative PSA progression-free survival. Subgroup analyses were done for node-negative and node-positive patients, as well as Gleason score. Gleason score and T stage were not significantly different between patients who received an ePLND and sPLND. The pN1 rate for ePLND and sPLND were 20% (28/142) and 6% (10/162), respectively. There was no difference in the use of adjuvant treatments in the pN0 patients. Significantly, more ePLND pN1 patients received adjuvant androgen deprivation therapy (25/28 vs. 5/10 P=0.012) and radiation (27/28 vs. 4/10 P=0.002). Yet, no difference in biochemical recurrence between ePLND and sPLND was observed (P=0.44). This remained true in subgroup analyses of node-positive (P=0.26), node-negative (P=0.78), Gleason Score 6-7 (P=0.51), and Gleason Score 8-10 (P=0.77). PLND provided no additional therapeutic benefit, even though ePLND patients were significantly more likely to have node-positive disease and undergo adjuvant treatment, compared to a sPLND.

Hypofractionated, Dose Escalation Radiation Therapy for High-Risk Prostate Cancer: The Safety Analysis of the Prostate Cancer Study-5, a Groupe de Radio-Oncologie Génito-Urinaire de Quebec Led Phase 3 Trial

The low α\β ratio of 1.2 to 2 for prostate cancer (PCa) suggests high radiation-fraction sensitivity and predicts a therapeutic advantage of hypofractionated (HF) radiation therapy (RT). To date, no phase 3 randomized clinical trial has compared moderately HF RT with standard fractionation (SF) exclusively in high-risk PCa patients. We are reporting the safety of moderate HF RT in high-risk PCa in an initially noninferiority-designed phase 3 clinical trial. From February 2012 to March 2015, 329 high-risk PCa patients were randomized to receive either SF or HF RT. All patients received neoadjuvant, concurrent, and long-term adjuvant androgen deprivation therapy. Standard fractionation RT consisted of 76 Gy in 2 Gy per fraction to the prostate, where 46 Gy was delivered to the pelvic lymph nodes. Hypofractionated RT included concomitant dose escalation of 68 Gy in 2.72 Gy per fraction to the prostate and 45 Gy in 1.8 Gy per fraction to the pelvic lymph nodes. The coprimary endpoints were acute and delayed toxicity at 6 and 24 months, respectively. The trial was originally designed as a noninferiority with a 5% absolute margin. Given the lower-than-expected toxicities in both arms, the noninferiority analysis was completely dropped. Of the 329 patients, 164 were randomized to the HF and 165 to the SF arms. In total, there were more grade 1 or worse acute gastrointestinal (GI) events in the HF arm, 102 versus 83 events in the HF and SF arm, respectively (P=.016). This did not remain significant at 8 weeks of follow-up. There were no differences in grade 1 or worse acute GU events in the 2 arms, 105 versus 99 events in the HF and SF arm, respectively (P=.3). At 24 months, 12 patients in the SF arm and 15 patients in the HF arm had grade 2 or worse delayed GI-related adverse events (hazard ratio, 1.32; 95% CI, 0.62-2.83; P=.482). There were 11 patients in the SF arm and 3 patients in the HF arm with grade 2 or higher delayed genitourinary (GU) toxicities (hazard ratio, 0.26; 95% CI, 0.07-0.94; P=.037). There were 3 grade 3 GI and one grade 3 GU delayed toxicities in the HF arm and 3 grade 3 GU and no grade 3 GI toxicities in the SF arm. No grade 4-toxicities were reported. This is the first study of moderate HF dose-escalated RT in exclusively high-risk patients with prostate cancer treated with long-term androgen deprivation therapy and pelvic RT. Although our data were not analyzed as a noninferiority, our results demonstrate that moderately HF RT is well-tolerated, similar to SF RT at 2 years, and could be considered an alternative to SF RT.

PSMA-PET-guided dose-escalated volumetric arc therapy for newly diagnosed lymph node-positive prostate cancer: 5 Year outcomes following the FROGG and EviQ node-positive guidelines.

The Royal Australian and New Zealand College of Radiologists (RANZCR) Faculty of Radiation Oncology Genitourinary Group (FROGG) guidelines and online EviQ protocols incorporate prostate-specific membrane antigen (PSMA) positron emission tomography (PET)-guided dose-escalated intensity-modulated radiation therapy (DE-IMRT) for newly diagnosed lymph node (LN) positive prostate cancer. We evaluated late toxicity and efficacy outcomes following the FROGG and EviQ approach. Patients with LN-positive-only metastases on PSMA-PET imaging were offered curative therapy with 3 months neoadjuvant androgen deprivation therapy (ADT) followed by DE-IMRT and 3 years adjuvant ADT. IMRT was delivered via volumetric arc therapy (VMAT). We aimed to deliver 81 Gy in 45 fractions (Fx) to the prostate and PET-positive LNs, and 60 Gy in 45 Fx to elective pelvic nodes, contoured using the PIVOTAL guidelines. Forty-five patients were included. The median number of PET-positive nodes boosted was 2 (range 1-6) and median boost volume 1.16 cc (range 0.15-4.14). Seventeen (38%) patients had PET-positive nodes outside of PIVOTAL contouring guidelines. With 60 months median follow-up, disease-free, metastasis-free, prostate cancer-specific and overall survival were 88.1%, 95.3%, 100% and 91.5%. There were no in-field nodal failures. Late grade 1, 2 and 3 gastrointestinal toxicities occurred in 4%, 2% and 0% of patients, and genitourinary toxicity in 18%, 18% and 4%. Lower limb grade 2 lymphoedema occurred in three patients (7%). Outcomes following FROGG guidelines and EviQ are promising, with high long-term disease control and low toxicity. Contouring guidelines require modification due to the high rate of PET-positive nodes demonstrated beyond recommended coverage.

Management of Pathologic Node-Positive Prostate Cancer following Radical Prostatectomy.

Approximately 15% of prostate cancer patients have lymph node metastases at the time of radical prostatectomy (RP). However, there is no universally accepted standard of care for these men. The options for treatment in this subset of patients range from observation to a combination of adjuvant androgen deprivation therapy (aADT) and radiation therapy (RT). A recent systematic review showed that there was no clear choice out of the options above to treat these patients. Studies have shown that patients treated with adjuvant radiation therapy have lower all-cause mortality when compared to patients treated with salvage radiation therapy. In this review, we summarize treatment options for pathologic node-positive (pN1) patients and discuss the urgent need for robust clinical trials that includes observation as the control group to help establish a standard of care for treating patients with node-positive prostate cancer after RP.

MP61-07 EARLY SECONDARY TREATMENT OF LYMPH NODE POSITIVE PROSTATE CANCER AFTER RADICAL PROSTATECTOMY IS ASSOCIATED WITH AGGRESSIVE TUMOR FEATURES AND DETECTABLE PROSTATE SPECIFIC ANTIGEN

You have accessJournal of UrologyCME1 Apr 2023MP61-07 EARLY SECONDARY TREATMENT OF LYMPH NODE POSITIVE PROSTATE CANCER AFTER RADICAL PROSTATECTOMY IS ASSOCIATED WITH AGGRESSIVE TUMOR FEATURES AND DETECTABLE PROSTATE SPECIFIC ANTIGEN Daniel Triner, Ji Qi, Udit Singhal, Michael Sessine, Kevin Ginsburg, Brian Lane, and Todd Morgan Daniel TrinerDaniel Triner More articles by this author , Ji QiJi Qi More articles by this author , Udit SinghalUdit Singhal More articles by this author , Michael SessineMichael Sessine More articles by this author , Kevin GinsburgKevin Ginsburg More articles by this author , Brian LaneBrian Lane More articles by this author , and Todd MorganTodd Morgan More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003319.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Patients with lymph node positive (pN+) disease found at the time of radical prostatectomy (RP) and pelvic lymphadenectomy (PLND) are at high risk of disease recurrence and progression. There is ongoing debate with regards to optimal care of pN+patients. While data supports the use of adjuvant androgen deprivation therapy (ADT) with or without radiation (RT), most guidelines include observation as an alternative. We sought to understand contemporary practice patterns of patients with pN+prostate cancer (PCa) in a diverse, statewide quality collaborative. METHODS: Patients in the Michigan Urologic Surgery Improvement Collaborative (MUSIC) with PCa who underwent RP with PLND and pN+on final pathology and 12 months follow up between March 2012 and Feb 2021 were identified. Patients who received neoadjuvant therapy were excluded. The primary outcome was early post-RP treatment (ADT, RT, ADT+RT) within 12 months of diagnosis, which was categorized as either adjuvant (PSA<0.1 ng/ml) or salvage (PSA≥0.1 ng/ml). Time to any post-RP treatment and type of treatment were secondary outcomes. Multivariable logistic and Cox regression models were fit to identify factors associated with post-RP treatment. Kaplan-Meier analysis was performed to assess treatment-free survival. RESULTS: We identified 425 patients who had pN+disease at the time of RP, of which 280 (66%) underwent early post-RP treatment (86 adjuvant and 194 salvage) and 145 (34%) were observed. One year treatment-free survival for patients with first post-RP PSA≥0.1 was 18% (95% CI 14%-24%) compared to 58% (95% CI 51%-65%) for PSA<0.1 ng/ml (p<0.001). In the multivariable Cox model, pathologic grade group, tumor stage, margin status, first post-RP PSA, and race were associated with time to secondary treatment (p<0.05 for each). Of 145 patients on initial observation, 23% had post-RP PSA≥0.1. ADT was most common early adjuvant therapy (45.4%), followed by ADT+RT (36%), RT alone (17.4%), and other (1.2%) CONCLUSIONS: Most patients with pN+PCa in MUSIC received early post-RP treatment and men with a first post-RP PSA<0.1ng/mL had improved secondary treatment free survival. Early treatment, which was predominantly ADT±RT, is influenced by aggressive disease features and detectable post-RP PSA. Nearly one out of four patients with pN+cancer not receiving early post RP treatment had a detectable PSA, suggesting an opportunity for quality improvement by increasing use of postoperative therapy. Source of Funding: Blue Cross Blue Shield of Michigan © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e855 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Daniel Triner More articles by this author Ji Qi More articles by this author Udit Singhal More articles by this author Michael Sessine More articles by this author Kevin Ginsburg More articles by this author Brian Lane More articles by this author Todd Morgan More articles by this author Expand All Advertisement PDF downloadLoading ...

PD16-07 POST-PROSTATECTOMY ADJUVANT ANDROGEN DEPRIVATION THERAPY-- PATIENT OPINIONS AND GOALS OF CARE

You have accessJournal of UrologyCME1 Apr 2023PD16-07 POST-PROSTATECTOMY ADJUVANT ANDROGEN DEPRIVATION THERAPY-- PATIENT OPINIONS AND GOALS OF CARE Max Levitt, Ameeta Nayak, Dean Fergusson, Luke Lavallee, Christopher Morash, Ilias Cagiannos, and Rodney Breau Max LevittMax Levitt More articles by this author , Ameeta NayakAmeeta Nayak More articles by this author , Dean FergussonDean Fergusson More articles by this author , Luke LavalleeLuke Lavallee More articles by this author , Christopher MorashChristopher Morash More articles by this author , Ilias CagiannosIlias Cagiannos More articles by this author , and Rodney BreauRodney Breau More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003271.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Despite the proven benefit of adjuvant androgen deprivation therapy (ADT) for patients receiving primary radiation, few studies evaluate adjuvant ADT after prostatectomy. We surveyed Canadian prostate cancer patients about adjuvant ADT with the goal of informing an adjuvant ADT clinical trial. METHODS: An electronic survey was devised and distributed using a modified Dillman approach. The survey was sent to members of Prostate Cancer Canada, a patient advocacy group. In addition to demographic information, we asked patients about their experience with prostate cancer, if they received post-operative therapy, and about their opinions to inform the design of an adjuvant ADT clinical trial. The survey was sent on May 2021, and all responses were received by July 2021. RESULTS: Forty patients completed the survey. The average participant age was 71±7.3 years old. The average age at prostate cancer diagnosis was 64±6.7 years. Thirty-eight (95%) patients were previously treated with radical prostatectomy and 24 (60%) subsequently developed biochemical recurrence. If it had been available, 30 (75%) participants indicated that they would have been interested in an adjuvant ADT trial to prevent biochemical recurrence. Most (15; 37.5%) stated that 12 months would be the longest duration of ADT that they would consider. The remainder of participants would have considered up to 6 months (9; 22.5%), up to 18 months (3; 7.5%), up to 24 months (5; 12.5%), or greater than 24 months (8; 20%) of adjuvant ADT. A daily oral tablet (31; 52.5%) or injection every 6 months (9; 22.5%) were favoured in a clinical trial over an injection at shorter time intervals. The most important outcomes for a trial of adjuvant ADT were prevention of cancer related death (38; 95%) and cancer recurrence (37; 92%). If 1 year of adjuvant ADT reduced PSA recurrence by 50%, many (29; 47.5%) stated they would have chosen this intervention. CONCLUSIONS: Few trials have assessed adjuvant ADT after radical prostatectomy and many patients claim they would have been interested in participating in a trial if it had been available. Based on these results, a randomized trial is warranted and patient preferences should be incorporated in trial design. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e491 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Max Levitt More articles by this author Ameeta Nayak More articles by this author Dean Fergusson More articles by this author Luke Lavallee More articles by this author Christopher Morash More articles by this author Ilias Cagiannos More articles by this author Rodney Breau More articles by this author Expand All Advertisement PDF downloadLoading ...

Results of a multicenter, randomized, phase 3 trial of trimodality therapy with I-125 brachytherapy, external beam radiation therapy, and long- versus short-term androgen deprivation therapy for localized high-risk prostate cancer (TRIP/TRIGU0907).

305 Background: The TRIP trial was a multicenter, phase 3 randomized investigation designed to determine whether 30 months of androgen deprivation therapy (ADT) was superior to 6 months of ADT when combined with brachytherapy and external beam radiotherapy (EBRT) for localized high-risk prostate cancer. Methods: The trial was done in 37 hospitals in Japan. Men between 40 to 79 years old with stage T2c-3a, or a prostate-specific antigen (PSA) &gt;20 ng/ml or a Gleason score &gt;7 received 6 months of ADT combined with I-125 brachytherapy at a prescription dose of 110 Gy, followed by EBRT of 45 Gy. Patients were randomly assigned either no further treatment (short arm) or 24 months of adjuvant ADT (long arm) after stratification. The primary endpoint was biochemical progression-free survival using the Phoenix definition of failure. Secondary endpoints included clinical progression, metastasis, salvage treatment, disease-specific survival, overall survival, and grade 3 or higher of adverse events. An intention-to-treat analysis was conducted with survival estimates determined using competing risk analyses. Results: Of 332 patients, 165 were randomized to the short and 167 to the long arm. The median follow-up periods were 9.43 and 9.24 years, respectively. 24 patients have died in each arm. The cumulative incidence for biochemical progression in the short vs. long arm were 10.4% (95% confidence interval [CI] 6.62-16.42) vs 9.5% (5.85-15.46) at 9 years, respectively (p=0.647). The cumulative incidences for clinical progression, distant metastases, salvage treatment, and disease-specific mortality events were not significantly different between the two arms. The overall survival rates of the short arm vs long arm were 87.2% (82.13-92.63%) and 85.9% (80.41-91.77%) at 9 years, respectively (p=0.914). Endocrine-related grade 3 morbidity for short arm vs long arm was 0.6% vs 1.8% (p=0.623), and radiation-related grade 3 morbidity was 1.2% vs 0.6% (p=0.622). Conclusions: In localized high-risk prostate cancer, TRIP did not demonstrate the superiority of 30 months vs. 6 months of ADT when combined with brachytherapy and EBRT. These data suggest that ultra-high radiation doses can be combined with a shorter course of ADT without compromising survival. Clinical trial information: UMIN000003992 .

Duration of androgen deprivation with radiotherapy for high-risk or locally advanced prostate cancer: A network meta-analysis.

To evaluate various outcomes of different lengths of androgen deprivation therapy in high- and very-high-risk prostate cancer, we conducted a network meta-analysis of randomized trials. The treatment of high-risk PC comprises the use of radical radiotherapy associated with various durations of androgen deprivation therapy, with luteinizing hormone releasing hormone analogues initiated during or immediately before the beginning of radiation. This study followed the PRISMA extension statement to report network meta-analyses. We systematically searched online databases, including MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, for all randomized trials published up to April 2022. The primary outcomes were overall survival, prostate cancer-specific mortality, and metastasis-free survival. Network meta-analyses were performed under a Bayesian framework using the "gemtc" package (https://gemtc.drugis.org). The network meta-analysis included 12 studies (10 treatments) on overall survival outcomes. None of the arms showed superiority to radiotherapy alone with respect to overall deaths. Nine studies and 10 treatment arms had prostate cancer-specific mortality data. Overall, 36 months of adjuvant androgen deprivation therapy resulted in a better outcome than radiotherapy alone, three months of neoadjuvant androgen deprivation therapy, or 12 or 24 months of adjuvant androgen reprivation therapy, and it was the better treatment (73%) in terms of cancer mortality. Treatment involving luteinizing hormone releasing hormone analogues for 6 months before and during radiotherapy ranked the highest in reducing distant metastases (42%). We found that 36 months of adjuvant androgen deprivation therapy after radiotherapy was the optimal duration of endocrine treatment with regard to cancer mortality for high-risk and locally advanced prostate cancer.

Does inflammation markers or treatment type moderate exercise intensity effects on changes in muscle strength in cancer survivors participating in a 6-month combined resistance- and endurance exercise program? Results from the Phys-Can trial

BackgroundResistance exercise has a beneficial impact on physical function for patients receiving oncological treatment. However, there is an inter-individual variation in the response to exercise and the tolerability to high-intensity exercise. Identifying potential moderating factors, such as inflammation and treatment type, for changes in muscle strength is important to improve the effectiveness of exercise programs. Therefore, we aimed to investigate if inflammation and type of oncological treatment moderate the effects of exercise intensity (high vs. low-moderate) on muscular strength changes in patients with breast (BRCA) or prostate cancer (PRCA).MethodsParticipants with BRCA (n = 286) and PRCA (n = 65) from the Physical training and Cancer study (Phys-Can) were included in the present study. Participants performed a combined resistance- and endurance exercise program during six months, at either high or low-moderate intensity. Separate regression models were estimated for each cancer type, with and without interaction terms. Moderators included in the models were treatment type (i.e., neo/adjuvant chemotherapy—yes/no for BRCA, adjuvant androgen deprivation therapy (ADT)—yes/no for PRCA)), and inflammation (interleukin 6 (IL6) and tumor necrosis factor-alpha (TNFα)) at follow-up.ResultsFor BRCA, neither IL6 (b = 2.469, 95% CI [− 7.614, 12.552]) nor TNFα (b = 0.036, 95% CI [− 6.345, 6.418]) levels moderated the effect of exercise intensity on muscle strength change. The same was observed for chemotherapy treatment (b = 4.893, 95% CI [− 2.938, 12.724]). Similarly, for PRCA, the effect of exercise intensity on muscle strength change was not moderated by IL6 (b = − 1.423, 95% CI [− 17.894, 15.048]) and TNFα (b = − 1.905, 95% CI [− 8.542, 4.732]) levels, nor by ADT (b = − 0.180, 95% CI [− 11.201, 10.841]).ConclusionsThe effect of exercise intensity on muscle strength is not moderated by TNFα, IL6, neo/adjuvant chemotherapy, or ADT, and therefore cannot explain any intra-variation of training response regarding exercise intensity (e.g., strength gain) for BRCA or PRCA in this setting.Trial registration: ClinicalTrials.gov NCT02473003.