Prostate-specific Antigen Failure Research Articles

Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047)

The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Long-term Outcomes from a Phase 1 Dose Escalation Study Using Stereotactic Body Radiotherapy for Patients with Low- or Intermediate-risk Prostate Cancer

BackgroundUltrahypofractionated stereotactic body radiation therapy (SBRT) has become a standard treatment intervention for localized prostate cancer. ObjectiveTo report final long-term tumor control outcomes and late gastrointestinal (GI) and genitourinary (GU) toxicities from a single-center phase 1 dose escalation study using SBRT for patients with low- or intermediate-risk prostate cancer. Design, setting and participantsBetween 2009 and 2012, 136 patients were enrolled and treated. The initial dose level was 32.5 Gy in five fractions. Doses were then sequentially escalated to 35 Gy, 37.5 Gy, and 40 Gy in five fractions delivered every other day. Outcome measurements and statistical analysisThe primary endpoint was late treatment-related toxicity. Secondary endpoints included prostate-specific antigen (PSA) failure. Results and limitationsThe median follow-up was 10.5 yr for the 32.5-Gy group, 9.9 yr for the 35-Gy group, 8.2 yr for the 37.5-Gy group, and 7.3 yr for the 40-Gy group. The 8-yr cumulative incidence of PSA failure was 26% for 32.5 Gy, 15% for 35 Gy, 3.4% for 37.5 Gy, and 6.6% for 40 Gy. Higher radiation dose (37.5–40 Gy) and favorable intermediate risk (vs unfavorable intermediate risk) were associated with better PSA recurrence rates (p = 0.011 and 0.002, respectively). The 8-yr actuarial probability rates for survival free from late grade ≥2 toxicity were 94% for GI toxicity and 86% for GU toxicity. No grade 4 events were recorded. Higher dose levels were not associated with higher rates of late grade ≥2 GI (p = 0.2) or GU (p > 0.9) toxicity. ConclusionsSBRT doses ranging from 32.5 to 40 Gy were associated with low incidence of moderate or severe toxicities. Higher doses resulted in superior disease control outcomes 8 yr after treatment. Patient summaryWe investigated the association between the radiotherapy dose used and the rate of control of prostate cancer. We found that higher doses resulted in more favorable outcomes without excess toxicity.This trial is registered on ClinicalTrials.gov as NCT00911118.

Risk of Short-Term Prostate-Specific Antigen Recurrence and Failure in Patients With Prostate Cancer

A shorter time interval to prostate-specific antigen (PSA) failure is associated with worse clinical outcomes; however, specific factors defining this state remain unknown. To evaluate the factors of a short time interval to PSA failure in order to identify patients for treatment escalation randomized clinical trials. This secondary analysis of a randomized clinical trial was a secondary analysis of the Dana-Farber Cancer Institute 05-043 trial and included 350 patients with nonmetastatic unfavorable risk prostate cancer (PC). Patients were randomized 1:1 to receive androgen deprivation therapy (ADT) and radiation therapy (RT) plus docetaxel vs ADT and RT. Cumulative incidence rates curves of PSA failure, defined as PSA nadir plus 2 ng/mL or initiation of salvage therapies, and the Fine and Gray competing risks regression was used to assess the prognostic association between these factors and time to PSA failure. The study included 350 males who primarily had a good performance status (330 [94.3%] with Eastern Cooperative Oncology Group score of 0), median (range) age of 66 (43-86) years, with 167 (46.6%) having Gleason scores of 8 to 10, and 195 (55.2%) presenting with a baseline PSA of more than 10 ng/mL. After a median (IQR) follow-up of 10.2 (8.0-11.4) years, having a PSA level of 10 ng/mL to 20 ng/mL (subdistribution hazard ratio [sHR], 1.98; 95% CI, 1.28-3.07; P = .002) and a Gleason score of 8 to 10 (sHR, 2.55; 95% CI, 1.63-3.99; P < .001) were associated with a shorter time to PSA failure, and older age (sHR, 0.82; 95% CI, 0.72-0.93; P = .002) was associated with reduced risk for PSA failure after adjusting for other baseline clinical factors. The high-risk category, defined by these 3 factors, was associated with a shorter time to PSA failure (sHR, 2.69; 95% CI, 1.84-3.93; P < .001). In this secondary analysis of a randomized clinical trial of males with unfavorable risk PC, young age, PSA of 10 ng/mL or more, and a Gleason score of 8 to 10 estimated a shorter time to PSA failure. A subgroup of males at very high-risk for early PSA failure, as defined by our study, may benefit from treatment escalation with androgen receptor signaling inhibitors or cytotoxic chemotherapy and should be the subject of a prospective randomized clinical trial. NCT00116142.

Initial Clinical Outcomes of a Phase II Trial of Focal Salvage LDR Brachytherapy for Local Recurrence of Prostate Cancer after External Beam Radiation Therapy.

To evaluate the clinical outcomes of focal salvage low dose rate brachytherapy (FSB) for biopsy proven local recurrence of prostate cancer after definitive external beam radiation therapy (EBRT). Patients with a Phoenix definition PSA recurrence (nadir + 2.0ng/dL) after definitive EBRT for localized prostate cancer and a negative metastatic work up were enrolled in a Phase II clinical trial. Patients first underwent MR-guided transperineal mapping biopsy of the prostate using a template grid. Patients with a pathologically confirmed recurrence underwent FSB using iodine-125 seeds to a prescription dose of 145 Gy. The brachytherapy planning target volume (PTV) was defined by the positions of the pathologically negative core biopsies adjacent to the positive core biopsies as recorded on the template grid during the biopsy procedure. An intraoperative treatment plan was then developed to cover the PTV with the 145 Gy isodose line. Follow up included assessment of genitourinary (GU) and gastrointestinal (GI) toxicities using Common Terminology Criteria for Adverse Events version 4.03 (CTCAEv4.03), patient reported outcomes using the International Prostate Symptom Score (IPSS) and Expanded Prostate Cancer Index-26 (EPIC-26) forms, and serial PSA blood draws. Ten patients underwent FSB. The median prior EBRT dose was 7805 cGy (interquartile range IQR 7560-7920) and the median time from completion of EBRT to FSB was 81 months (IQR 68-134). The median PSA prior to FSB was 3.2 ng/dL (IQR 2.3 - 4.5). The median follow up after FSB was 32 months (IQR 18-57). Eight patients were free of Phoenix definition PSA failure at last follow up. Of the two patients who experienced a PSA failure, one developed distant metastases 5 months after FSB and the other a biopsy proven seminal vesicle recurrence 3 years after FSB. The median change in post FSB IPSS score compared to the pre-FSB IPSS score was an increase of 1.5 (IQR -1.5 to 8) at 3 month follow up and an increase of 3.5 (IQR 0.5 to 5.5) at last follow up (≥1 year). The median change in post FSB EPIC-26 urinary domain score compared to the pre-FSB score was -1 (IQR -26 to +14.5) at 3 month follow up and +2 (IQR -12.5 to +14.5) at last follow up (≥1 year). The median change in post FSB EPIC-26 bowel domain score compared to the pre-FSB score was -2 (IQR -9.5 to 0.0) at 3 month follow up and 0 (IQR -6.0 to +3.0) at last follow up (≥1 year). No patients experienced post FSB Grade 3 or higher GU or GI toxicities. High dose FSB for a local recurrence of prostate cancer after EBRT can be delivered with good biochemical control and a favorable toxicity profile. Further clinical trial enrollment and longer follow up will be needed to better assess long term outcomes.

Impact of Prophylactic Pelvic Lymph Node Irradiation in De-Novo Oligometastatic Prostate Cancer.

To evaluate the impact of prophylactic pelvic nodal irradiation in de-novo oligometastatic prostate cancer treated with radiotherapy (RT) for both primary tumor and all metastatic lesions. This was a single-center prospective cohort study. De novo oligometastatic prostate cancer patients with RT for both primary tumor and all metastatic lesions were included. Kaplan-Meier method, log rank test and cox regression were used to calculate OS and PFS. PFS included PSA failure, local or distant failure assessed by imaging. This study analyzed 202 patients from 10/2011 to 1/2022 with median follow-up of 48 months. A total of 126 (62.4%) patients were treated with pelvic lymph node RT. The dose was 47.5 Gy with 1.9 Gy per fraction. Among them, 66 (32.7%) patients were treated with whole pelvic RT (WPRT), which the upper limit was at the aortic bifurcation. 60 (29.7%) patients were treated with mini-WPRT, which the upper limit was at the lower margin of obturator foramen. The incidence of diarrhea (P = 0.038) and leukocyte reduction (P = 0.040) in the WPRT subgroup during radiotherapy was significantly higher than that in the mini-WPRT and non-pelvic RT subgroup. For the whole cohort, the median OS and PFS were not reached. The subgroup analysis showed that the elective pelvic nodal irradiation could improve PFS (P = 0.042). However, there was no difference of PFS between standard WPRT and mini-WPRT. The study suggests that for de-novo oligometastatic prostate cancer, elective pelvic nodal irradiation may improve PFS. For patients who cannot tolerate WPRT, mini-WPRT may be an alternative option. However, it needs to be verified in the prospective RCT study.

Androgen Deprivation Therapy Use among Intermediate Risk Prostate Cancer Patients Undergoing Radiation Therapy across a Statewide Radiation Oncology Quality Consortium

For men with intermediate (INT) risk prostate cancer, the addition of androgen deprivation therapy (ADT) reduces risk of PSA failure, distant metastasis, and cancer-related mortality. Moreover, the relative reduction in cancer-related adverse outcomes with ADT use appears consistent across all INT risk subgroups. The absolute benefit of ADT, however, varies by baseline risk. In contemporary practice, it is unknown which clinical factors are most strongly associated with intended ADT use. Therefore, we sought to identify such factors within the diverse practices of the Michigan Radiation Oncology Quality Consortium (MROQC). Patients with localized prostate cancer undergoing definitive radiation therapy were enrolled from 6/9/20 to 11/4/22 (n = 599). Standardized patient, physician, and physicist forms were used to collect baseline and follow-up information. Intended ADT use, defined by the treating physician, was prospectively collected and is the primary outcome of this analysis. Univariable (UVA) and multivariable analyses (MVA) associations with patient (age, race, comorbidities), tumor (T stage, Gleason, percent cores positive, and PSA), and practice-related (academic vs private) factors were performed. In addition, advanced modality testing (PET, MRI, and genomic classifiers) was available as of March 2021, and subgroup analysis were performed where appropriate. A total 351 patients across 26 centers were enrolled with INT risk disease. ADT use was intended for 46% of men (n = 162/351) which differed by men with NCCN favorable INT (21%, n = 22/105) vs unfavorable INT risk disease (57%, n = 140/246), p<0.001. Sixty two percent (n = 100/162) had an intended ADT duration of 4-6 months and 21% (n = 34/162) had ≥12 months. Older age was associated with ADT use (70 vs 67, p < 0.01); there were no significant differences by race or comorbidities number. MVA showed Gleason 4+3 (OR 4.61 [2.91 - 7.42]) and > = 50% positive cores (2.56 [1.52 - 4.37]) were significantly associated with ADT use. No significant differences were noted based on practice setting. Pelvic MRI was obtained for 71% of men (n = 197/279), genomic classifiers in 47% (n = 130/279), and PET in 2% (n = 6/282). In the subset with MRI (n = 197), adverse features (ECE, SVI, or equivocal LNs) were associated with intended ADT use (OR 3.0 [1.4 - 7.1]) after adjustment for NCCN favorable/unfavorable INT risk classification. Within a state-wide consortium, intended ADT use for intermediate prostate cancer is most strongly associated with Gleason score, ≥50% positive cores, NCCN unfavorable intermediate risk classification, and adverse features on MRI. Nearly half of men had genomic classifier testing underscoring the importance ongoing trials such as NRG/GU 010.

Prostate-specific membrane antigen positron emission tomography detected local failure after post-prostatectomy radiation therapy: Low rates of out-of-field recurrence validates current Australian prostate bed contouring guidelines.

The Australian Faculty of Radiation Oncology Genitourinary Group (FROGG) developed prostate bed clinical target volume (CTV) contouring guidelines which were subsequently used to develop the National EviQ guidelines for adjuvant and salvage post-prostatectomy radiotherapy (PPRT). These guidelines were based mainly upon consensus agreement. With the advent of prostate-specific membrane antigen (PSMA) positron emission tomography (PET), sites of recurrence can now be detected with low prostate-specific antigen (PSA) levels following radical prostatectomy. We evaluated sites of recurrence in patients treated with FROGG/EviQ CTVs to inform upcoming modifications of these guidelines. At our institution, we use the FROGG/EviQ guidelines for PPRT. From 2015, patients with PSA failure following PPRT have been re-staged using PSMA PET imaging. We identified patients with PET-avid local, nodal, and distant recurrences, fusing them with original treatment plans to determine whether recurrences were within or outside the prostate bed CTV. Regional nodal failures were reviewed to determine if they were within current elective node contouring guidelines. Ninety-four patients had positive PSMA PET following PPRT. Nine (9.6%) recurrences were local, seven being local-only. One local recurrence (1.1%) was just superior to the contoured prostate bed CTV, located within the vas deferens. Seventy-three (77.7%) patients had a component of node failure, with 56 (59.6%) having node-only failure. Sites of nodal relapses were covered by standard contouring guidelines 60.3% of the time. The low recurrence rate outside of current prostate bed CTV contouring guidelines is consistent with other studies using contemporary contouring, and validates the efficacy of the current FROGG/EviQ prostate bed CTV definition.

Detection of recurrence sites using 18F-fluorocholine PET/CT in prostate cancer patients with PSA failure.

The optimal condition for the clinical application of 18F-fluorocholine positron emission tomography-computed tomography (FCH-PET/CT) to detect recurrence sites in prostate-specific antigen (PSA) failure remains unclear due to the heterogeneity of prostate cancer failure. We aimed to evaluate the detection rate of FCH-PET/CT in prostate cancer patients with PSA failure and to determine the optimal PSA level for performing FCH-PET/CT. FCH-PET/CT was conducted in 89 patients diagnosed with PSA failure after radical treatment (radical prostatectomy in 75 and definitive radiotherapy in 14) between November 2018 and May 2021. Detection rates were examined via receiver operating characteristic (ROC) analysis, and multivariable logistic regression was performed to identify factors affecting positive FCH-PET/CT findings. We also conducted subgroup analyses according to the PSA failure patterns after the radical treatment (persistently high PSA [N=48] and biochemical recurrence [BCR] [N=41]). FCH-PET/CT demonstrated a 59.6% overall detection rate, and the optimal PSA threshold for detecting positive findings was ≥ 1.00ng/mL at the time of imaging. On multivariable analysis, PSA > 1.00ng/mL (P<0.001) was a significant predictor of positive FCH-PET/CT findings, especially regarding distant bone metastases (P<0.001) and recurrence outside the pelvis (P<0.001). In a subgroup analysis of patients with BCR after initial radical treatment, the area under the ROC curve (AUC) was 0.82, and PSA ≥ 1.75ng/mL was the optimal value for identifying positive FCH-PET/CT findings. This PSA value was also associated with significantly higher detection rates of distant bone metastases and outside-pelvis metastasis (P<0.001, both). FCH-PET/CT is a clinically useful tool for detecting tumor recurrence sites in prostate cancer patients with PSA failure if PSA has exceeded a certain value at the time of imaging. Particularly, higher AUC values were observed when FCH-PET/CT was performed in patients with BCR after initial treatment.

Zonal origin of prostate cancer: comparison of long-term outcomes after radical prostatectomy

PurposeTo assess the impact of zonal origin on positive bladder neck (BN) margins and prostate-specific antigen (PSA) failure or early adjuvant therapy in the patients with complete long-term follow-up after radical prostatectomy (RP).MethodsA set of 4512 men were identified who underwent RP in Western Australia (WA) from March 2000 to December 2016 and had complete long-term follow-up. The t-test, Pearson chi-square test and Kaplan–Meier method with the log-rank test were used to evaluate differences between the transition zone (TZ) and peripheral/central zone (PZ/CZ) cancer. Univariate and multivariable Cox proportional hazard regression models were applied to assess parameters on PSA failure and early treatment.ResultsThe positive BN margin rate for TZ cancer fell significantly over the study period. However, BN margin rates increased for PZ/CZ cancer over the time. Data of 4512 patients with median follow-up of 9.1 years confirmed that the high-risk TZ tumours with negative margins had a significant lower rate of PSA failure or early treatment compared to those high-risk PZ/CZ tumours with negative margins.ConclusionProstate cancer zonal origin significantly impacts long-term biochemical outcomes in high-risk and margin-negative patients. BN invasion with margin involvement is more frequent in the TZ cancer and can be reduced by pre-operative identification of cancer zonal origin and adjustment of surgical procedures.

Abstract CT157: Combination of nivolumab with standard of care in the management of grade group 5 prostate cancer: Interim analysis of a phase II trial

Abstract Survival outcomes of grade group 5 (GG5) prostate cancer (PCa) after standard of care therapy (SOC) remain poor. Evidence suggest that high dose rate brachytherapy (HDR) and androgen depravation therapy (ADT) can serve as immune modulators. We hypothesize that the combination of HDR, ADT, and immune checkpoint inhibitors (ICI) may synergize to improve immune response and disease control. Here we report an interim analysis of a single-center single-arm phase II trial exploring this novel combination therapy with nivolumab for GG5 PCa. Patients were enrolled from 9/2018 to 4/2021 and required to have GG5 PCa with &amp;gt; 30% positive cores and receive ICI plus SOC regimen, comprising ADT, external beam RT (EBRT), and HDR. ICI (240 mg) was administered every 2 weeks for 4 doses beginning 4 weeks prior to HDR. HDR consisted of two 1150 cGy implants. EBRT followed HDR and consisted of 4500 cGy in 25 fractions. Total ADT length and elective nodal radiotherapy were per physician discretion. Biopsies were taken at time of diagnosis, HDR, and 1-month post HDR. Biopsy tumor samples underwent genomic profiling. Major pathologic response (MPR) was defined as &amp;lt; 17% positive cores. Wilcoxon test and Area Under the Curve (AUC) Receiver Operating Characteristics (ROC) curves were used for statistical analyses. Toxicity was evaluated according to CTCAE v5.0. The historic control cohort consisted of all patients treated with SOC between 1/2013 to 11/2021 and met all study inclusion/exclusion criteria. Cox regression was used to calculate 2-year (2Y) risk of metastasis with censorship at 24 months (m). Median follow up (mFUP) defined from diagnostic biopsy. Of 34 patients who received 2 or more doses of ICI, 1 patient (3%) experienced a dose limiting toxicity of autoimmune hepatitis (AH). The incidence of all grade 3 toxicity related to ICI at 3 and 6 months were both 3% (n=1; AH and QT prolongation, respectively). There was no grade 4+ toxicity at 3 m, nor any grade 3+ toxicity at 6 m. Two subjects were withdrawn from study, leaving 32 evaluable for clinical outcomes. mFUP of ICI cohort was 32 m with a 2Y PSA failure rate of 6%. CD8A, STING, ANPEP, and multiple immune signatures were associated with an early MPR (p &amp;lt; 0.05) with ICI. The Ricketts_Immunosuppression genomic signature strongly correlated with MPR to ICI (AUC = 0.7, p = 0.01). The control cohort consisted of 59 patients with a mFUP of 35 m and a 2Y PSA failure rate of 19%. ICI demonstrated an 88% reduction in 2Y risk of metastasis compared to controls (HR = 0.12, 95% CI, 0.02 - 1.0, p = 0.05). Combination of ICI with SOC for GG5 PCa is safe and associated with a clinically significant improvement in disease control. Key genomic features were identified to predict for early MPR to ICI. Ricketts_Immunosuppression was identified as a potential biomarker for ICI-sensitive tumor subtypes. Final analyses are anticipated in late 2023. Clinical trial information: NCT03543189. Citation Format: John Michael Bryant, Maria Sandoval, Ryan Putney, Corrado Caslini, Shivanshu Awasthi, Esther Katende, Angelina Fink, Syeda Mahrukh H Naqvi, Youngchul Kim, Jingsong Zhang, Jong Park, Amparo Serna, Julio Pow-Sang, Michael Poch, Roger Li, Brandon Manley, Arash Naghavi, Javier Torres-Roca, G. Daniel Grass, Sungjune Kim, Kujtim Latifi, Dylan Hunt, Peter A. Johnstone, Jasreman Dhillon, Rohit Jain, Daniel Fernandez, Kosj Yamoah. Combination of nivolumab with standard of care in the management of grade group 5 prostate cancer: Interim analysis of a phase II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT157.

Study protocol for a prospective, multi-centered randomized controlled trial comparing pelvic fascia-sparing radical prostatectomy with conventional robotic-assisted prostatectomy: The PARTIAL trial

BackgroundPelvic fascia-sparing robotic-assisted radical prostatectomy (PFS-RARP) is a novel approach that spares the endopelvic fascia ventral to the prostate. The preservation of more native structures compared to conventional robotic-assisted radical prostatectomy (RARP) may lead to faster recovery of urinary function, fewer penile changes, and decreased inguinal hernia sequelae, but may have a higher risk for positive surgical margins and poorer cancer control. However, high-level evidence is absent. The PARTIAL trial is a surgical randomized controlled trial (RCT) aiming to bridge this evidence gap (NCT05155501). MethodsWe describe a prospective RCT with a projected enrollment of 600 men randomized to PFS-RARP vs. RARP. The primary outcome is cancer control (positive surgical margins and prostate-specific antigen failure) and secondary outcomes include health-related quality of life pertaining to urinary and sexual function, decision regret, and adverse events (30-day complications, inguinal hernias, penile shortening, and Peyronie's disease). The anticipated duration of trial participation is 24 months. Study participation is incentivized with the use of innovative methodologies such as a novel, two-stage informed consent and a validated web-based interface to monitor patient-reported symptoms and empower individuals to improve their recovery. ConclusionIf PFS-RARP is non-inferior to RARP in terms of cancer control and has better functional outcomes, it should be the surgical standard of care for men with localized prostate cancer. Using the innovative two-stage consent process, completion of the trial will not only provide much needed evidence on one of the most common cancer surgeries but also insight on improving surgical RCT methodology.Trial statusThis trial is registered at ClinicalTrials.gov (NCT05155501; first posted on December 13, 2021); Institutional approval number: WCM IRB # 21-07023781, BRANY's initial approval event ID # 186333. The trial is not yet recruiting.

Prostate-Specific Antigen Level at the Time of Salvage Therapy After Radical Prostatectomy for Prostate Cancer and the Risk of Death.

Both the performance characteristics of prostate-specific membrane antigen positron emission tomography and insurance approval improves with increasing prostate-specific antigen (PSA) level causing some physicians to delay post-radical prostatectomy salvage radiation therapy (sRT) after PSA failure. Yet, it is unknown for men with at most one high-risk factor (ie, pT3/4 or prostatectomy [p] Gleason score 8-10) whether a PSA level exists above which initiating sRT is associated with increased all-cause mortality (ACM)-risk and was investigated. Using a multinational database of 25,551 patients with pT2-4N0 or NXM0 prostate cancer, multivariable Cox regression analysis evaluated whether an association with a significant increase in ACM-risk existed when sRT was delivered above a prespecified PSA level beginning at 0.10 ng/mL and in 0.05 increments up to 0.50 ng/mL versus at or below that level. The model was adjusted for age at and year of radical prostatectomy, established prostate cancer prognostic factors, institution, and the time-dependent use of androgen deprivation therapy. After a median follow-up of 6.00 years, patients who received sRT at a PSA level >0.25 ng/mL had a significantly higher ACM-risk (AHR, 1.49; 95% CI, 1.11 to 2.00; P = .008) compared with men who received sRT when the PSA was ≤0.25 mg/mL. This elevated ACM-risk remained significant for all PSA cutpoints up to 0.50 ng/mL but was not significant at PSA cutpoint values below 0.25 ng/mL. Among patients with at most one high-risk factor, initiating sRT above a PSA level of 0.25 ng/mL was associated with increased ACM-risk.

The natural history of a delayed detectable PSA after radical prostatectomy

IntroductionMen with a detectable PSA after radical prostatectomy (RP) are often offered salvage therapy while those with an undetectable PSA are monitored. We aim to better characterize the natural history of men with an initially undetectable PSA who subsequently developed a detectable PSA > 6 months after RP.MethodsRetrospective analysis of men who underwent RP for clinically localized prostate cancer at the University of California, San Francisco from 2000 to 2022. The primary outcome was biochemical recurrence, defined as 2 consecutive PSA > = 0.03 ng/mL starting 6 months after surgery. Secondary outcomes were salvage treatment, post-salvage treatment, metastasis free survival (MFS), prostate cancer specific mortality (PCSM), and all-cause mortality (ACM). This cohort was compared to a previously described cohort who had an immediately detectable post-operative PSA.ResultsFrom our cohort of 3348 patients, we identified 2868 men who had an undetectable post-op PSA. Subsequently, 642 men had a delayed detectable PSA at a median of 25 months (IQR 15, 43) with median follow-up of 72 months after RP. PSA at time of failure was <0.10 ng/mL for 65.7% of men. Of those with a delayed detectable PSA, 46% underwent salvage treatment within 10 years after RP at a median PSA of 0.08 ng/mL (IQR 0.05, 0.14). High CAPRA-S score (HR 1.09, CI 1.02–1.17, p = 0.02) and PSA doubling time (PSA-DT) of <6 months (HR 7.58, CI 5.42–10.6, p < 0.01) were associated with receiving salvage treatment. After salvage treatment, 62% of men had recurrent PSA failure within 10 years. Overall, MFS was 92%, PCSM 3%, and ACM 6% at 10 years. For those who received tertiary treatment for recurrent PSA failure, MFS was 54%, PCSM 23% and ACM 23% at 10 years’ time.ConclusionsMen who develop a detectable PSA > 6 months post-operatively may have excellent long-term outcomes, even in the absence of salvage therapy.

Radiotherapy of the Primary Tumor and All Metastatic Lesions in Oligometastatic Prostate Cancer

<h3>Purpose/Objective(s)</h3> The aim of this study was to evaluate the survival in oligometastatic prostate cancer patients treated with radiotherapy (RT) for both primary tumor and all metastatic lesions. <h3>Materials/Methods</h3> This was a single-center cohort study. Oligometastatic prostate cancer patients with RT for both primary tumor and all metastatic lesions were included. Kaplan–Meier method, log rank test and cox regression were used to calculate OS and PFS. PFS included PSA failure, local or distant failure assessed by imaging. <h3>Results</h3> This study analyzed 395 patients from 10/2011 to 1/2022 with median follow-up of 42 months. 264 patients (66.8%) were hormone sensitive (HSPC) and 131patients (33.2%) were castrate resistant (CRPC) at the time of RT. 212 patients (53.7%) were synchronous oligometastatic status, 58 patients (14.7%) were metachronous oligometastatic status, and 105 patients (26.6%) were oligoprogressive status. PSMA-PETCT was used for 238 men (60.3%). Before radiotherapy, 12 patients (3.0%) did not receive androgen deprivation therapy (ADT), 252 patients (63.8%) were treated with luteinizing hormone releasing hormone analogue (LHRHa) with or without bikaluamide. 131 patients (33.2%) were treated with LHRHa combined with novel ADT (abiraterone, enzalutamide, apalutamide, etc.), including 3 patients treated with enzalutamide, 2 patients treated with apalutamine, and the rest treated with abiraterone. The most common fractionation scheme of the primary tumor was 2.8Gy for 25 fractions (81.5%). The median BED₃ was 135.3Gy (IQR:128.3-135.3Gy). A total of 247 (62.5%) patients were treated with whole pelvic RT (WPRT). A total of 718 metastatic lesions were treated with RT. The median BED₃ was 121.3Gy (IQR:113.3-131.3Gy). For the whole cohort, the PFS and OS were 62.5% and 92.7% at 3 year, 53.1% and 81.7% at 5 years. Median PFS for men with HSPC was not reached compared with 10 months in men with CRPC. On univariable analysis, HSPC, shorter interval between diagnosis and RT, lower pre-RT PSA, lower Gleason score, lower metastatic burden/volume, use of WPRT, ADT type, chemotherapy were associated with improved PFS. <h3>Conclusion</h3> Our study suggests that RT for the primary tumor and all metastatic lesions has better survival than clinical studies of prostate radiotherapy alone, especially for patients with HSPC, shorter interval between diagnosis and RT and lower metastatic burden/volume.

Phase III Trial of Dose Escalated Radiation Therapy and Standard Androgen Deprivation Therapy (ADT) vs. Dose Escalated Radiation Therapy and Enhanced ADT with TAK-700 for Men with High-Risk Prostate Cancer (NRG Oncology/RTOG 1115)

<h3>Purpose/Objective(s)</h3> RTOG 1115 was a randomized phase III trial evaluating the addition of orteronel (TAK-700), a novel CYP17A1 inhibitor, to dose escalated radiation plus ADT in men with high risk, localized prostate cancer. Originally designed to evaluate overall survival, the trial was halted early due to discontinuation of orteronel development in prostate cancer. We report here the initial primary endpoint analysis. <h3>Materials/Methods</h3> The study was designed to enroll 900 men with high-risk prostate cancer (Gleason 9-10, PSA > 20, or clinical stage T2 or higher with Gleason ≥ 8). Ultimately, 238 patients were enrolled (May 2012-Sept 2014), and randomized 1:1 to receive standard therapy (Arm A), or standard therapy plus two years of twice daily orteronel (Arm B). Radiation therapy entailed dose-escalated external beam radiation (EBRT) to the prostate and pelvis to 45 Gy in 25 fractions, followed by a boost to 79.2 Gy using EBRT or either HDR or LDR. The analysis plan was reframed around detecting a reduction in rate of a composite biochemical failure endpoint (Phoenix biochemical failure, local/regional or distant disease, or salvage ADT). With 238 patients enrolled and followed, the study would have 70% power to detect a 40% decrease in the composite failure primary endpoint after 70 events had occurred. <h3>Results</h3> 231 patients were evaluable for efficacy and toxicity, 115 in Arm A and 116 in Arm B, and median follow up was 6.2 years. Grade 3 adverse events were observed in 35% and 60% of men in Arm A and B, respectively, with most common being urinary or gastrointestinal disturbance. Time to grade 3 adverse event was significantly faster in Arm B (log rank P value < 0.001). There were four deaths due to adverse events, three of which were in Arm A, and all were deemed unlikely related to treatment. Notably, only 29% of men in Arm B received 80% or more of the planned dose of orteronel due to a variety of factors that impacted drug tolerability. With respect to the primary outcome, patients did well overall with 6-year failure rates of 22.5% and 16.1%, respectively, in Arms A and B (hazard ratio [HR] 0.83, 95% CI 0.47-1.48). By Phoenix definition, PSA failure was only 18.4% and 12.1% in Arms A and B through 6 years. Distant failure occurred in 10.0% and 4.0% of patients (HR 0.71, 95% CI 0.29-1.75). Quality of life outcomes will be reported separately. While all efficacy trends favored the experimental arm, due to the small number of patients and events none of the differences between arms achieved statistical significance. <h3>Conclusion</h3> The addition of orteronel to dose escalated RT and ADT did not result in statistically significant improvement in efficacy outcomes, although results were limited by early termination of accrual and impaired drug tolerability. Intensification of hormonal therapy with better tolerated novel agents remains an appealing strategy for the treatment of high-risk localized prostate cancer.

Long-term Outcomes of Radiation Therapy for Prostate Cancer in Elderly Patients Aged ≥75 Years.

This study aimed to evaluate the treatment outcomes of radiation therapy (RT) for localized prostate cancer in elderly patients aged ≥75 years. We retrospectively investigated data of patients aged ≥75 years with prostate cancer who underwent intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) with doses of 70-78 Gy in 35-39 fractions between September 2008 and June 2016. Overall survival (OS), recurrence-free (RF) rates, and occurrence rates of toxicities were calculated. Eighty-eight patients were enrolled in the study. Nineteen patients died, and nine patients reported PSA failure within the follow-up period. The median follow-up time was 83.5 months. The median age was 77 years. In the cohort, 6 were low-risk, 36 were intermediaterisk, and 46 were high-risk patients. The 5-/7-year OS and RF rates were 87.9%/80.2% and 93.5%/89.1%, respectively. By risk, the 5-/7-year RF rates were 100%/80% in the low-, 100%/100% in the intermediate-, and 87.6%/82.7% in the high-risk groups, respectively. The cumulative incidence rates of Grade ≥3 genitourinary and gastrointestinal toxicities were 1.3% and 3.5% at 5 years and 3.3% and 3.5% at 7 years, respectively. IMRT and VMAT are effective treatment options for elderly patients with prostate cancer and in a good general condition.

Tumor Suppressor Role and Clinical Significance of the FEV Gene in Prostate Cancer.

Background In our previous research, we developed a 32-gene risk index model that may be utilized as a robust prognostic method for predicting prostate cancer (PCa) recurrence after surgery. Among the 32 genes, the Fifth Ewing Variant (FEV) gene was one of the top downregulated genes in relapsed PCa. However, current understanding of the FEV gene and its involvement in PCa is limited. Methods FEV mRNA expression was analyzed and correlated to clinical outcomes in PCa patients who underwent prostatectomy at the Massachusetts General Hospital. Specimens from tissue microarray (TMA) including 102 prostate cancer patients were analysis for the expression of FEV. Meanwhile, FEV expression profiles were also assessed in PCa cell lines and in BPH-1 prostate epithelial cells using western blotting and quantitative reverse transcription-PCR (qRT-PCR). Furthermore, we transfected LNCaP and PC-3 cells with either an empty vector or full-length FEV gene and performed in vitro cell functional assays. The part FEV plays in tumor xenograft growth was also assessed in vivo. Results Of the 191 patients included in this study base on the DASL dataset, 77 (40.3%) and 24 (13.6%), respectively, developed prostate-specific antigen (PSA) relapse and metastasis postradical prostatectomy. Significant FEV downregulation was observed in PCa patients showing PSA failure and metastasis. The protein expression of FEV was significantly negatively correlated with the Gleason score and pathological stage in prostate cancer tissues. Similarly, FEV expression significantly decreased in all PCa cell lines relative to BPH-1 (all P < 0.05). Functional assays revealed that FEV expression markedly inhibited PCa cell growth, migration, and invasion, which in turn significantly repressed the growth of tumor xenografts in vivo. Conclusion The results of this study suggest an association between downregulated FEV expression and PSA relapse in PCa patients. In addition, FEV may act as a tumor suppressor in PCa.

A Case of late-onset hypogonadism syndrome with rapidly elevated prostate specific antigen

ABSTRACT Introduction Cases of developing prostate cancer during hormone therapy for late-onset hypogonadism syndrome are rare. Objective We report a case of prostate cancer that developed and died during hormone therapy for late-onset hypogonadism syndrome. Case A 63-year-old man was diagnosed with depression around 2010. In 2011, he visited a private urologic clinic with complaints of depression and decreased libido, and was started on androgen replacement therapy (ART) with a diagnosis of late-onset hypogonadism (LOH) syndrome. His PSA was 0.87 ng/mL in 2012, but was 3.335 ng/mL at the time of his 2017 municipal checkup. He continued to receive hormone injections every 1-2 months, but his PSA was not retested. In August 2018, he had difficulty in urination and visited his local physician, who referred him to our hospital because of a markedly elevated PSA of 213.3 ng/mL. Prostate biopsy showed adenocarcinoma, Gleason score 5+4, and CT scan showed supraclavicular, mediastinal, and retroperitoneal lymph node metastases. He underwent maximal androgen blockade therapy with castration and bicalutamide. He died after PSA failure despite chemotherapy and other treatments. Conclusions There is no evidence that ART, which is the main treatment for LOH syndrome, directly causes prostate cancer. In this case, a rapid increase in PSA was observed during ART treatment, which may indicate that the treatment caused latent prostate cancer to become apparent, resulting in a rapid increase in PSA. However, in this case, the detection of prostate cancer might have been delayed because PSA levels, which were required during ART treatment, were not measured regularly. In addition, the psychiatric symptoms of LOH syndrome are similar to those of depression, and it is difficult to differentiate them. When there is a history of depression, as in this case, a more careful diagnosis and treatment strategy are required. Disclosure Work supported by industry: no.

PO-1375 Detection of recurrence sites using FCH PET/CT in prostate cancer patients with PSA failure

PO-1375 Detection of recurrence sites using FCH PET/CT in prostate cancer patients with PSA failure

PD03-09 THE NATURAL HISTORY OF A DETECTABLE SERUM PSA AFTER RADICAL PROSTATECTOMY

You have accessJournal of UrologyCME1 May 2022PD03-09 THE NATURAL HISTORY OF A DETECTABLE SERUM PSA AFTER RADICAL PROSTATECTOMY Julie A. Szymaniak, Samuel L. Washington, Janet E. Cowan, Matthew R. Cooperberg, Peter E. Lonergan, Hao G. Nguyen, and Peter R. Carroll Julie A. SzymaniakJulie A. Szymaniak More articles by this author , Samuel L. WashingtonSamuel L. Washington More articles by this author , Janet E. CowanJanet E. Cowan More articles by this author , Matthew R. CooperbergMatthew R. Cooperberg More articles by this author , Peter E. LonerganPeter E. Lonergan More articles by this author , Hao G. NguyenHao G. Nguyen More articles by this author , and Peter R. CarrollPeter R. Carroll More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002518.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Radical prostatectomy (RP) is a common form of definitive treatment for men with localized prostate cancer. A detectable postoperative serum PSA is thought to represent treatment failure and such patients are often offered salvage therapy while those with an undetectable PSA are monitored closely. We aim to better characterize the natural history of patients with a delayed detectable PSA after RP using a “ultrasensitive” cut point (0.03 ng/ml), a more contemporary value. METHODS: A retrospective analysis of men who underwent RP for non-metastatic prostate cancer at the University of California, San Francisco from 2000 to 2021, who consented for research, and had extensive follow-up was performed. Each participant in the delayed group reached an undetectable post-operative PSA within 6 months. The primary outcome was biochemical recurrence, defined as 2 consecutive PSA>=0.03 starting 6 months after surgery. Secondary outcomes were salvage treatment, post-salvage treatment, metastasis (nodal or bone) free survival (MFS), prostate cancer specific mortality (PCSM), and all-cause mortality (ACM). RESULTS: From our cohort of 3132 patients, we identified 2684 men who had an undetectable post-op PSA. The median follow-up after RP was 55 months. Subsequently, 646 men had a delayed detectable PSA at a median time of 29 months (IQR 16, 54). PSA at time of failure was <0.1 for 63.9% of men, 0.1-0.2 for 19.8%, and >0.2 for 16.1%. Of those with a delayed detectable PSA, 42% underwent salvage treatment within 10 years after RP. PSA at diagnosis (HR 1.02, CI 1.01-1.03, p=0.003), high Decipher score (HR 1.56, CI 1.02-2.38, p=0.04), and surgical CAPRA-S (HR 1.13, CI 1.06-1.2, p=0.0003) were associated with risk of receiving salvage treatment. In terms of treatment type, 95% received radiation +/- ADT, 4.4% received ADT alone, and 0.4% had advanced treatment. After salvage treatment, 63% of men had recurrent PSA failure within 10 years. In this subcohort, 20% had radiation, 76% received hormonal therapy, and 3.3% had advanced treatment. Overall, MFS was 95%, PCSM 2%, and ACM 5% at 10 years. For those with recurrent PSA failure after salvage treatment, MFS was 70%, PCSM 22% and ACM 22% at 10 years' time. CONCLUSIONS: Men who develop a detectable serum PSA >6 months post-operatively may have excellent long-term outcomes. Such information can be used to assess the timing and type of additional treatment. Source of Funding: Goldberg-Benioff Program in Translational Cancer Biology in the UCSF Department of Urology © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e45 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Julie A. Szymaniak More articles by this author Samuel L. Washington More articles by this author Janet E. Cowan More articles by this author Matthew R. Cooperberg More articles by this author Peter E. Lonergan More articles by this author Hao G. Nguyen More articles by this author Peter R. Carroll More articles by this author Expand All Advertisement PDF DownloadLoading ...