High-risk Prostate Adenocarcinoma Research Articles

PRIORITI: Phase 4 study of triptorelin or active surveillance in high-risk prostate cancer.

To evaluate the efficacy and safety of triptorelin after radical prostatectomy (RP) in patients with negative lymph nodes. PRIORITI (NCT01753297) was a prospective, open-label, randomized, controlled, phase 4 study conducted in China and Russia. Patients with high-risk (Gleason score ≥ 8 and/or pre-RP prostate-specific antigen [PSA] ≥ 20ng/mL and/or primary tumor stage 3a) prostate adenocarcinoma without evidence of lymph node or distant metastases were randomized to receive triptorelin 11.25mg at baseline (≤ 8weeks after RP) and at 3 and 6 months, or active surveillance. The primary endpoint was biochemical relapse-free survival (BRFS), defined as the time from randomization to biochemical relapse (BR; increased PSA>0.2ng/mL). Patients were monitored every 3 months for at least 36 months; the study ended when 61 BRs were observed. The intention-to-treat population comprised 226 patients (mean [standard deviation] age, 65.3 [6.4] years), of whom 109 and 117 were randomized to triptorelin or surveillance, respectively. The median BRFS was not reached. The 25th percentile time to BRFS (95% confidence interval) was 39.1 (29.9-not estimated) months with triptorelin and 30.0 (18.6-42.1) months with surveillance (p=0.16). There was evidence of a lower risk of BR with triptorelin versus surveillance but this was not statistically significant at the 5% level (p=0.10). Chemical castration was maintained at month 9 in 93.9% of patients who had received triptorelin. Overall, triptorelin was well tolerated and had an acceptable safety profile. BRFS was observed to be longer with triptorelin than surveillance, but the difference was not statistically significant.

Mainstream Model of Genetic Testing for Prostate Cancer at a Large Tertiary Cancer Centre

BackgroundAn estimated 20% to 30% of men with advanced prostate cancer carry a mutation in DNA damage repair genes, of which half are estimated to be germline. Eligibility criteria for germline genetic testing expanded significantly for Ontario patients in May 2021 and many centers adopted a “mainstream” model, defined as oncologist-initiated genetic testing. MethodsWe conducted a retrospective chart review to report on the first-year mainstream experience of a large tertiary oncologic center, the Sunnybrook Odette Cancer Centre. All patients who underwent mainstream at the discretion of their treating physician were included. A subset underwent somatic profiling as part of clinical trial screening. Descriptive statistics were used to report baseline clinicopathologic characteristics and treatments received. ResultsBetween May 1, 2021, and May 30, 2022, 174 patients with prostate cancer underwent mainstream germline genetic testing with a 19-gene panel. Median age was 75 (IQR 68-80), and 82% of patients were diagnosed with either de novo metastatic or high-risk localized prostate adenocarcinoma. Fourteen patients (8%; 95% CI 4%-12%) were found to have a deleterious germline mutation, including pathogenic or likely pathogenic variants in BRCA1/2, ATM, CHEK2, PMS2, RAD51C, HOXB13, and BRIP1. Forty-nine patients (28%; 95% CI 21%-35%) were found to have a variant of uncertain significance. Thirty-four patients also had next-generation sequencing (NGS) of their somatic tissue. Among this subset, 8 of 34 (23%) had an alteration in homologous recombination repair (HRR) genes. Of the 14 patients with a germline mutation, none had a prior personal history of malignancy and 6 (43%) did not have any first- or second-degree relatives with history of prostate, pancreatic, breast, or ovarian cancer. ConclusionWe report on the real-world characteristics of prostate cancer patients who underwent mainstream germline genetic testing. Personal history and family history of cancer cannot reliably stratify patients for the presence of pathogenic germline variants.

Long-term results of dose escalation (80 vs 70 Gy) combined with long-term androgen deprivation in high-risk prostate cancers: GETUG-AFU 18 randomized trial.

LBA259 Background: Radiotherapy (RT) delivered in combination with androgen deprivation therapy (ADT) improve survival for patients with prostate adenocarcinoma. RT given at a dose of 80 Gy is generally well tolerated but the occurrence of grade 3-4 toxicities is significantly more frequent than at a dose of 70 Gy. Furthermore, ADT has been reported to increase RT-related toxicity. Thus, we aimed to evaluate the efficacy and safety of dose escalation in combination with long term ADT in high-risk prostate cancer patients. Methods: The GETUG-AFU 18 study, sponsored by Unicancer, is a phase III randomized trial. Eligible patient had high-risk (cT3-T4 or PSA≥ 20 ng/ml or Gleason score ≥ 8-10) prostate adenocarcinoma with negative lymph-nodes status on CT-scan or MRI. Patients were randomly assigned to dose-escalated RT (80 Gy) or conventional-dose (70 Gy) with 3 years of ADT in both arms. Randomization (1:1) was stratified on pelvic lymph-nodes dissection (PLND; yes or no) and institution. Pelvic nodal irradiation (46 Gy) was performed for all patients except in case of negative PLND. The primary endpoint is the biochemical or clinical progression-free survival (bcPFS) at 5 years following ASTRO-Phoenix definition. Secondary endpoints are overall survival (OS), acute and late toxicity (CTCAE v3), and quality of life. To improve bcPFS from 65 to 75% (Hazard Ratios [HR] = 0.67), 500 patients were required (a= 5% and 1-b= 80%) with 197 events at 5 years. Results: 505 patients were included between June 2009 and January 2013. Main characteristics of the population were median age of 70.6 years (range 52-80); 268 (53.1%) patients with a Gleason score ≥ 8; median PSA value of 13.8 ng/ml (0.4-109.9); 62.3% of patient with cT3, and 16.4% with PLND. There was no imbalance between groups for major prognostic factors. The bcPFS was significantly improved in the dose-escalated RT arm compared with conventional RT arm (HR = 0.56, [95% CI, 0.40-0.76], p = 0.0005). The 5-year bcPFS was 91.4% (95% CI, 87.0-94.4) and 88.1% (95% CI, 83.2-91.6), and the 7-year bcPFS 88.1% (95% CI, 83.1-91.7) and 79.2% (95% CI, 73.1-84.0) in dose-escalated RT and conventional RT, respectively. We did observe significant differences in prostate cancer-specific survival (HR = 0.48 [95% CI, 0.27-0.83], p = 0.0090) and overall survival (HR = 0.61 [95% CI, 0.44-0.85], p = 0.0039). No prognostic factors were identified for bcPFS. Regarding late toxicities, there was no significant difference between arms with 78.2% and 76.1% of ≥Grade 2 toxicity with dose-escalated RT and conventional RT, respectively. Conclusions: Dose-escalation RT in combination with long-term ADT is effective and safe, increasing not only the bcPFS rate but also specific survival and overall survival in high-risk prostate cancer patients without increasing long-term toxicity. Clinical trial information: NCT00967863 .

Microboost dose escalation for localized prostate cancer within a statewide radiation oncology quality consortium.

298 Background: The phase III FLAME trial demonstrated that in localized prostate cancer, an external beam radiotherapy (EBRT) simultaneous integrated microboost to an MRI-defined dominant intraprostatic lesion improves biochemical control without affecting toxicity and quality of life. Given the complexity required to deliver high microboost doses, we hypothesized that practice patterns are variable in clinical practice. We aimed to characterize microboost utilization and evaluate dosimetric parameters within the statewide Michigan Radiation Oncology Quality Consortium (MROQC). Methods: Men with intermediate or high-risk prostate adenocarcinoma treated with curative intent radiotherapy for intact disease were included. Data was prospectively collected, including T/N-category, Gleason score, prostate-specific antigen, and percent positive biopsy cores. Full DICOM files were available for dosimetric data. Multivariable analyses (MVA) were used to evaluate associations between receipt of microboost, known prognostic factors, and fiducial marker and rectal spacer placement (advanced image guided radiation therapy (IGRT)). Results: From 10/26/20 to 06/26/23, 741 patients across 26 centers were enrolled, 71% (n=528) with intermediate-risk and 29% (n=213) with high-risk disease. Androgen deprivation therapy was planned in 61%. EBRT + whole-gland brachytherapy boost was utilized in 29% (n=217/741) of patients. Of those treated with EBRT (71%, n=524/741), 10% received a microboost (n = 53/524). Brachytherapy boost and microboost were used in 9 and 7 centers, respectively. Most patients received either conventional fractionation or moderate hypofractionation- 11% and 66% in EBRT without microboost and 21% and 60% with microboost, respectively. Microboost treatment was associated with use of a planning MRI (91% vs. 62%, p <0.0001) as well as fiducial marker and rectal spacer placement (76% vs. 45%, p <0.0001). Median prostate planning target volume (PTV) was smaller in microboost patients (127 cc vs. 91 cc, p = 0.002); median boost volume was 21 cc. Median boost dose (D0.1cc) was 117% (IQR 115% – 119%) of the PTV prescription. Microboost patients had significantly higher mean bladder D1cc[%] (105.7% vs. 103.4%, p = 0.002) and numerically lower rectal D1cc[%] (90.7% vs. 94.1%, p = 0.065). On MVA, receipt of microboost was significantly associated with grade group 4 or 5 disease, planning MRI use, and fiducial and rectal spacer use. Conclusions: Within a large, diverse prospective cohort of men with prostate cancer treated in both academic and community settings, a microboost was utilized in 10% of EBRT cases. Microboost use was associated with higher grade group, MRI planning, and advanced IGRT. EBRT microboost is an emerging dose escalation strategy and further studies confirming safety and improved clinically meaningful outcomes may increase uptake in routine practice.

Prostate-Specific Antigen Response to Androgen Deprivation Therapy in the Neoadjuvant Setting for High-Risk Prostate Adenocarcinoma (PIRANHA): Pooled Analysis of Two Randomized Clinical Trials

A suboptimal prostate-specific antigen (PSA) response to neoadjuvant androgen deprivation therapy (ADT) among men who go on to receive definitive radiation therapy for prostate cancer might suggest the existence of castration-resistant disease or altered androgen receptor signaling. This in turn may portend worse long-term clinical outcomes, especially in men with high-risk disease. We set out to evaluate the prognostic impact of poor PSA response to neoadjuvant ADT in men with high-risk prostate cancer. This was a post hoc analysis of the multicenter TROG 03.04 RADAR and PCS IV randomized clinical trials. Inclusion criteria for this analysis were patients with high-risk prostate cancer (defined as Gleason score ≥8, initial PSA ≥20 ng/mL, or cT3a disease or higher) who received definitive radiation therapy, at least 18 months of ADT, and had a preradiation therapy PSA level drawn after at least 3 months of neoadjuvant ADT. Poor PSA response was defined as PSA >0.5 ng/mL. Cox regression and Fine-Gray models were used to test whether poor PSA response was associated with metastasis-free survival, biochemical recurrence, prostate-cancer specific mortality, and overall survival. Nine hundred thirty men met inclusion criteria for this analysis. Median follow-up was 130 months (interquartile range [IQR], 89-154 months). After a median of 3 months (IQR, 3-4.2 months) of neoadjuvant ADT, the median PSA was 0.60 ng/mL (IQR, 0.29-1.59). Overall, 535 men (57%) had a PSA >0.5 ng/mL. Poor PSA response was associated with significantly worse metastasis-free survival (hazard ratio [HR], 3.93; P = .02), worse biochemical recurrence (subdistribution HR, 2.39; P = .003), worse prostate-cancer specific mortality (subdistribution HR, 1.50; P = .005), and worse overall survival (HR, 4.51; P = .05). Patients with PSA >0.5 mg/mL after at least 3 months of neoadjuvant ADT had worse long-term clinical outcomes and should be considered for treatment intensification.

Prospective study of HDR brachytherapy (BT), external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT): 10-years experience of an MRI-guided approach

ObjectivesTo evaluate the predictive factors for biochemical failure and distant metastases in a prospective cohort of patients with localized prostate cancer treated with the combination of HDR BT and EBRT. Methods and materialsPatients with intermediate (IR) or high-risk (HR) prostate adenocarcinoma received a single fraction of HDR of 15 Gy combined with RT of 37.5 Gy in 15 fractions. ADT duration was used depending on risk-group. Descriptive analyses were performed. Univariate and multivariate Hazard Ratios were obtained. Finally, the Kaplan-Meier model was used to describe the survival of the events of interest. Results309 patients were treated prospectively (199 were IR and 110 HR). Median age was 72 years; 58.3 % were MRI stage ≤ T2c, 34.1 % T3a and 7.6 % T3b; ISUP-grade 1–3 in 78.9 % and ISUP 4–5 in 21.1 %. 71.8 % of patients had ≤ 50 % positive-cores in biopsy and 28.2 % had > 50 %. Median pre-treatment PSA was 9.9 ng/mL. After a median follow-up of 88 months, 41 patients presented biochemical failure and 18 developed distant metastases. Multivariate cox-regression analyses found that MR-T3b Stage (HR 3.88, p = 0.001) and ADT use (HR 3.99, p = 0.03) were the only predictive factors for biochemical failure and the number of positive cores (>50 %) the only independent predictive factor of distant metastases (HR 4.36, p = 0.002). ConclusionsPatients with mpMRI evidence of invasion of the SV and involvement of more than 50% of the cores in the prostate biopsy are patients with a higher risk of presenting a biochemical recurrence or developing metastasis due to their prostate cancer, respectively.

A False-Positive Bone Oligometastatic Prostate Cancer in 18F-Choline PET/CT: Be Aware of Chronic Vascular Pitfalls.

We report the case of a 71-year-old man undergoing initial assessment for a high-risk group prostate adenocarcinoma. His medical history includes gastric carcinoma treated with surgery and chemotherapy. 18F-choline PET/CT was performed for initial staging and displayed several intense foci uptake of sternum and thoracic vertebrae, suggestive of bone metastasis. Because of a chronic right jugulosubclavian confluent thrombosis related to his implantable chamber, a control was performed 3 weeks later. It showed spontaneous disappearance of those uptakes, consistent with pitfalls related to the collateral circulation induced by the chronic right subclavian vein thrombosis, despite the chronic anticoagulation.

Prostatic bed calcification with [99mTc]Tc-MDP uptake: Easy to miss on planar images.

A 65 years old man with high-risk prostate adenocarcinoma underwent bone scintigraphy with 99mTc-methylene diphosphate ([99mTc]Tc-MDP). The scan revealed a focus of radiotracer uptake in the left pubic region, which was suspicious for metastatic involvement. Additional imaging with single photon emission computed tomography (SPECT/CT) confined the uptake to be extra-osseous and contributed to the calcified zone in the prostate bed. Prostatic bed calcification with [99mTc]Tc-MDP uptake mimics metastasis and can be easily missed on planar images.

PSOR5 Presentation Time: 11:50 AM: Interstitial Hyperthermia and High Dose-Rate Brachytherapy Combined with Short-Term Androgen Deprivation Therapy and External-Beam Radiation in High- and Very High-Risk Prostate Cancer

<h3>Purpose</h3> Multimodality treatment of high- and very-high risk prostate cancer has evolved tremendously in recent years to incorporate long-term androgen deprivation therapy (ADT), external-beam radiation therapy (EBRT), and brachytherapy, resulting in improved biochemical progression-free survival (bPFS). However, outcomes remain imperfect, and many patients are unwilling or unable to tolerate long-term ADT use. Existing studies show that hyperthermia is a potent and well-tolerated radiosensitizer. We report the outcomes of patients treated with short-term ADT, EBRT, and high dose-rate (HDR) brachytherapy combined with interstitial hyperthermia. <h3>Materials and Methods</h3> In a single-institution, retrospective study, we reviewed all patients with high- or very high-risk prostate adenocarcinoma who began definitive treatment between December 2016 and March 2020 with up to six months of ADT, whole-pelvis EBRT, and a combination of HDR brachytherapy boost and interstitial hyperthermia. Our primary endpoint was bPFS based on the Phoenix definition (PSA nadir +2 ng/mL) calculated from time of ADT initiation. We also report data on type of failure, survival, and toxicity. <h3>Results</h3> 56 patients were reviewed, including 21 with high-risk and 35 with very high-risk prostate adenocarcinoma. Median age was 72 years (range 52-82 years). Median duration of ADT use was 4 months (range 0-6 months). All patients received whole-pelvis EBRT of 45Gy/25fx. 55 patients (98%) received a 5.4Gy/3fx EBRT boost to the prostate and seminal vesicles. All patients received two Iridium-192 HDR implants to further boost the prostate and seminal vesicles, with each implant separated by at least one week (median 2 weeks, range 1-6 weeks) and consisting of two fractions of 5.5Gy separated by five to seven hours, for a total of 22Gy/4fx. All patients received at least one interstitial hyperthermia treatment of at least 45 minutes in between fractions of the same implant. 50 patients (89%) received both planned hyperthermia treatments of at least 60 minutes each at a goal temperature of 42-43 degrees Celsius. Median duration of follow-up was 28 months for all patients, with 34 months for high-risk and 28 months for very-high risk disease. The estimated two/three-year bPFS-rates were 100%/100% for high-risk and 92.0%/87.7% for very high-risk disease. Figure 1 represents the Kaplan-Meier curve for bPFS. Of the three very high-risk patients who failed biochemically, one failed regionally at 25 months, and two failed distantly at 15 and 23 months. There were no local failures. Two patients with very-high risk disease have died, both of unrelated lung disease at nine and 13 months. Four patients stopped their hyperthermia treatment early due to intolerance, with one developing an acute perineal burn that fully healed three months later. There were otherwise no grade 3 or higher acute toxicities. Four patients (7%) developed late grade 3 toxicities, all genitourinary-related. <h3>Conclusions</h3> Multimodality treatment of prostate cancer with short-term ADT, EBRT, HDR brachytherapy, and interstitial hyperthermia is safe and well-tolerated. For patients with high-risk disease, it provides excellent biochemical control while sparing long-term use of ADT. Patients with very high-risk disease may benefit from long-term use of ADT and/or other forms of systemic therapy. Longer follow-up and prospective trials are needed to validate our findings.

3-Dimensional Volumetric Distribution and Dispersion Analysis of the Radioenhancer NBTXR3 in Various Solid Malignancies

<h3>Purpose/Objective(s)</h3> NBTXR3, a first-in-class radioenhancer, composed of functionalized hafnium oxide nanoparticles, is administered by one-time intratumoral (IT) injection and activated by radiotherapy (RT). NBTXR3 is designed to locally amplify the tumor-killing effect of RT without additional toxicity to surrounding healthy tissue. In addition, NBTXR3 has been shown to prime the adaptive immune response in cancer models, with clinical indication of systemic response. NBTXR3 obtained EU marketing approval in preoperative treatment of locally advanced soft tissue sarcomas (STS) and is under investigation in multiple tumor types. Here we report on the feasibility and intra-tumor dispersion of IT NBTXR3 injection in patients with various solid malignancies, including STS, head and neck squamous cell carcinoma (HNSCC), hepatocellular carcinoma (HCC), liver metastases, lung metastases, and intra-prostate injection in patients with prostate adenocarcinoma. <h3>Materials/Methods</h3> In the phase II/III randomized Act.in.Sarc [NCT02379845] trial patients with locally advanced STS received either NBTXR3+RT or RT alone followed by tumor resection. Elderly patients with HNSCC of the oropharynx or oral cavity, ineligible to cisplatin or cetuximab, received a single IT injection of NBTXR3 and IMRT [NCT01946867]. In a Phase I trial patients with HCC or liver metastases received an IT injection of NBTXR3 followed by SBRT [NCT02721056]. Safety and efficacy of NBTXR3 + SBRT in combination with anti-PD-1 is being evaluated in three cohorts of patients with advanced cancers in the Phase I 1100 [NCT03589339] trial. In a phase I study evaluating NBTXR3 intra prostate injection patients with newly diagnosed Unfavorable Intermediate Risk (UIR) or High Risk (HR) prostate adenocarcinoma were treated with EBRT or brachytherapy boost and EBRT. <h3>Results</h3> IT injection in patients with STS, HNSCC, HCC, liver or lung metastases, and intra-prostate injection in patients with prostate adenocarcinoma is feasible. There was no leakage of NBTXR3 observed in surrounding healthy tissues as assessed by CT scan. IT dispersion of NBTXR3 ranged from 4.9%-28.2% of tumor volume in patients, depending on tumor size, with treatment doses of NBTXR3 ranging from 5-22% in HNSCC, HCC, lung metastasis, STS, and prostate. Favorable signs of efficacy were observed among these patients indicating the potential for NBTXR3 to improve patient outcomes at the doses tested and with dispersion within the tumor of up to 28.3%. <h3>Conclusion</h3> IT injection of NBTXR3 is feasible and safe in multiple tumor types. NBTXR3 injection has shown favorable safety and is continuing to be assessed in several Phase I studies. NBTXR3 demonstrated efficacy in a Phase II/III study in patients with STS. and promising signs of efficacy have been observed in other tumor types. Future consideration of dispersion analysis may include association with response and possibly dose-painting with simultaneous integrated boost secondary to preferential NBTXR3 loading.

The novel transcriptomic signature of angiogenesis predicts clinical outcome, tumor microenvironment and treatment response for prostate adenocarcinoma

Angiogenesis plays the critical roles in promoting tumor progression, aggressiveness, and metastasis. Although few studies have revealed some angiogenesis-related genes (ARGs) could serve as prognosis-related biomarkers for the prostate cancer (PCa), the integrated role of ARGs has not been systematically studied. The RNA-sequencing data and clinical information of prostate adenocarcinoma (PRAD) were downloaded from The Cancer Genome Atlas (TCGA) as discovery dataset. Twenty-three ARGs in total were identified to be correlated with prognosis of PRAD by the univariate Cox regression analysis, and a 19-ARG signature was further developed with significant correlation with the disease-free survival (DFS) of PRAD by the least absolute shrinkage and selection operator (LASSO) Cox regression with tenfold cross-validation. The signature stratified PRAD patients into high- and low-ARGs signature score groups, and those with high ARGs signature score were associated with significantly poorer outcomes (median DFS: 62.71 months vs unreached, p < 0.0001). The predicting ability of ARGs signature was subsequently validated in two independent cohorts of GSE40272 & PRAD_MSKCC. Notably, the 19-ARG signature outperformed the typical clinical features or each involved ARG in predicting the DFS of PRAD. Furthermore, a prognostic nomogram was constructed with three independent prognostic factors, including the ARGs signature, T stage and Gleason score. The predicted results from the nomogram (C-index = 0.799, 95%CI = 0.744–0.854) matched well with the observed outcomes, which was verified by the calibration curves. The values of area under receiver operating characteristic curve (AUC) for DFS at 1-, 3-, 5-year for the nomogram were 0.82, 0.83, and 0.83, respectively, indicating the performance of nomogram model is of reasonably high accuracy and robustness. Moreover, functional enrichment analysis demonstrated the potential targets of E2F targets, G2M checkpoint pathways, and cell cycle pathways to suppress the PRAD progression. Of note, the high-risk PRAD patients were more sensitive to immune therapies, but Treg might hinder benefits from immunotherapies. Additionally, this established tool also could predict response to neoadjuvant androgen deprivation therapy (ADT) and some chemotherapy drugs, such as cisplatin, paclitaxel, and docetaxel, etc. The novel ARGs signature, with prognostic significance, can further promote the application of targeted therapies in different stratifications of PCa patients.

68Ga-PSMA-11 PET/MRI in Patients with Newly Diagnosed Intermediate- or High-Risk Prostate Adenocarcinoma: PET Findings Correlate with Outcomes After Definitive Treatment.

Prostate-specific membrane antigen (PSMA) PET offers an accuracy superior to other imaging modalities in initial staging of prostate cancer and is more likely to affect management. We examined the prognostic value of 68Ga-PSMA-11 uptake in the primary lesion and presence of metastatic disease on PET in newly diagnosed prostate cancer patients before initial therapy. Methods: In a prospective study from April 2016 to December 2020, 68Ga-PSMA-11 PET/MRI was performed in men with a new diagnosis of intermediate- or high-grade prostate cancer who were candidates for prostatectomy. Patients were followed up after initial therapy for up to 5 y. We examined the Kendall correlation between PET (intense uptake in the primary lesion and presence of metastatic disease) and clinical and pathologic findings (grade group, extraprostatic extension, nodal involvement) relevant for risk stratification, and examined the relationship between PET findings and outcome using Kaplan-Meier analysis. Results: Seventy-three men (age, 64.0 ± 6.3 y) were imaged. Seventy-two had focal uptake in the prostate, and in 20 (27%) PSMA-avid metastatic disease was identified. Uptake correlated with grade group and prostate-specific antigen (PSA). Presence of PSMA metastasis correlated with grade group and pathologic nodal stage. PSMA PET had higher per-patient positivity than nodal dissection in patients with only 5-15 nodes removed (8/41 vs. 3/41) but lower positivity if more than 15 nodes were removed (13/21 vs. 10/21). High uptake in the primary lesion (SUVmax > 12.5, P = 0.008) and presence of PSMA metastasis (P = 0.013) were associated with biochemical failure, and corresponding hazard ratios for recurrence within 2 y (4.93 and 3.95, respectively) were similar to or higher than other clinicopathologic prognostic factors. Conclusion: 68Ga-PSMA-11 PET can risk-stratify patients with intermediate- or high-grade prostate cancer before prostatectomy based on degree of uptake in the prostate and presence of metastatic disease.

Acute, Subchronic, and Chronic Complications of Radical Prostatectomy Versus Radiotherapy With Hormone Therapy in Older Adults With High-Risk Prostate Adenocarcinoma.

PurposeTo compare acute, subchronic, and chronic complications between older patients with high-risk localized prostate cancer (HR-LPC) receiving radical prostatectomy (RP) and high-dose intensity-modulated radiotherapy (IMRT) combined with long-term hormone therapy (HT).Patients and MethodsWe recruited older patients (≥80 years) with HR-LPC from the Taiwan Cancer Registry database. After propensity score matching, logistic regression analysis was used to compare the acute, subchronic, and chronic complication rates between patients who underwent RP (the RP group) and high-dose IMRT combined with long-term HT (the IMRT+HT group).ResultsBenign prostatic hyperplasia (BPH) symptoms and urinary incontinence (UI) were the most common complications over 5 years (BPH symptoms: RP, 17.69%; IMRT+HT, 29.58%; UI: RP, 10.47%; IMRT+HT, 5.50%). Compared with the RP group, the IMRT+HT group had higher odds of BPH symptoms and lower odds of UI and hernia after the 5-year follow-up period. The impotence rates were significantly higher in the IMRT+HT group than in the RP group at 3 months and 1 year after treatment and became nonsignificant after 2 years. At 5 years after treatment, the IMRT+HT group had lower risks of UI (adjusted odds ratio [aOR], 0.50; 95% confidence interval [CI], 0.28–0.88) and hernia (aOR, 0.21; 95% CI, 0.11–0.82) and a higher risk of BPH symptoms (aOR, 4.15; 95% CI, 2.82–7.37) than the RP group.ConclusionIMRT+HT was associated with lower UI and hernia risks than RP. By contrast, RP was associated with fewer complications of BPH over the follow-up period and less impotence during the first year after treatment. Our findings provide important and valuable references for shared decision-making for optimal therapy selection among older men with HR-LPC.

68Ga-PSMA-11 PET/CT Initial Staging in Black and White South African Males with ISUP Grade Group 1 and 2 Prostate Adenocarcinoma.

Prostate adenocarcinoma (PCa) is a leading cause of mortality. Black males with high-risk PCa have a poorer prognosis compared to white males. Patients with International Society of Urological Pathology (ISUP) Grade Group (GG) 1 and 2 PCa have little potential for metastases post radical prostatectomy. 68Gallium prostate specific membrane antigen (68Ga-PSMA) PET/CT imaging for metastatic PCa is superior to conventional imaging in staging high-risk PCa. No strong evidence is available to support imaging low-risk patients. We aimed to evaluate the value of 68Ga-PSMA PET/CT in black and white South African (BSA and WSA) males with GG1 and 2 PCa at initial staging. We evaluated 25 WSA and 123 BSA males. The image findings were correlated with prostate specific antigen (PSA). PSA levels significantly correlated with both primary tumor and whole-body PSMA-tumor volume (PSMA-TV) and were higher in BSA males. No differences were noted in the occurrence of metastases; however, PSA, seminal vesicle invasion and black race predicted metastases. Our findings suggest higher PSMA expression and tumor burden in BSA with histologically low-risk PCa, and future research with immunohistochemistry evaluation will be essential to confirm these findings.

Long-Term Outcomes of a Phase I Trial of Weekly Docetaxel, Total Androgen Blockade, and Image Guided Intensity Modulated Radiation Therapy for Localized High-Risk Prostate Adenocarcinoma

PurposeOur purpose was to describe the long-term outcomes seen with the addition of concurrent weekly docetaxel to high-dose intensity modulated radiation (IMRT) to the prostate and androgen deprivation therapy in patients with high-risk nonmetastatic adenocarcinoma of the prostate. Methods and MaterialsNineteen patients with high-risk, localized prostate cancer were treated in a phase I trial with concurrent docetaxel at doses of 10 to 30 mg/m2, in a dose-escalated scheme, in addition to IMRT (77.4 Gy/43 fx) and neoadjuvant and concurrent combined androgen blockade (gonadotropin-releasing hormone agonist and antiandrogen). A gonadotropin-releasing hormone agonist was continued for an additional 24 months post radiation. Kaplan-Meier analysis was used to estimate the survival probabilities. ResultsAt a median follow-up of 10.5 years, 5-year and 10-year overall survival were found to be 89.5% and 68.4%, respectively. The median metastasis-free survival and progression-free survival were determined to be 11.3 years and 9.0 years, respectively. ConclusionsThis regimen produced a 10-year overall survival of 68% with a 10-year metastasis-free survival of 58%. Grade >2 toxicity was minimal. These limited data suggest that the addition of concurrent weekly docetaxel to high-dose IMRT for high-risk prostate cancer warrants further investigation.

NEAR trial: A single-arm phase II trial of neoadjuvant apalutamide monotherapy and radical prostatectomy in intermediate- and high-risk prostate cancer

ObjectiveTreatment efficacy of androgen deprivation therapy with radical prostatectomy for intermediate- to high-risk prostate cancer is less well-studied. The NEAR trial is a single-arm, phase II investigation of neoadjuvant apalutamide monotherapy and radical prostatectomy (RP) in the treatment of D’Amico intermediate- and high-risk prostate cancer (NCT03124433).Materials and methodsPatients with histologically-proven, D’Amico intermediate- to high-risk prostate adenocarcinoma received apalutamide 240 mg once-daily for 12 weeks followed by RP + /−lymphadenectomy. Primary outcome was pathological complete response (pCR) rate. Secondary outcomes included rate of biochemical response (defined by PSA < 0.03 ng/mL at week 24 from starting apalutamide without subsequent PSA relapse), treatment-related adverse events, and RP complication rates. Correlative biomarker analyses were performed to examine for molecular predictors of treatment responses.ResultsFrom 2017 to 2019, 30 patients were recruited, of which 20 and 10 were high and intermediate risk, respectively; 25 completed treatment as per-protocol. We did not observe any pCR on trial; median reduction of cancer burden was 41.7% (IQR: 33.3%–60.0%). 18 out of 25 patients were classified as having a biochemical response (4 did not achieve PSA of <0.03 ng/mL at week 24 and 3 developed PSA relapse subsequently). Dry skin (N = 16; 53.3%), fatigue (N = 10; 33.3%) and skin rash (N = 9; 30.0%) were the most common adverse events, and there was no major peri-operative complication. We observed an association between tumours of low androgen receptor activity and PAM50 basal status with biochemical non-responders, albeit these molecular phenotypes were not associated with pathological response.ConclusionsA 12-week course of neoadjuvant apalutamide prior to RP did not meet the primary endpoint of pCR in this trial. Tumours with low androgen receptor activity or of the PAM50 basal subtype may have a reduced response to apalutamide.

Long-Term Outcomes of a Phase I Trial of Weekly Docetaxel, Total Androgen Blockade, and Image-Guided Intensity-Modulated Radiotherapy for Localized High-Risk Prostate Adenocarcinoma

<h3>Purpose/Objective(s)</h3> In high-risk localized prostate cancer (HRLPC), the standard of care is dose-escalated radiation therapy (DERT) with long-term androgen deprivation therapy (LTADT). Unfortunately, outcomes are less than ideal. There is significant interest in improving outcomes by intensifying treatment for these patients using docetaxel (D). This phase I study was designed to find the maximum tolerable dose (MTD) of concurrent weekly D when combined with DERT to the prostate with long-term androgen deprivation therapy (LTADT) in HRLPC patients. Initial results reported demonstrated a MTD for docetaxel of 25 mg/m² with acceptable toxicities. Here we describe the long-term outcomes in these patients. <h3>Materials/Methods</h3> We enrolled 19 patients with HRLPC (≥1 of ≥cT2c, PSA ≥20ng/ml, or Gleason ≥8) on this phase 1 study. Patients received neoadjuvant combined androgen blockade for 2 months and then during radiation of 77.4 Gy to the prostate and 45 Gy to the seminal vesicles with concurrent weekly D. No pelvic/nodal radiotherapy was given. D was administered in a standard dose-escalated scheme requiring ≥3 patients per cohort, starting at 10mg/m² and increasing to 30mg/m² in 5mg/m² increments. The GnRH agonist was continued for an additional 24 months. The primary objective of the study was to determine the MTD of D in combination with DERT and LTADT. Secondary end points included progression free survival (PFS), metastasis free survival (MFS) and overall survival (OS). Kaplan-Meier analysis was used to estimate the survival probabilities. <h3>Results</h3> MTD was found to be 25mg/m². There was no grade ≥3 toxicity at this or lower dose levels. At a median follow up of 10.5 years the median OS was not reached. 5-year and 10-year OS was found to be 89.5% and 68.4%, respectively. Median MFS was found to be 11.3 years with 5- and 10-year MFS of 84.2% and 57.9%. Median PFS was 9.0 years with 73.7% and 42.1% at 5 and 10 years, respectively. <h3>Conclusion</h3> In the setting of high-dose IMRT to the prostate with concurrent LTADT the MTD of concurrent weekly docetaxel is 25mg/m². This study showed a 5-year OS of 89.5% with a median OS not reached with > 10 years of follow-up. This mature data suggests that the addition of concurrent weekly docetaxel at 25mg/m² to high-dose IMRT to the prostate is safe and may provide cancer control rates similar to those recently reported for adjuvant full-dose D.

Contemporary outcomes following robotic prostatectomy for locally advanced and metastatic prostate cancer.

While radical prostatectomy (RP) plays a prominent role in the management of localized prostate cancer, its role in high risk or metastatic disease is less clear. Due to changes in prostate cancer screening patterns, particularly those made by the United States Preventive Services Task Force, data is suggesting increasing incidences of high risk and metastatic disease, underlying the importance of continued research in this area. While past approaches to management may have discouraged surgical intervention, more contemporary approaches have attempted to evaluate its effectiveness and utility. The purpose of this review is an updated discussion of the current literature regarding surgical approaches to high risk prostate cancer. The PubMed and Medline databases were queried for English language articles related to the surgical management of high-risk prostate adenocarcinoma. In this review, we examine the utility of surgery as a single or multimodal approach to management with patients with high risk, locally advanced, and metastatic prostate cancer. Outcomes measures are reviewed including data on survival and recurrence rates. Functional outcomes are an important consideration in prostate cancer management and while data is more limited, this review examines some of the key findings. Finally, a discussion regarding surgical complication rates and ongoing clinical trials is addressed. While surgery appears to be promising in this patient cohort, there remains significant heterogeneity in the data that ongoing trials may be able to address. At its current level of understanding, surgery should be considered as a potential tool in patient management, but may play a more prominent role in a multi-modality setting for optimal outcomes.

Surgical Delay and Pathological Outcomes for Clinically Localized High-Risk Prostate Cancer

There is a lack of data evaluating the association of surgical delay time (SDT) with outcomes in patients with localized, high-risk prostate cancer. To investigate the association of SDT of radical prostatectomy and final pathological and survival outcomes. This cohort study used data from the US National Cancer Database (NCDB) and identified all patients with clinically localized (cT1-2cN0cM0) high-risk prostate adenocarcinoma diagnosed between 2006 and 2016 who underwent radical prostatectomy. Data analyses were performed from April 1 to April 12, 2020. SDT was defined as the number of days between the initial cancer diagnosis and radical prostatectomy. SDT was categorized into 5 groups: 31 to 60, 61 to 90, 91 to 120, 121 to 150, and 151 to 180 days. The primary outcomes were predetermined as adverse pathological outcomes after radical prostatectomy, including pT3-T4 disease, pN-positive disease, and positive surgical margin. The adverse pathological score (APS) was defined as an accumulated score of the 3 outcomes (0-3). An APS of 2 or higher was considered a separate outcome to capture cases with more aggressive pathological features. The secondary outcome was overall survival. Of the 32 184 patients included in the study, the median (interquartile range) age was 64 (59-68) years, and 25 548 (79.4%) were non-Hispanic White. Compared with an SDT of 31 to 60 days, longer SDTs were not associated with higher risks of having any adverse pathological outcomes (odds ratio [OR], 0.95; 95% CI, 0.80-1.12; P = .53), pT3-T4 disease (OR, 0.99; 95% CI, 0.83-1.17; P = .87), pN-positive disease (OR, 0.79; 95% CI, 0.59-1.06; P = .12), positive surgical margin (OR, 0.88; 95% CI, 0.74-1.05; P = .17), or APS greater than or equal to 2 (OR, 0.90; 95% CI, 0.74-1.05; P = .17). Longer SDT was also not associated with worse overall survival (for SDT of 151-180 days, hazard ratio, 1.12; 95% CI, 0.79-1.59, P = .53). Subgroup analyses performed for patients with very high-risk disease (primary Gleason score 5) and sensitivity analyses with SDT considered as a continuous variable yielded similar results. In this cohort study of patients who underwent radical prostatectomy within 180 days of diagnosis for high-risk prostate cancer, radical prostatectomy for high-risk prostate cancer could be safely delayed up to 6 months after diagnosis.

Ductal Prostate Cancers Demonstrate Poor Outcomes with Conventional Therapies

BackgroundDuctal prostate adenocarcinoma (DAC) is a rare, aggressive, histologic variant of prostate cancer that is treated with conventional therapies, similar to high-risk prostate adenocarcinoma (PAC). ObjectiveTo assess the outcomes of men undergoing definitive therapy for DAC or high-risk PAC and to explore the effects of androgen deprivation therapy (ADT) in improving the outcomes of DAC. Design, setting, and participantsA single-center retrospective review of all patients with cT1–4/N0–1 DAC from 2005 to 2018 was performed. Those undergoing radical prostatectomy (RP) or radiotherapy (RTx) for DAC were compared with cohorts of high-risk PAC patients. Outcome measurements and statistical analysisMetastasis-free survival (MFS) and overall survival (OS) rates were analyzed using Kaplan-Meier and Cox regression models. Results and limitationsA total of 228 men with DAC were identified; 163 underwent RP, 34 underwent RTx, and 31 had neoadjuvant therapy prior to RP. In this study, 163 DAC patients and 155 PAC patients undergoing RP were compared. Similarly, 34 DAC patients and 74 PAC patients undergoing RTx were compared. DAC patients undergoing RP or RTx had worse 5-yr MFS (75% vs 95% and 62% vs 93%, respectively, p < 0.001) and 5-yr OS (88% vs 97% and 82% vs 100%, respectively, p < 0.05) compared with PAC patients. In the 76 men who received adjuvant/salvage ADT after RP, DAC also had worse MFS and OS than PAC (p < 0.01). A genomic analysis revealed that 10/11 (91%) DACs treated with ADT had intrinsic upregulation of androgen-resistant pathways. Further, none of the DAC patients (0/15) who received only neoadjuvant ADT prior to RP had any pathologic downgrading. The retrospective nature was a limitation. ConclusionsMen undergoing RP or RTx for DAC had worse outcomes than PAC patients, regardless of the treatment modality. Upregulation of several intrinsic resistance pathways in DAC rendered ADT less effective. Further evaluation of the underlying biology of DAC with clinical trials is needed. Patient summaryThis study demonstrated worse outcomes among patients with ductal adenocarcinoma of the prostate than among high-grade prostate adenocarcinoma patients, regardless of the treatment modality.