Biochemical Progression Research Articles

68Ga]Ga-PSMA-11 PET/CT for monitoring response to treatment in metastatic prostate cancer: is there any added value over standard follow-up?

BackgroundThe aim of the current study was to assess whether and to what extent monitoring response to treatment using prostate-specific membrane antigen (PSMA)-based positron-emitting tomography/computerized tomography (PET/CT) studies contribute clinically relevant data to routine clinical follow-up during treatment of patients with metastatic prostate cancer (PCa).ResultsFifty-two patients with metastatic PCa who underwent [68Ga]Ga-PSMA-11 PET/CT imaging and serum prostate-specific antigen (PSA) level measurements before and during treatment were investigated. Response was categorized by serum PSA dynamics according to improvement, stable disease, and disease progression and compared to change in imaging findings on pre- and post-treatment PET/CTs. McNemar’s test was used to assess agreement between PET/CT- and PSA-based responses to treatment.Thirty-four patients (65.4%) had compatible biochemical- and imaging-based response to treatment. However, the imaging and biochemical responses were discrepant in 18/52 patients (34.6%). PET/CT showed progressive disease in 5/52 patients (9.6%) and improvement/stable disease in 13/52 (25%) compared to biochemical assessment results. Discrepancy between imaging and biochemical response was most prominent in biochemically stable patients (90.9%), followed by patients with biochemical progression (33.3%), and in only few (8.7%) patients with biochemical improvement. The imaging-based response was suitable for choosing subsequent treatment in 22 of 30 patients (73.3%) with longer follow-up (median time of 10.3 months (IQR 6.3–18.2)). The relevance of the imaging methodology was reflected by its ability to assess individual lesions in cases of heterogeneous lesion responses, reveal the appearance of new lesions, and identify lesions that required specific consideration, such as targeted radiotherapy.ConclusionsResults of this retrospective analysis showed that biochemical responses to treatment and [68Ga]Ga-PSMA-11 PET/CT-based responses to treatment differ in one third of metastatic PCa patients. The latter additionally enabled lesion-based and not solely patient-based analysis. Monitoring response during treatment by [68Ga]Ga-PSMA-11 PET/CT is suitable for decision-making in patient management and choice of treatment in the majority of patients.

Docetaxel Versus Surveillance After Radical Radiotherapy for Intermediate- or High-risk Prostate Cancer—Results from the Prospective, Randomised, Open-label Phase III SPCG-13 Trial

BackgroundDocetaxel combined with androgen deprivation therapy (ADT) has improved patient survival for advanced prostate cancer (PCa). ObjectiveThis randomised trial aimed to evaluate whether six courses of docetaxel improved biochemical disease–free survival (BDFS) after radical radiotherapy (RT) for intermediate- or high-risk PCa patients. Design, setting, and participantsA total of 376 patients were randomised in this multinational phase III study, and received either six cycles of adjuvant docetaxel 75 mg/m2 every 3 wk without continuous prednisone (arm A, n = 188) or surveillance (arm B, n = 188) after RT (NTC006653848). Neoadjuvant/adjuvant ADT was mandatory for all the patients. The primary endpoint was rising prostate-specific antigen (PSA) ≥2 ng/ml above the nadir PSA value. Intermediate- or high-risk PCa was defined as T2 with a Gleason score (GS) of 4 + 3, PSA > 10; T2, GS 8–10, ≤ 70 ng/ml; or any T3. The patients were followed for 5 yr by assessing PSA levels every 3 mo for 2 yr and every 6 mo thereafter. Outcome measurements and statistical analysisThe study power was 89% to detect a difference in BDFS between groups, and the sample size calculation accounted for the T2/T3 distribution, where a 12%/15% difference in BDFS was assumed for the T2/T3 patients. Results and limitationsAll six cycles were completed in 147 (78%) of the patients in arm A. The median age was 67 yr in both treatment groups, 75% had T3 disease, and 47% had GS 8–10. The median follow-up was 59 mo (range 1–111 mo). The primary endpoint was observed for 58 patients in arm A (docetaxel) and for 57 patients in arm B (surveillance). The Kaplan-Meier analysis showed no difference in the BDFS curves (p = 0.6) between the treatment groups. The 5-yr estimated biochemical progression rates were 31% for arm A and 28% for arm B. Febrile neutropenia occurred in 16% of the docetaxel patients. No deaths were related to the docetaxel treatment. There were 43 deaths during the trial, including 20 in arm A and 23 in arm B, of which nine and seven, respectively, were due to PCa. The hazard ratio from Cox multivariate analysis for PSA progression of arm A (docetaxel) versus arm B (surveillance) was 1.14 (95% confidence interval 0.79–1.64, p = 0.5). ConclusionsAdjuvant docetaxel without prednisone did not improve BDFS after radical RT with ADT for intermediate- or high-risk PCa. Patient summaryWe compared six cycles of adjuvant docetaxel given after radical external radiotherapy plus androgen deprivation therapy to surveillance in intermediate- and high-risk localised prostate cancer. We found no overall benefit in this setting.

Randomized prospective phase 3 trial of 68Ga-PSMA-11 PET/CT molecular imaging for prostate cancer salvage radiotherapy planning [PSMA-SRT

TPS5101 Background: Salvage radiotherapy (SRT) for prostate cancer (PCa) recurrence after prostatectomy offers long-term biochemical control in about 50–60% of patients. SRT is commonly initiated in patients with serum PSA levels < 1 ng/mL, a threshold at which standard-of-care imaging is insensitive for detecting recurrence. As such, SRT target volumes are usually drawn in the absence of radiographically visible disease. 68Ga-PSMA-11 (PSMA) PET/CT molecular imaging is highly sensitive and may offer anatomic localization of PCa biochemical recurrence. However, it is unclear if incorporation of PSMA PET/CT imaging into the planning of SRT could improve its likelihood of success. The purpose of this trial is to evaluate the success rate of SRT for recurrence of PCa after prostatectomy with and without planning based on PSMA PET/CT. Methods: We will randomize 193 patients to proceed with standard SRT (control arm 1, n = 90) or undergo a PSMA PET/CT scan (free of charge for patients) prior to SRT planning (investigational arm 2, n = 103). The primary endpoint is the success rate of SRT measured as biochemical progression-free survival (BPFS) after initiation of SRT. Biochemical progression is defined by PSA ≥ 0.2 ng/mL and rising. The randomization ratio of 1:1.13 is based on the assumption that approximately 13% of subjects randomized to Arm 2 will not be treated with SRT because of PSMA-positive extra-pelvic metastases. These patients will not be included in the primary endpoint analysis but will still be followed. The choice of treating the prostate bed alone vs prostate bed and pelvic lymph nodes, with or without androgen deprivation therapy (ADT), is selected by the treating radiation oncologist. The radiation oncologist may change the radiation plan depending on the findings of the PSMA PET/CT scan. Any other imaging is allowed for SRT planning in both arms if done per routine care. Patients will be followed until either one of the following conditions occur: 5 years after the date of initiation of randomization, biochemical progression, diagnosis of metastatic disease, initiation of any additional salvage therapy, death. Discussion: This is the first randomized phase 3 prospective trial designed to determine whether PSMA PET/CT molecular imaging can improve outcomes in patients with PCa early BCR following radical prostatectomy. Clinical trial information: NCT03582774.

Circulating tumor DNA fraction (ctDNA) as a surrogate predictive biomarker in metastatic castration-resistant prostate cancer (mCRPC).

5039 Background: Plasma ctDNA is a promising minimally invasive biomarker in mCRPC. Pre-treatment high levels of ctDNA reflect poor prognosis (Romanel et al, Sci Transl Med 2015; Annala et al, Cancer Discov 2018). However, the role of plasma ctDNA in prostate tumour monitoring is largely unexplored. We aimed to determine if monitoring tumour response by quantifying ctDNA levels in plasma could enable early assessment of therapy efficacy for mCRPC. Methods: Between January 2011 and June 2016, 132 sequential plasma samples from 54 mCRPC patients (pts) (30 pre- and 24 post-chemotherapy) treated with abiraterone (abi) were collected. Targeted next-generation sequencing was performed on the PGM Ion Torrent using a 316 or 318 Chip to account for 1000X expected coverage per target. We estimated the global tumour content for each sequential plasma sample from study patients by using the approach developed in (Carreira et al, Sci Trasl Med 2014; Romanel et al, Sci Transl Med 2015 ), which extends the CLONET framework (Prandi et al, Genome Biol 2014). Prostate Cancer Working Group -3 (PCWG3) criteria were used to assess clinical, biochemical (PSA) and radiographic (RAD) progression disease (PD). We considered ctDNA PD any increase of ctDNA from baseline value. Results: In our cohort of 54 pts (median age: 75 years, range 70-78), we observed 17 (31.5%) PD, 14 (25.9%) stable disease, and 23 (42.6%) partial/complete response after the first 3 months (mo) abi therapy. The odds ratio (OR) for PD having any increase in ctDNA and a PSA decline < 50% at ~3-mo therapy was 10.83, 95% CI 2.55-45.95, P = 0.001, and 3.27, 95% CI 0.89-12.3, P = 0.074, respectively. In addition, we assessed all 3 types of median PD time from starting abi treatment, suggesting the ability of ctDNA variation to predict overall PD [RAD PD = 6.8 mo, PSA PD = 4.4 mo, and ctDNA PD = 3.0 mo, P = 0.008). An increase of ctDNA levels during the first 3-mo abi treatment was significantly associated with a long-term androgen deprivation therapy (ADT) before plasma sample collection (previous ADT > 24 mo vs 12 > previous ADT ≤23 mo vs < 12 mo: P = 0.036). Conclusions: In mCRPC, an early change in ctDNA fraction may be considered as a predictive biomarker playing a key role in individualized disease monitoring. Prospective evaluation of treatment decisions based on ctDNA is now required.

CALGB 90203 (Alliance): Radical prostatectomy (RP) with or without neoadjuvant chemohormonal therapy (CHT) in men with clinically localized, high-risk prostate cancer (CLHRPC).

5079 Background: Neoadjuvant CHT followed by RP did not increase 3-year biochemical progression free-survival (bPFS) compared to RP alone in men with CLHRPC. However, there is evidence that bPFS and overall survival over time was improved. In the current analysis we assessed whether CHT followed by RP improved pathological specimen features compared to RP alone. Methods: CALGB 90203 (Alliance) is a Phase III study which randomly assigned, in a 1:1 fashion, men with CLHRPC [biopsy Gleason Grade Group (GGG) 4 or 5 or Kattan pre-op nomogram bPFS < 60%] to RP alone or RP plus neoadjuvant CHT [androgen deprivation plus docetaxel (75 mg/m2 every 3 weeks for 6 cycles)]. We conducted an exploratory analysis comparing histologic findings, determined at the treating center, in the RP specimens of men receiving CHT plus RP and men treated with RP alone. We used the Chi-square test, with P-values adjusted by the Holm method for multiple comparisons. Results: A total of 788 men (median age, 62; range: 32-83 years) were randomized, with 738 ultimately undergoing RP. There was no difference in pathologic GGG (Table). Men treated with neoadjuvant CHT had a lower pathologic T-stage and lower likelihood of having seminal vesicle invasion (SVI), positive pelvic lymph nodes, or positive surgical margins (SM) (Table). Conclusions: Most pathologic features in the RP specimen were improved in men receiving neoadjuvant CHT compared to RP alone. The relationship between pathologic changes and the development of metastasis and survival require further analysis. RP pathologic outcomes. Summary statistics are calculated for the number of patients with non-missing data for each characteristic. Clinical trial information: NCT00430183. [Table: see text]

Safety and Efficacy of Pre-Operative, Short Course Radiation Therapy for Prostate Cancer: Results From a Phase I Trial

Up to 60% of patients (pts) with prostate cancer that extends beyond the prostatic capsule will have positive resection margins following radical prostatectomy. Post-operative radiation therapy (PostOp) is routinely offered to those pts. Although this improves local control and overall survival, it results in significantly more late toxicity than surgery alone. Pre-operative radiation therapy (PreOp) has become the standard for soft tissue sarcoma and rectal cancer, improving local control and reducing toxicity compared to PostOp. We report the results of a Phase I trial, investigating the use of PreOp for prostate pts at high risk of extra-capsular extension. Following REB approval, prostate cancer pts at high risk of extra-capsular extension were prospectively identified for inclusion based on T-stage, N-stage, PSA and Gleason score. Since this was a Phase I study of safety and efficacy for a novel treatment regimen, a small sample size was used (15 pts). Patients received 25 Gy in 5 daily fractions to the prostate-only, followed by a radical prostatectomy 1-2 weeks after RT completion. Study endpoints were descriptive in nature due to the small sample size, and included intra-operative morbidity, early, late and ultra-late urinary (U) and gastrointestinal (GI) toxicity (using RTOG and CTCAE grading (G) systems). Between 2001 and 2004, 15 pts enrolled in the trial and all received 25 Gy over 5 consecutive fractions. Fourteen pts were irradiated with a 6-field conformal plan, and one with IMRT. Planning constraints were used to limit the dose to the femoral heads, bladder and rectal walls. Patients were treated with a full bladder / empty rectum protocol, employing daily portal image guidance based on intra-prostatic markers. G2 diarrhea (1 pt) and G2 cystitis (1 pt) were reported during RT. Fourteen pts went on to receive a non-nerve sparing radical retropubic prostatectomy, which included bilateral lymph node dissection for 13 pts. Four pts required a blood transfusion, and 3 pts had adhesions surrounding the prostate. Surgical margins were positive in 7 pts, PSA was detectable immediately after surgery in 5 pts. By 45 months, one patient had reported one episode of rectal bleeding that resolved with corticosteroids. Eleven pts reported urinary incontinence (73%), 3 had a urethral stricture (20%), and 1 reported G2 intermittent haematuria. To date, the median follow-up is 147 months. Two pts (14%) report G2 U toxicity, and 6 pts (43%) G3 U toxicity. One patient experienced transient G2 proctitis. At last follow-up, 8 (57%) and 6 (43%) pts have biochemical and metastatic progression, respectively. There were two prostate cancer related deaths. Delivery of short-course radiation therapy followed by an immediate prostatectomy is feasible. However, the incidence of late U toxicity is approximately 3-fold higher in this study than in Phase III trials of PostOp, with no appreciable benefit in biochemical or metastases free survival compared to those PostOp studies. Future studies of this regimen must be cautiously considered, and should include radiotherapy and surgical advances that might reduce toxicity, and multiparametric and/or molecular imaging to more precisely identify pts who may benefit from such an approach. This study emphasizes the need for long term follow-up data to fully appreciate the toxicity of such novel approaches.

Retrospective Institutional Acute Toxicity and Response Analysis for HDR Monotherapy for Prostate Cancer Using 27 Gy in Two Fractions Three Weeks Apart

Various High-Dose Rate (HDR) monotherapy dose regimens are currently being used to treat low and intermediate risk prostate cancer patients. There is no consensus on the regimen with the best long-term outcomes. The objective of this study is to assess the Southeastern Regional Medical Center (SERMC) institutional experience with HDR monotherapy for low and intermediate prostate cancers. Biochemical progression free survival and toxicity was evaluated for patients receiving two fractions of 13.5 Gy with three weeks between each fraction.

Active surveillance outcomes in prostate cancer patients: the use of transperineal template-guided mapping biopsy for patient selection.

To evaluate active surveillance (AS) outcomes including overall survival (OS), freedom from distant metastases (FDM), freedom from therapeutic intervention (FTI), and quality of life (QOL) outcomes in prostate cancer patients using transperineal template-guided mapping biopsy (TTMB) for patient selection. From April 2005-January 2016, 226 consecutive, prospectively evaluated prostate cancer patients underwent TTMB for either low-grade prostate cancer or persistently elevated prostate-specific antigen (PSA) and/or the presence of ASAP. Evaluated outcomes included OS, FDM, FTI and QOL including urinary, bowel, sexual function and depression. Repeat biopsy was based on PSA kinetics and/or abnormal digital rectal examination. Of the 226 patients, 212 (93.8%) were Gleason 3 + 3 and 14 (6.2%) were Gleason 3 + 4. The median follow-up was 5.0years (range 0.8-13.0years). The mean prostate volume was 61.3cm3 with a mean of 59.5 TTMB cores/patient. At the time of AS enrollment, an average of 72.9 cores (TRUS + TTMB) had been obtained for each patient. At 8years, OS, FTI and FDM were 92.5, 96.8 and 100%. Two hundred and twenty-two patients (98.2%) had a PSA doubling time of more than 3years. No statistical changes in urinary function, bowel function or depression were noted. At 8years, 73% of the patients maintained erectile function. Within the confines of the follow-up of this study, the use of TTMB for patient selection identifies a cohort of patients unlikely to develop biochemical or clinical progression and maintain a favorable quality of life.

TGF-β/PI3K/AKT/mTOR/NF-kB pathway. Clinicopathological features in prostate cancer

Prostate cancer is one of the most common cancers in the male population. The objective of this investigation was to study the relationship of components of transforming growth factor-B (TGF-β)/phosphoinositide-3-kinases (PI3K)/AKT/mammalian target of rapamycin (mTOR)/nuclear factor kappa B (NF-kB) transduction pathway with clinical-pathological markers. By immunohistochemical methods, we determined the expression of several factors [TGF-β, Transforming Growth Factor B Receptor I (TGFBRI), TGFBRII, PI3K, AKT-Ser, AKT-Thr, mTOR, p-mTOR, inhibitor kB kinase (IKK), pIKK, inhibitor kB (IkB), pIkB, NF-kBp50, and NF-kBp65]. To know their relationship with established classical markers (Preoperative serum prostate specific antigen, pathological tumor stage, clinical tumor stage, Gleason score, perineural invasion, node involvement, positive surgical margins, biochemical progression, and survival) and their importance in the prognosis of biochemical progression, Spearman test, survival analysis, Log-rang test, Kaplan–Meier curves, univariate and multivariate Cox proportional Hazard regression analyses were performed. Spearman analysis showed that there was at least one correlation between TGF-β, TGFBRI, PI3K, pAKT-Thr, p-mTOR, NF-kBp50, and classical markers. Cox multivariate analysis between the prognostic variables (pathological tumor stage, Gleason score, and node involvement) and inmunohistochemical parameters confirmed TGFBR1 and PI3K as a prognostic and independent marker of biochemical progression in prostate cancer. Our results suggest that TGFBR1 and PI3K could be used as useful biomarkers for early diagnosis and prognoses for biochemical recurrence in prostate cancer after radical prostatectomy.

Systemic and tumor-directed therapy for oligometastatic prostate cancer: study protocol for a phase II trial for veterans with de novo oligometastatic disease

BackgroundThe treatment paradigm for metastatic hormone-sensitive prostate cancer (mHSPC) patients is evolving. PET/CT now offers improved sensitivity and accuracy in staging. Recent randomized trial data supports escalated hormone therapy, local primary tumor therapy, and metastasis-directed therapy. The impact of combining such therapies into a multimodal approach is unknown. This Phase II single-arm clinical trial sponsored and funded by Veterans Affairs combines local, metastasis-directed, and systemic therapies to durably render patients free of detectable disease off active therapy.MethodsPatients with newly-diagnosed M1a/b prostate cancer (PSMA PET/CT staging is permitted) and 1–5 radiographically visible metastases (excluding pelvic lymph nodes) are undergoing local treatment with radical prostatectomy, limited duration systemic therapy for a total of six months (leuprolide, abiraterone acetate with prednisone, and apalutamide), metastasis-directed stereotactic body radiotherapy (SBRT), and post-operative fractionated radiotherapy if pT ≥ 3a, N1, or positive margins are present. The primary endpoint is the percent of patients achieving a serum PSA of < 0.05 ng/mL six months after recovery of serum testosterone ≥150 ng/dL. Secondary endpoints include time to biochemical progression, time to radiographic progression, time to initiation of alternative antineoplastic therapy, prostate cancer specific survival, health related quality-of-life, safety and tolerability.DiscussionTo our knowledge, this is the first trial that tests a comprehensive systemic and tumor directed therapeutic strategy for patients with newly diagnosed oligometastatic prostate cancer. This trial, and others like it, represent the critical first step towards curative intent therapy for a patient population where palliation has been the norm.Trial registrationClinicaltrials.gov identifier: NCT03298087 (registration date: September 29, 2017).

Accuracy of CAPRA-S Score for Predicting Long-Term Biochemical Progression After Radical Prostatectomy.

The Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) score is a tool to stratify patients into groups according to their risk for biochemical recurrence after radical prostatectomy. The aim of this study was to assess the accuracy of the CAPRA-S score for predicting biochemical progression at 5 and 10 years in our cohort of patients after radical prostatectomy. Between June 2004 and December 2015, radical prostatectomy was performed as the main treatment option for patients with localized prostate cancer. Patients who had received adjuvant or neoadjuvant treatment were excluded from this study. Biochemical progression after radical prostatectomy was considered in patients by prostate-specific antigen (PSA) > 0.1 ng/mL after surgery (biochemical persistence) and by at least 2 determinations of PSA > 0.2 ng/mL in those patients with initial undetectable postoperative PSA any time during their follow-up (biochemical failure). Cox proportional hazard model and Kaplan-Meier analysis were used for the statistical analysis. Of 531 patients who underwent radical prostatectomy, 479 met the inclusion criteria. Mean follow-up was 85 months (min-max, 13-153 months). The rate of biochemical progression-free survival at 10 years was 84.2%, 55.1%, and 32.8%, respectively, for high-, intermediate-, and low-risk patients according to the CAPRA-S score. The concordance index for CAPRA-S predicting biochemical progression at 5 years was 0.71 and at 10 years was 0.70. The CAPRA-S score is a useful and easy-to-use tool in patients after radical prostatectomy to classify their risk for biochemical progression, thus helping decide if adjuvant treatment should be required.

High dose rate brachytherapy boost for prostate cancer: Biochemical control and the impact of transurethral resection of the prostate and hydrogel spacer insertion on toxicity outcomes.

To examine the long-term outcomes of high dose rate brachytherapy boost (HDR-BT) combined with external beam radiotherapy (EBRT) for intermediate and high-risk prostate cancer patients. Data from 95 patients who underwent combined EBRT (50.4Gy) and HDR-BT to the prostate between 2010 and 2017 were retrospectively analysed. Biochemical progression free survival (bPFS), local recurrence free survival (LRFS), metastatic free survival (MFS) and overall survival (OS) were estimated using Kaplan-Meier method. Regression analysis was conducted to identify important predictors of outcomes. A total of 24 patients received an initial HDR-BT dose of 18Gy in three fractions, with the remaining 71 patients receiving 16Gy in two fractions as per departmental protocol changes. Most patients (88%) received androgen deprivation therapy. A transurethral resection of the prostate (TURP) was performed in 14 patients and hydrogel spacers (HS) were used in 30 patients. Median follow-up was 58months. The 5-year bPFS, LRFS, MFS and OS were 92%, 100%, 92% and 88%. Univariate regression revealed no statistical association between patient characteristics and time to relapse (all P>0.1). Late > grade 2 genitourinary (GU) toxicity was 6.3%. The use of HS or prior TURP had no impact on late GU toxicity. Late Grade 1 gastrointestinal (GI) toxicity was 5.3%. The combined HDR-BT with EBRT resulted in excellent bPFS. The cumulative risk of late GU and GI toxicity was low and can be further improved with preventative strategies such as a pre-emptive TURP and/or HS insertion.

Randomized phase III trial of 68Ga-PSMA-11 PET/CT molecular imaging for prostate cancer salvage radiotherapy planning [PSMA-SRT

TPS136 Background: Salvage radiotherapy (SRT) for prostate cancer (PCa) biochemical recurrence (BCR) after radical prostatectomy (RP) is commonly initiated in patients with PSA &lt; 1 ng/mL, a threshold at which standard-of-care imaging is insensitive for detecting recurrence. The purpose of this randomized phase 3 trial is to evaluate the success rate of SRT for PCa BCR after RP with and without planning based on 68Ga-PSMA-11 PET/CT (PSMA). Here we present the study protocol. Methods: This is an interventional phase 3 randomized prospective open label clinical trial with parallel assignment designed for superiority. Patients who are planned to undergo SRT for PCa BCR with PSA &gt; 0.1 ng/ml are eligible. The choice of treating the prostate bed with/without pelvic lymph nodes, with/without androgen deprivation therapy, is left to the discretion of the treating radiation oncologist (RO). RO may or may not change the RT plan depending on the PSMA findings. Any other imaging is allowed for SRT planning if done per routine care. The primary endpoint is the success rate of SRT measured as biochemical progression-free survival (PFS) after initiation of SRT. Biochemical progression is defined by PSA≥0.2 ng/mL and rising. Based on literature data we hypothesized that 1) the incorporation of PSMA to SRT planning will improve 5-year PFS by 20%, 2) the 5-year PFS will be 60% in standard Arm 1 and 80% in interventional Arm 2, and 3) 13% of subjects randomized to Arm 2 will have extra-pelvic metastasis detected by PSMA and will not be included in analysis of the primary endpoint. We will randomize 193 patients (1:1.13 ratio) to proceed with standard SRT (n = 90) or undergo PSMA scan (free of charge for patients) prior SRT planning (n = 103). Patients will be followed for 5 years after the date of initiation of SRT. Discussion: Main pitfalls in study design include 1) drop-out of patients randomized to the control arm and 2) potential FDA approval of PSMA PET imaging probes in the near future (no randomization to standard arm would be then acceptable). This is the first prospective randomized phase 3 trial designed to determine whether PET/CT can improve outcome of SRT in patients with BCR. Clinical trial information: NCT03582774.

Abiraterone acetate plus prednisone/prednisolone compared with enzalutamide in metastatic castration resistant prostate cancer before or after chemotherapy: A retrospective study of real-world data (ACES).

303 Background: Abiraterone acetate (a prodrug of abiraterone, which is a selective inhibitor of androgen biosynthesis) combined with prednisone/prednisolone (AA+P) and enzalutamide (ENZ) (an androgen-receptor–signalling inhibitor) have proven survival benefit in men with metastatic castration resistant prostate cancer (mCRPC) in chemo naïve and prior chemo patients. There have been no studies directly comparing the effectiveness of ENZ to AA+P in mCRPC patients. Methods: A retrospective, survival analysis study of 143 real world mCRPC patients (90 in AA+P and 53 in ENZ group) was conducted. Patients who started their treatment between 1st February 2012 and 31st May 2016 were included. The primary endpoint was biochemical progression free survival (PFS). Secondary end points were radiographic progression free survival (rPFS) and overall survival (OS). Data was analysed using Cox proportional hazards models, adjusting for covariates: prior radical or palliative treatment; Gleason score; baseline PSA; age; and chemo naïve or not. Results: After median follow up of 15 months (IQR 7 to 23) 112 events of biochemical progression were observed (71 in AA+P and 41 in ENZ). 41%in AA+P group and 30% patients in ENZ group received prior chemo. The chance of biochemical progression was significantly lower among ENZ patients than AA+P patients, when adjusting for all covariates in the Cox PH model (Hazard Ratio 0.54, 95% CI 0.35 to 0.82, p=0.004. There was a trend implying the chance of rPFS could be higher among ENZ patients than AA+P patients (HR 1.24, 95% CI 0.76 to 2.02, p=0.4). OS is lower among ENZ patients than AA+P patients, when adjusting for all covariates in the Cox PH model (HR 0.91, 95% CI 0.59 to 1.41, p=0.7). 38% of ENZ patients reported fatigue compared to 16% of AA+P patients while hypertension was reported slightly more in AA+P patients than in ENZ patients. Conclusions: This study showed a statistically significant difference in biochemical progression-free survival, favouring ENZ, but no significant difference in radiographic progression-free survival or overall survival.

Metacure: Multi-arm multimodality therapy for very high risk localized and low volume metastatic prostatic adenocarcinoma.

TPS349 Background: Therapeutic advances in the management of metastatic castration-resistant prostate cancer (mCRPC) have not been matched in non-castrate states. A key obstacle is the traditional paradigm in which therapies with significant benefit in mCRPC are then studied in patients (pts) with localized, rising PSA or early metastatic disease using time-to-event (TTE) outcomes (e.g. biochemical recurrence, radiographic progression or death). These trials are costly, lengthy and often give inconclusive results that do not change practice nor provide a methodology to rank regimens based on efficacy. A new strategy is needed that gives a rapid efficacy readout and prioritizes approaches for large-scale testing. Methods: Metacure is a multi-arm, multi-stage randomized Phase 2 trial in which novel systemic therapies are studied in the context of a multimodality approach, which includes radical prostatectomy + pelvic and retroperitoneal lymph node dissection, if applicable, stereotactic radiotherapy (RT) to osseous metastases, and an option for adjuvant RT based on risk factors. The arms include combinations of ADT + apalutamide +/- abiraterone acetate and prednisone. Non-castrate prostate cancer pts with high probability of relapse or death from disease ranging from very high risk localized to low-volume metastatic disease are eligible. The primary endpoint is pathologic complete response and minimal residual disease. The secondary endpoint is undetectable PSA with non-castrate levels of testosterone. Both are binary endpoints that circumvent interpretations of the clinical relevance of TTE outcomes, providing a read-out of success or failure in a shorter time frame with fewer pts. The uniform entry criteria and continuous randomization enables ranking and prioritization of the strategies evaluated for further development in large-scale trials so that only the most effective ones move forward. This multicenter trial is managed by the Prostate Cancer Clinical Trials Consortium, funded by Janssen and is currently open and actively accruing. Future plans include opening a cohort of pts with aggressive non-castrate disease harboring DNA damage repair alterations. Clinical trial information: NCT03436654.

Prostate Radiotherapy for Metastatic Hormone-sensitive Prostate Cancer: A STOPCAP Systematic Review and Meta-analysis

BackgroundMany trials are evaluating therapies for men with metastatic hormone-sensitive prostate cancer (mHSPC). ObjectiveTo systematically review trials of prostate radiotherapy. Design, setting, and participantsUsing a prospective framework (framework for adaptive meta-analysis [FAME]), we prespecified methods before any trial results were known. We searched extensively for eligible trials and asked investigators when results would be available. We could then anticipate that a definitive meta-analysis of the effects of prostate radiotherapy was possible. We obtained prepublication, unpublished, and harmonised results from investigators. InterventionWe included trials that randomised men to prostate radiotherapy and androgen deprivation therapy (ADT) or ADT only. Outcome measurements and statistical analysisHazard ratios (HRs) for the effects of prostate radiotherapy on survival, progression-free survival (PFS), failure-free survival (FFS), biochemical progression, and subgroup interactions were combined using fixed-effect meta-analysis. Results and limitationsWe identified one ongoing (PEACE-1) and two completed (HORRAD and STAMPEDE) eligible trials. Pooled results of the latter (2126 men; 90% of those eligible) showed no overall improvement in survival (HR=0.92, 95% confidence interval [CI] 0.81–1.04, p=0.195) or PFS (HR=0.94, 95% CI 0.84–1.05, p=0.238) with prostate radiotherapy. There was an overall improvement in biochemical progression (HR=0.74, 95% CI 0.67–0.82, p=0.94×10−8) and FFS (HR=0.76, 95% CI 0.69–0.84, p=0.64×10−7), equivalent to ∼10% benefit at 3yr. The effect of prostate radiotherapy varied by metastatic burden—a pattern consistent across trials and outcome measures, including survival (<5, ≥5; interaction HR=1.47, 95% CI 1.11–1.94, p=0.007). There was 7% improvement in 3-yr survival in men with fewer than five bone metastases. ConclusionsProstate radiotherapy should be considered for men with mHSPC with a low metastatic burden. Patient summaryProstate cancer that has spread to other parts of the body (metastases) is usually treated with hormone therapy. In men with fewer than five bone metastases, addition of prostate radiotherapy helped them live longer and should be considered.

A comparative analysis of overall survival between high-dose-rate and low-dose-rate brachytherapy boosts for unfavorable-risk prostate cancer

PurposeExternal beam radiation therapy (EBRT) with low-dose-rate (LDR) brachytherapy boost has been associated with improved biochemical progression–free survival and overall survival (OS) compared with dose-escalated EBRT (DE-EBRT) alone for unfavorable-risk prostate cancer. However, it is not known whether high-dose-rate (HDR) boost provides a similar benefit. We compare HDR boost against LDR boost and DE-EBRT with respect to OS. MethodsUsing the National Cancer Database, we identified 122,896 patients who were diagnosed with National Comprehensive Cancer Network intermediate- or high-risk prostate cancer between 2004 and 2014 and treated with DE-EBRT (75.6–86.4 Gy), LDR boost, or HDR boost. We compared the OS among the three groups using multivariable Cox proportional hazards regression. Inverse probability treatment weighting was used to adjust for covariate imbalance. ResultsOn multivariable Cox proportional hazards regression, HDR boost was associated with a similar OS to LDR boost (adjusted hazard ratio [AHR] 1.03 [0.96, 1.11]; p = 0.38) but significantly better OS than DE-EBRT (AHR 1.36 [1.29, 1.44]; p < 0.001). Inverse probability treatment weighting analysis yielded similar results. There was no significant difference between LDR and HDR boosts for National Comprehensive Cancer Network intermediate-risk (AHR 1.05 [0.96, 1.15]; p = 0.32) and high-risk (AHR 1.00 [0.89, 1.12]; p = 0.98) subgroups (p-interaction = 0.55). ConclusionsOur results suggest that HDR brachytherapy boost yields similar OS benefits compared with LDR brachytherapy boost for unfavorable-risk prostate cancer. HDR boost may be a suitable alternative to LDR boost.

Randomized prospective phase III trial of 68Ga-PSMA-11 PET/CT molecular imaging for prostate cancer salvage radiotherapy planning [PSMA-SRT

BackgroundSalvage radiotherapy (SRT) for prostate cancer (PCa) recurrence after prostatectomy offers long-term biochemical control in about 50–60% of patients. SRT is commonly initiated in patients with serum PSA levels < 1 ng/mL, a threshold at which standard-of-care imaging is insensitive for detecting recurrence. As such, SRT target volumes are usually drawn in the absence of radiographically visible disease. 68Ga-PSMA-11 (PSMA) PET/CT molecular imaging is highly sensitive and may offer anatomic localization of PCa biochemical recurrence. However, it is unclear if incorporation of PSMA PET/CT imaging into the planning of SRT could improve its likelihood of success. The purpose of this trial is to evaluate the success rate of SRT for recurrence of PCa after prostatectomy with and without planning based on PSMA PET/CT.MethodsWe will randomize 193 patients to proceed with standard SRT (control arm 1, n = 90) or undergo a PSMA PET/CT scan (free of charge for patients) prior to SRT planning (investigational arm 2, n = 103). The primary endpoint is the success rate of SRT measured as biochemical progression-free survival (BPFS) after initiation of SRT. Biochemical progression is defined by PSA ≥ 0.2 ng/mL and rising. The randomization ratio of 1:1.13 is based on the assumption that approximately 13% of subjects randomized to Arm 2 will not be treated with SRT because of PSMA-positive extra-pelvic metastases. These patients will not be included in the primary endpoint analysis but will still be followed. The choice of treating the prostate bed alone vs prostate bed and pelvic lymph nodes, with or without androgen deprivation therapy (ADT), is selected by the treating radiation oncologist. The radiation oncologist may change the radiation plan depending on the findings of the PSMA PET/CT scan. Any other imaging is allowed for SRT planning in both arms if done per routine care. Patients will be followed until either one of the following conditions occur: 5 years after the date of initiation of randomization, biochemical progression, diagnosis of metastatic disease, initiation of any additional salvage therapy, death.DiscussionThis is the first randomized phase 3 prospective trial designed to determine whether PSMA PET/CT molecular imaging can improve outcomes in patients with PCa early BCR following radical prostatectomy.AcronymPSMA-SRT Phase 3 trial.Clinical trial registration■ IND#130649◦ Submission: 04.26.2016◦ Safe-to-proceed letter issued by FDA: 05.25.2016■ UCLA IRB #18–000484,■ First submission: 3.27.2018■ Date of approval: 5.31.2018■ UCLA JCCC Short Title NUC MED 18–000484■ NCI Trial Identifier NCI-2018-01518■ ClinicalTrials.gov Identifier NCT03582774■ First Submitted: 06.19.2018■ First Submitted that Met QC Criteria: 06.27.2018■ First Posted: 07.11.2018■ Last Update Submitted that Met QC Criteria: 07.17.2018■ Last Update Posted: 07.19.2018Trial statusCurrent Trial Status Active as of 08/13/2018Trial Start Date 09/01/2018-ActualPrimary Completion Date 09/01/2023-AnticipatedTrial Completion Date 09/01/2024-Anticipated

PITX2 methylation: a novel and effective biomarker for monitoring biochemical recurrence risk of prostate cancer.

Aims:Prostate cancer is one of the most common malignancies in men. Biochemical recurrence (BCR) and progression following curative treatment pose a significant public health challenge. Thus, it is essential to explore effective biomarkers for disease progression monitoring and risk stratification. The promoter region of the paired-like homeodomain transcription factor 2 (PITX2) gene has been found to be frequently methylated in prostate cancer. However, the prognostic role of PITX2 methylation in prostate cancer and which patients most likely to be recommended for PITX2 methylation tests to assess BCR risk remain controversial. Therefore, a systematic review was performed to explore the relationship of PITX2 methylation with the BCR risk of prostate cancer.Methods:The PubMed, EMBASE, and Cochrane Library databases were systematically searched for eligible studies. Seven studies with a total of 2185 patients were included. Pooled hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated.Results:The overall HR was 2.71 (95% CI, 2.21–3.31), suggesting that PITX2 methylation has an adverse impact on BCR of prostate cancer. The pooled estimate of 5-year BCR-free survival for patients with a high methylation status was significantly lower than that for patients with a low methylation status (71% vs 90%; odds ratio [OR] = 3.50; 95% CI, 2.67–4.60, P = .000). A subgroup analysis was conducted according to detection method; the combined HRs were 2.68 (95% CI, 2.02–3.55) for quantitative methylation-specific PCR (qMSP) and 3.29 (95% CI, 2.31–4.68) for microarray EpiChip. In subgroups defined by region, Gleason score, pathological stage, surgical margin status and ethnicity, high methylation status was also associated with BCR of prostate cancer.Conclusions:As an effective biomarker, PITX2 methylation is feasible for individualized BCR risk assessment of prostate cancer following radical prostatectomy.

Impact of Clinical Versus Biochemical Progression on Post-Progression Survival in Multiple Myeloma

Background: Overall response rate and response duration in newly diagnosed multiple myeloma (ndMM) has increased in the last decade. However, majority of patients eventually progress and receive multiple lines of therapy. Progression in MM is defined by rise in monoclonal protein and/or clinical manifestations of end-organ damage. However, there is a lack of evidence on the prognostic implication of pattern of progression in the current era. We have hypothesized that patients with clinical manifestations of end-organ damage at first progression have an inferior post-progression overall survival (OS) compared to those with biochemical progression alone.Method: We evaluated all ndMM patients between 1/1/2008 and 12/31/2015 at the Cleveland Clinic. Key inclusion criterion was patients experiencing first progression requiring an additional line of therapy. Patients with primary refractory disease and those in continued 1st remission at latest follow-up were excluded. Progression was categorized into 2 groups: Biochemical Progression (BP) and Clinical Progression (CP; implying CRAB features). Patients with CP were further stratified based on the presence of extramedullary disease (EM): CP+EM and CP-EM. Progression-free survival (PFS) and OS from first progression were estimated with Kaplan-Meier curves and compared among groups with log-rank test. Cox analysis was used to identify prognostic factors for OS and PFS. Potential prognostic factors included progression pattern, age, gender, race, ISS stage at diagnosis, FISH cytogenetics at diagnosis, metaphase cytogenetics at diagnosis, time from diagnosis to first progression, best response at first remission, frontline autologous stem cell transplant (ASCT), and whether progression occurred while on therapy.Results: A total of 527 patients with ndMM were evaluated, among which, 257 experiencing 1st progression were included in our analysis. The median age at progression was 64 years. The median time from diagnosis to first progression was 23 months. An autologous stem cell transplantation (ASCT) after induction therapy in 1st remission was performed in 26% of patients. At 1st progression, BP alone was noted in 52% (n=134), CP -EM in 34% (n=87) and CP+EM in 14% (n=36) of patients. In the CP-EM group, the most common mode of progression was development of new bone lesions (76%) followed by anemia (33%), renal insufficiency (18%) and hypercalcemia (13%), with ≥1 mode in approximately one-third of patients. In the CP+EM group, the most common mode of EM progression was development of new plasmacytomas (89%), followed by emergence of circulating plasma cells (14%), with 1 patient having both. A total of 84% of patients progressed on anti-myeloma therapy, which reflects the contemporary practice of continuous therapy in MM. After first progression, 68% received proteasome inhibitors (PIs), 64% received immunomodulatory drugs (IMiDs) and 11% received monoclonal antibodies (MoAbs). Salvage ASCT in 2nd remission was performed in 12% of patients.A total of 105 patients (41%) were alive at latest follow-up, with the median follow-up of survivors being 26 months from 1st progression. Median time from diagnosis to 1st progression was shorter in the CP+EM (12 months) compared to CP-EM (25 months) and BP (24 months) groups (P<0.001). There was no significant difference in the progression pattern by depth of 1st remission. The 2-year post-progression OS in BP, CP-EM and CP+EM groups was 81%, 40% and 12% respectively (P<0.001; Figure I). The 2-year post-progression PFS in the respective groups were 35%, 8% and 7% respectively (P<0.001). On multivariable analysis for OS, independent prognostic factors included progression pattern, age at 1st progression and high-risk FISH cytogenetics at diagnosis (Table I).Conclusion: In the era of PIs, IMiDs and MoAbs, the pattern of 1st progression in MM has a strong and independent prognostic impact on post-progression OS. Patients progressing with clinical manifestations of end-organ damage or extramedullary disease have an inferior PFS and OS compared to those progressing with biochemical criteria alone. These results should be further validated in large prospective studies with data on FISH cytogenetics at relapse. It has clinical implication at the individual level and can also inform the design of clinical trials in relapsed MM. [Display omitted] DisclosuresMajhail:Anthem, Inc.: Consultancy; Incyte: Honoraria; Atara: Honoraria.