Undetectable PSA Research Articles

A phase Ib/II trial of perioperative intratumoral MVA-BN-brachyury (MVA) plus systemic PROSTVAC and atezolizumab (Atezo) for intermediate-risk and high-risk localized prostate cancer (AtezoVax).

TPS382 Background: Many patients with intermediate or high-risk localized prostate cancer relapse after prostatectomy, identifying an unmet need. Cancer vaccines increase the infiltrating lymphocyte concentration in localized and metastatic prostate cancer (PMID 25255802, 29858218). We hypothesize that treatment with a combination of two vaccines plus PD-L1 inhibition will be safe and significantly stimulate immune infiltration within the tumor microenvironment. MVA is a modified vaccinia virus that is replication-deficient, inducing the generation of tumor antigen-specific killer T-cells. PROSTVAC is a poxviral based cancer vaccine using a vaccinia virus prime and fowlpox based boost along with co-stimulatory molecules B7.1, leukocyte function-associated antigen-3, and intercellular adhesion molecule-1. Methods: This study is a single-arm,, phase I/II investigator initiated trial (NCT04020094). Primary objectives: 1) Safety, 2) Quantitative change in infiltrating CD8+ lymphocytes between the biopsy and prostatectomy as measured by immunofluorescence. Secondary endpoints: 1) 6- and 12-month undetectable PSA rate; 2) PSA-PFS compared to institutional historic control. Inclusion criteria: unfavorable intermediate to very high-risk prostate adenocarcinoma (per NCCN). Exclusion criteria: non-adenocarcinoma histology and metastatic disease (including regional nodal metastasis). A total of 22 patients will be enrolled starting with a 6 patient safety lead in. Prostate MRI will be obtained prior to treatment. Treatment schema: 2 neoadjuvant cycles (Atezo + MVA + PROSTVAC), followed by prostatectomy then 6 additional adjuvant cycles (Atezo + PROSTVAC). Neoadjuvant cycle 1: atezolizumab (1200mg IV Q3wks), PROSTVAC-V (Prime, 2x108 Inf.U subcutaneous), MVA (2 x 108 Inf.U/0.5 ml, intra-tumoral injection, volume determined by MRI). Neoadjuvant cycle 2: atezolizumab, PROSTVAC-F (Boost, 1x109 Inf.U, subcutaneous), MVA. Adjuvant: atezolizumab and PROSTVAC-F. Clinical trial information: NCT04020094.

Undetectable PSA after radical prostatectomy is more likely in low burden N+ prostate cancer patients when an extended lymph node dissection is performed

ObjectivesTo analyze the likelihood of undetectable PSA (<0.01 ng/mL) after extended (ePLND) versus standard pelvic lymph-nodes dissection (sPLND) in pN+ patients. Materials and MethodsThe institutional prospectively maintained Prostate Cancer Database was queried for patients who underwent radical prostatectomy with PLND and were found with three or less lymph-nodal metastases between 2007 and 2017. The extension of the PLND was defined according to the number of lymph-nodes (LN) removed. Patients in the 75th or higher percentile of lymph-nodes removed were considered as the ePLND group; patients in the 25th or lower percentile in the sPLND group. Groups were compared in clinical and pathological variables. Student t-test was used for comparing continuous variables; chi-square test was used for categorical variables. Multivariable logistic regression assessed the probability of undetectable PSA at 3rd month postoperatively. Kaplan–Meier method estimated the probability of biochemical recurrence. Differences between the groups were compared by Log-rank test. Results1478 patients were treated within the time span considered. 95 with 1–3 lymph-nodal metastases were extracted. After accounting for inclusion criteria, 23 patients with a median of 11 L N removed were included in the sPLND group (25th percentile); 23 patients with >27 L N were included in ePLND group (75th percentile). Surgical time was longer for ePLND. Sixteen patients (69.6%) who underwent ePLND had undetectable PSA postoperatively. At multivariable analysis, the probability of undetectable PSA at 3rd month was higher in patients who received an ePLND (HR = 5.18; IC95% = 1.16–23.11; p = 0.03). ConclusionsePLND is more likely to predict undetectable PSA at third month after radical prostatectomy, irrespective of disease characteristics.

Frecuencia de PSA indetectable en pacientes con cáncer de próstata N+ baja carga tras prostatectomía radical y linfadenectomía ampliada

ObjectivesTo analyze the likelihood of undetectable PSA (< 0.01 ng/mL) after extended (ePLND) versus standard pelvic lymph-nodes dissection (sPLND) in pN+ patients. Materials and methodsThe institutional prospectively maintained Prostate Cancer Database was queried for patients who underwent radical prostatectomy with PLND and were found with 3or less lymph-nodal metastases between 2007 and 2017. The extension of the PLND was defined according to the number of lymph-nodes (LN) removed. Patients in the 75th or higher percentile of lymph-nodes removed were considered as the ePLND group; patients in the 25th or lower percentile in the sPLND group. Groups were compared in clinical and pathological variables. Student T-test was used for comparing continuous variables; chi-square test was used for categorical variables. Multivariable logistic regression assessed the probability of undetectable PSA at 3rd month postoperatively. Kaplan-Meier method estimated the probability of biochemical recurrence. Differences between the groups were compared by Log-rank test. Results1478 patients were treated within the time span considered. 95 with 1 to 3 lymph-nodal metastases were extracted. After accounting for inclusion criteria, 23 patients with a median of 11 LN removed were included in the sPLND group (25th percentile); 23 patients with > 27 LN were included in ePLND group (75th percentile). Surgical time was longer for ePLND. Sixteen patients (69.6%) who underwent ePLND had undetectable PSA postoperatively. At multivariable analysis, the probability of undetectable PSA at 3rd month was higher in patients who received an ePLND (HR=5.18; IC 95%=1.16–23.11; P=.03). ConclusionsePLND is more likely to predict undetectable PSA at third month after radical prostatectomy, irrespective of disease characteristics.

Baseline genomic and circulating tumor cell (CTC) correlative data from very high-risk (VHR), localized, node-negative prostate cancer patients.

e16563 Background: Few data exist on CTC frequency and number, genetic landscape, and tumor mutational burden (TMB) in VHR, node negative, localized prostate cancer (PCa). Methods: We are conducting a single-arm phase 2 trial of ultra-hypofractionated radiation (RT) with 6 months of abiraterone, apalutamide and leuprolide in VHR PCa, defined as: Gleason (Gl) 9-10 or 2 high risk features (including radiographic (r) T3/T4 disease) or &gt; 4 cores of Gl8. We report baseline correlatives in the first 38 screened patients (pts). CTCs were isolated using a non-selection based platform (EPIC Sciences). Additional analyses were conducted using MSK IMPACT, a next generation sequencing assay. Results: Median PSA was 14.8 ng/mL (IQR, 7.7-28.1); Gl7 was present in 5% (n = 2), Gl8 in 32% (n = 12), Gl9 in 61% (n = 23) and Gl10 in 2% (n = 1) of pts; on MR, 42% of pts were rT2 (n = 16), 39% had rT3a disease (n = 15) and 18% had rT3b disease (n = 7). CTC data were available on 31 pts; 74% (n = 23) had ≥1 detectable CTC (range, 0.8-14.6 cells per mL); 29% (n = 9) had CK+ clusters (range, 0.8-7.1 clusters per mL). IMPACT was available for 20 pts: KMT2D/C mutations were present in 25% (n = 4), TP53 missense mutations in 20% (n = 4), FOXA1 mutations in 20% (n = 4), PTEN truncating or missense mutations in 15% (n = 3), SPOP missense mutations in 15% (n = 3), PIK3CA activating mutations in 15% (n = 3), APC deletions in 15% (n = 3); 85% (17/20) had alterations in one of these genes. No clinically significant germline mutations were present. Median TMB was 2.63 mutations/mB (range, 0.87-60.56); the TMB-highest pt had an in-frame deletion in MSH2. Among IMPACTed pts with normalized testosterone post-protocol treatment (n = 16), there was a trend towards an association with SPOP/FOXA1 mutations and undetectable ( &lt; 0.05 ng/mL) PSA; 5/6 pts with mutations had undetectable PSA (83.3%) vs 3/10 without (30%) (p = 0.12). The trial is managed by the PCCTC and funded by Janssen. Conclusions: The genetic profile and TMB of VHR, localized PCa resembles non-castrate, metastatic disease. The frequency of detectable CTCs is high with implications for post-treatment surveillance. SPOP/FOXA1 mutations may predict initial response to RT with total androgen blockade. Clinical trial information: NCT02772588.

Randomized phase II trial of presurgical androgen deprivation therapy (ADT) with or without axitinib in prostate cancer (PCa) presenting with lymph node (LN) metastasis.

5078 Background: Strategies integrating androgen targeted and locoregional therapies are being increasingly used in PCa with regional spread, but are rarely curative. Angiogenesis inhibitors delay progression in castration resistant PCa and may synergize with ADT through endothelial cell apoptosis in hormone naïve patients (pts). We hypothesized that the frontline combination of ADT with the potent VEGF inhibitor Axi would improve PCa control relative to ADT alone and allow for meaningful time off systemic therapy after surgical consolidation. Methods: Pts with either clinically detected LN+ (TxN1M0 or TxNxM1a) or very high risk for LN PCa were treated with ADT for 2 mos and then randomized 2:1 to respectively add open label Axi (5 mg PO bid) vs. continue ADT alone for 4 mos until surgery. Those responding with PSA ≤5 ng/mL were offered prostatectomy and extended pelvic lymphadenectomy (RP). ADT +/- Axi was withheld postoperatively and PSA measured q3 mos until 1 y. Primary objective: proportion of pts progression free (FFP) 12 mos after RP, defined as PSA ≤1.0 ng/mL and no radiation or ADT, aiming to detect a 35% difference favoring ADT+Axi. Results: 72 pts completed accrual. We report on the 54 pts with LN+ disease: median age 62 y (range 42-76), pretreatment PSA 22.9 ng/mL (range 3.6 - 404.4), 38 N1 / 16 M1a. Table shows presurgical therapy outcomes. Path responses in the prostate were similar between arms, but in 5 ADT+Axi vs. 0 ADT LN+ pts there was no residual nodal disease. Testosterone recovery: 24/26 ADT+Axi and 9/9 ADT RP pts by 6 mos. 21/36 ADT+Axi and 15/18 ADT pts have failed; 1 y FFP estimates 48.0% (SE 8.6%) and 16.7% (SE 8.3%), respectively (p = 0.02). 1 y undetectable PSA 9 pts (6 ADT+Axi). No grade 4 toxicities or unexpected side-effects were observed. Conclusions: 1 year after RP, ADT+Axi resulted in proportionally greater number of LN+ PCa pts off treatment and progression free than ADT alone. Tissue analysis is evaluating predictors of benefit to further develop angiogenesis inhibition as part of combination strategies for hormone naïve PCa. Clinical trial information: NCT01409200. [Table: see text]

Correlation between innate cytokine levels and progression in men with biochemically recurrent prostate cancer treated with intermittent hormonal therapy.

e16554 Background: Suppressive cytokines have the potential to drive prostate cancer progression with consequent decreased survival. Assessing longitudinal cytokine changes may shed light on mechanisms of disease progression, resistance to therapy, and suggest new therapeutic targets. Methods: Thirty-seven men with biochemically recurrent (BCR) prostate cancer who received 6 months of androgen deprivation therapy (ADT) and were monitored until the time of PSA progression (TTPP) were identified from a previously conducted phase III trial (NCT00020085). Serum samples were archived at baseline, three months after administration of ADT, and at TTPP. Cytokine concentrations were quantified using a 36-parameter electrochemiluminescence assay (MesoScale Discovery). Wilcoxon signed rank sum test was used to compare paired observations between time points. Kaplan-Meier analysis was used to calculate progression function (TTPP) dichotomized by above or below the median value of cytokines with Bonferroni adjustment. Pearson’s rank correlation coefficient was used to compare continuous variables. Results: Median TTPP was 399 days (range, 114 - 1641). Median PSA at baseline and progression were 8.5 ng/ml, (range, 1.0 - 76.6) and 5.3 ng/mL (range, 1.2 - 19.4), respectively. Twenty-three patients (62%) achieved undetectable PSA with ADT. TNF-α (P = 0.002), IL-23 (P = 0.002), and IP-10 (P = 0.001) significantly increased from baseline to post ADT. Patients with a detectable PSA after ADT had moderately elevated levels of IL-6 (P = 0.049) and IL-8 (P = 0.013) at PSA progression as compared to those with an undetectable PSA. There was a trend toward shorter TTPP in patients with TNF-α levels above the median (P = 0.042). TNF-α was strongly correlated with IL-23 (r = 0.72, P &lt; 0.001) and IL-8 (r = 0.59, P &lt; 0.001) from baseline to after ADT and to PSA progression. NLR correlated strongly with IL-27 (r = 0.57, P &lt; 0.001) and MIP-3α (r = 0.56, P &lt; 0.001). Conclusions: Cytokines associated with the innate immune response were associated with an unfavorable clinical outcome in early prostate cancer. These data suggest cytokine blockade combined with ADT may warrant future investigation.

Immunomodulation by HDAC inhibition: Results from a phase Ib study with vorinostat and pembrolizumab in metastatic urothelial, renal, and prostate carcinoma patients.

2572 Background: Immunosuppressive factors such as regulatory T cells (Tregs) and myeloid-derived suppressive cells (MDSCs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been shown to have immunomodulatory effects. We have previously reported that HDAC inhibitors have synergistic antitumor effects in combination with PD-1 inhibition in tumor models by inhibiting the function of Tregs and MDSCs. Thus, we conducted a Phase Ib clinical study with the HDAC inhibitor vorinostat and the PD-1 inhibitor pembrolizumab in patients (pts) with metastatic urothelial, renal and prostate carcinoma. Methods: The primary objective was to evaluate the safety and tolerability of this combination strategy. The phase I portion consisted of two dose levels of vorinostat (100 and 200 mg, PO daily 2 weeks ON and one week OFF) and a fixed, standard dose of pembrolizumab (200 mg IV every 21 days). Patients were assigned to three cohorts: Cohort A (previously treated, anti-PD1/PD-L1 naïve urothelial and renal cancer pts = 15), Cohort B (previously treated, anti-PD1/PD-L1 resistant urothelial and renal cancer pts = 14), and Cohort C (prostate cancer pts = 14). Results: Dose levels 1 (4 enrolled, 3 evaluable) and 2 (4 enrolled, 3 evaluable) were completed without DLTs and 200 mg was the Phase II recommended dose for vorinostat. The most common resolved grade 3/4 toxicities were acute kidney injury (n = 1), anemia (n = 1), diarrhea (n = 1), and hypothyroidism (n = 1) in the dose expansion cohorts. We have enrolled 43 pts (37 evaluable) in the dose expansion cohorts. For Cohort A, B, and C the median PFS were 2.8 months, 5.2 months, and 3.5 months. Two PR were observed including the dose escalation phase. Two PCA pts have achieved undetectable PSA. We have performed several correlative studies including flow cytometry and gene expression analysis on peripheral blood mononuclear cells, PDL-1 staining and PSMA PET scans in a subset of pts. Conclusions: The results from this phase Ib suggest that the combination of vorinostat and pembrolizumab is relatively well tolerated and may be active in a subset of immune checkpoint resistant UC/RCC pts and immune checkpoint naïve PCA pts. Clinical trial information: NCT02619253.

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.

Preliminary results of a two stage phase II study of 18F-DCFPyL PET-MR for enabling oligometastases ablative therapy in subclinical prostate cancer.

250 Background: Despite maximal local therapies (MLT) (radical prostatectomy followed by radiotherapy [RT]), 20-30% of men will have incurable progression of prostate cancer (PC). Most recurrences in this scenario are characterized by continuous PSA rises and failure of standard imaging (bone scan [BS] and computed tomography [CT]) to detect recurrence sites. We conducted a phase II trial for men with rising PSA after MLT using 18F-DCFPyL PET-MR followed by targeted ablation of PET positive foci. We report the results of our pre-defined analysis. Methods: Patients with rising PSA (0.43.0 ng/mL) after MLT, negative BS/CT and no prior salvage ADT were eligible. All patients underwent 18F-DCFPyL PET-MR followed by immediate PET-CT acquisition. Those with limited disease, where possible, underwent stereotactic ablative RT (SABR) or surgery. No ADT was used. The primary endpoint was biochemical response rate (complete [undetectable PSA] or partial [PSA decline ≥50% compared to baseline]). A Simon’s two stage study design was employed. Stage 1 included 12 response evaluable patients, requiring 1 or more responses in the absence of grade 3+ toxicities to proceed to stage 2 (additional 25 response evaluable patients). Results: After a median of 58 months (range 29-120) post MLT, 20 patients underwent PET-MR/CT to have 12 response evaluable patients. Median PSA at enrollment was 1.3 ng/mL (range 0.4-2.8). Three patients had negative PET-MR/CT, while 17 had positive scans, of which 12 (60%) were amenable to response evaluable ablation. The median number of detected lesions in those treated was 2 (range 1-5). Ten patients underwent SABR (27-30 Gy/3 fractions) and 2 had surgery. One patient (8%) had complete and 4 (33%) had partial PSA responses at a median of 3.3 months (range 2.8-6.0) after ablation, while the remaining 7 (59%) did not have biochemical response. No grade 3+ toxicities were observed. Conclusions: 18F-DCFPyL PET/MR has high detection rates in men with rising PSA after MLT. We observed favorable early results with SABR or surgery (41% RR). Trial completion will inform if this approach offers potential for cure in an early molecularly-defined PC oligometastatic state. Clinical trial information: NCT03160794.

Time to PSA nadir and the risk of death from prostate cancer following radiation and androgen deprivation therapy.

4 Background: Whether the time to PSA nadir (TTN) has differential prognostic value in men who reach an undetectable versus detectable PSA nadir remains unknown. Methods: Two-hundred and four men from a prospective randomized controlled trial (RCT) involving radiation therapy with or without 6 months of androgen deprivation therapy (ADT) in unfavorable risk CaP at academic or community based centers in Massachusetts, enrolled between 1995 and 2001. Adjusted hazard ratios (AHR) of the risk of CaP-specific mortality (PCSM) calculated using Fine and Gray competing risk regression. Results: After a median follow-up of 18.17 years, 160 men died; 30 (18.75%) of CaP. Amongst men with a PSA nadir ≥ 0.2 ng/ml, a TTN &lt; median (12 months) was significantly associated with an increased PCSM-risk versus the median or more (AHR 5.07, 95% CI 2.10-12.23, p&lt;0.001); whereas this association was not observed among men with a PSA nadir of &lt;0.2 ng/ml, (AHR 9.9, 95% CI 0.23-433.8, p=0.23). Conclusions: Men with both a short TTN and detectable PSA nadir could be considered for entry on RCTs at a novel entry point prior to PSA failure at the time of PSA nadir to complete planned conventional ADT versus that plus agent(s) shown to improve outcomes in men with or at high risk of having castrate-resistant CaP.

Management of isolated local failures following stereotactic body radiation therapy for low to intermediate risk prostate cancer.

66 Background: SBRT is a safe and effective treatment option for patients with low to intermediate risk prostate cancer (PCa). SBRT delivers high biologically effective doses resulting in very low PSA nadirs. Strategies to diagnose and confirm salvageable isolated local failures (ILF) are needed. This study aims to examine the incidence and approach to management of ILF after SBRT in a large single institution cohort. Methods: All patients with low or intermediate risk PCa treated with SBRT at our institution were eligible for this study. Treatment was delivered using the robotic SBRT with doses of 35-36.25 Gy in five fractions. ILF were diagnosed using mpMRI and/or biopsy prompted by PSA rise after achieving long-term nadir. Choice of salvage therapy and post-salvage PSA were ascertained on follow up. Results: Between December, 2008 to August, 2018, 998 men with low to intermediate risk prostate cancer were eligible for analysis. Twenty patients (low risk, n = 4; intermediate risk, n = 16) were found to have ILF on either MRI (n = 15) and/or biopsy (n = 17). Three patients with MRI-identified ILF elected active surveillance in lieu of biopsy. Median pre-treatment PSA was 7.5 ng/ml. Median time to diagnosis of ILF was 72 months (37-96 months) with median PSA at the time of ILF of 2.3 ng/ml (1.1-10 ng/ml). Median PSA doubling time was 17 months (5-22 months). Thirteen patients with biopsy proven ILF proceeded with salvage therapy (cryotherapy n = 12, HIFU n = 1). Of 12 patients who underwent cryotherapy, 8 had a post-treatment PSA of &lt; 0.1ng/ml, two patient’s results were unavailable, one patient had a PSA nadir of 0.7 ng/ml and one patient had yet to undergo post-salvage PSA test at the time of this report. Conclusions: The incidence of ILF is rare in our series. Diagnosis and management of ILF post-SBRT continues to evolve in the era of successful salvage therapy. Our report suggests an important role for early utilization of MRI and confirmatory biopsy at relatively low PSA levels and long PSA doubling time. Additionally, undetectable PSA post-salvage therapy supports early treatment after identifying ILF. Larger trials are needed for refinement of patient selection and most appropriate salvage modality.

Effect of early salvage radiotherapy at PSA < 0.5 ng/ml and impact of post-SRT PSA nadir in post-prostatectomy recurrent prostate cancer.

For patients with recurrent prostate cancer after radical prostatectomy (RP), salvage radiotherapy (SRT) offers a second chance of cure. European guidelines (EAU) recommend SRT at a PSA < 0.5 ng/ml. We analyze the efficacy of SRT given according to this recommendation and investigate the predictive power of the post-SRT PSA nadir. Between 1998 and 2013, 301 patients of two university hospitals received SRT at a PSA < 0.5 ng/ml (median 0.192 ng/ml, IQR 0.110-0.300). Patients, who previously received androgen deprivation therapy, were excluded. All patients had 3D-conformal RT or intensity-modulated radiotherapy (IMRT, n = 59) (median 66.6 Gy). The median follow-up was 5.9 years. Progression and overall survival were the endpoints. After SRT, 252 patients re-achieved an undetectable PSA. In univariate analysis, pre-RP PSA ≥ 10 ng/ml, pT3-4, Gleason score (GS) 7-10 or 8-10, negative surgical margins, post-RP PSA ≥ 0.1 ng/ml, pre-SRT PSA ≥ 0.2 ng/ml and post-SRT PSA nadir ≥ 0.1 ng/ml correlated unfavorably with post-SRT progression. In a multivariable Cox model, pT3-4, GS 7-10, negative margins and a pre-SRT PSA ≥ 0.2 ng/ml were significant risk factors. If the post-SRT PSA was added to the analysis, it dominated the outcome (HR = 9.00). Of the patients with a pre-SRT PSA < 0.2 ng/ml, only 9% failed re-achieving an undetectable PSA. Overall survival in these patients was 98% after 5.9 years compared to 91% in patients with higher pre-SRT PSA (Logrank p = 0.004). SRT at a PSA < 0.2 ng/ml correlates significantly with achieving a post-SRT undetectable PSA (<0.1 ng/ml) and subsequently with improved freedom from progression. Given these overall favorable outcomes, whether additional androgen deprivation therapy is required for these men requires further study.

Late biochemical recurrence after radical prostatectomy is associated with a slower rate of progression.

To characterise the pattern of late biochemical recurrence (BCR) in the largest contemporary cohort of patients with localised prostate cancer treated with radical prostatectomy (RP) in the active surveillance era. Consecutive patients who underwent RP for localised prostate cancer between 2003 and 2017 were identified from a prospectively recorded, dedicated prostate cancer database. Patients who received neoadjuvant androgen-deprivation therapy were excluded. These patients were categorised into the following groups: no BCR, BCR at <12months (early), BCR at 12-60months (intermediate), and BCR at >60months (late), after RP. Clinicopathological characteristics were analysed using the Student's t-test, Mann-Whitney U-test, or chi-squared test where appropriate. Multivariable binomial logistic regression models were used to assess predictors of BCR at various time-points. In all, 2312 patients were included in the final analysis with up to 12years of follow-up data. The average patient had clinically localised prostate cancer, an elevated PSA level, and International Society of Urological Pathology (ISUP) Grade Group 2 on biopsy. In all, 88.7% of patients had ISUP Grade Group ≥2 at RP. A subgroup of 446 patients had undetectable PSA levels at 5years after RP; 11.7% of them progressed to experience BCR. In this subgroup, late recurrers had significantly higher-grade tumours on ISUP and Gleason sum (P <0.001 and P = 0.001, respectively), higher rates of extraprostatic extension (P = 0.022), and larger tumour volumes (P = 0.032). Logistic regression showed that RP ISUP Grade Group was a significant predictor of BCR (odds ratio 2.14, 95% confidence interval 1.43-3.20; P <0.001). This study characterises the pattern of late BCR in the largest contemporary active surveillance era cohort. We have identified that RP ISUP Grade Group is a strong predictive indicator for late BCR. We also propose that timing of BCR resides on a continuum of risk and that the potential concept of dormant micrometastatic involvement requires further research and evaluation.

Radiotherapy of prostate cancer in renal transplant recipients: single-center experience.

This study analyzed the long-term outcomes of localized prostate cancer in renal transplant recipients after radiotherapy treatment - mainly brachytherapy. We retrospectively analyzed clinical data of renal transplant recipients between 2003 and 2016 at a single tertiary center, and identified four patients with high serum PSA level during regular follow-up, 1-108 months after primary renal transplantation. The mean age of patients with detected high serum PSA level with 9.25µg/l median was 59.05 years. All four patients had functioning grafts. To prove prostate cancer, they underwent trans-rectal prostate biopsy, with no complications. Histological evaluation identified prostate adenocarcinoma (Gleason 6-7, stage T1-2cN0M0) in three patients. The biopsy in the fourth patient was negative and he therefore had trans-urethral prostate resection. Histological evaluation of resected prostate tissue revealed prostate adenocarcinoma (Gleason 7, 4+3). All patients began treatment with androgen deprivation therapy. Three patients were indicated for permanent prostate brachytherapy (BT) with iodine-125 (125I) seeds and the trans-urethral resection patient was referred for external beam radiotherapy (EBRT). After a mean follow-up of 49 months (range, 30-73), all patients, irrespective of type of radiotherapy, were in complete clinical and biochemical remission, with undetectable PSA levels. The kidney grafts remained functional, with a mean creatinine level of 99 µmol/l (range 64-123) and a glomerular filtration rate of 1.17 ml/s/1.73 m2 (range, 0.89-1.59). Radiation-induced late adverse effects were reported in two BT patients; one had clinically significant urine incontinency and the other suffered urethral stricture. Localized prostate tumor was identified in all reported patients, and all received radiotherapy plus androgen deprivation. All patients were disease-free at the time of the last follow-up. Therefore, combined BT and twelve months androgen deprivation appears both safe and effective for patients with prostate cancer after kidney transplantation.

Abstract 3269: Metformin to prevent metabolic syndrome associated with androgen deprivation therapy (ADT): Metabolic analysis from a placebo-controlled study of metformin in non-diabetic men initiating ADT for advanced prostate cancer (PCa)

Abstract Background: ADT results in metabolic syndrome, characterized by hyperinsulinemia, insulin resistance and obesity. The hyperinsulinemia may result in ADT resistance; therefore preventing metabolic syndrome could have a therapeutic impact on PCa. Metformin decreases glucose &amp; insulin by inhibiting hepatic gluconeogenesis. There is preclinical evidence for additional antineoplastic activity due to mTOR inhibition secondary to AMPK activation. Methods: We analyzed serum and PBMC from a recently completed clinical study of men with advanced PCa on ADT that were randomized 1:1 to metformin at 500mg TID or color matched placebo. Subjects serum insulin/glucose, metformin levels, weight and waist circumference (WC) was assessed at baseline, week 12 and 28. The primary endpoint of study was the metabolic consequences of metformin vs placebo cohort. Secondary endpoints were PSA response and PBMC analysis of downstream target of mTOR, phospho-S6 kinase. Results: There were 36 evaluable men. The mean age on study was 68.4. Mean weight, WC and insulin at baseline in metformin cohort was 187 lbs, 41.14 cm and 10.03 mIU/L respectively, and 177.65 lbs, 40.52 cm and 8.02 mIU/L in placebo cohort. An increase in mean weight, WC and insulin levels was seen in both cohorts. At week 12 and 28, no statistical difference in weight, WC and insulin was observe in either cohort. Four men randomized to metformin had undetectable serum drug levels despite drug-diary suggesting compliance; excluding them did not result in significant metabolic change. Assessing efficacy, 50% in metformin and 53.3% in placebo cohort achieved undetectable PSA at week 28; difference not statistically significant. PBMC analysis demonstrated variable down-regulation of phospho-S6 kinase in the metformin cohort. Conclusion: This study detected no impact of MET addition to ADT on the risk of metabolic syndrome and no additional anti-tumor effects. Control of hyperinsulinemia related to diabetes by MET does not necessarily imply MET has a similar action on hyperinsulinemia due to ADT. Citation Format: Devalingam Mahalingam, Salih Hanni, Christos Fountzilas, Joel Michalek, John Sarantopoulos, Sureshkumar Mulampurath Achuthan Pillai, John Kuhn, Michael Pollak, Ian Thompson. Metformin to prevent metabolic syndrome associated with androgen deprivation therapy (ADT): Metabolic analysis from a placebo-controlled study of metformin in non-diabetic men initiating ADT for advanced prostate cancer (PCa) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3269.

55 - The effect of lymphadenectomy extent on early postoperative undetectable PSA rate among prostate cancer pT3b R0 patients at West-Tallinn Central Hospital

55 - The effect of lymphadenectomy extent on early postoperative undetectable PSA rate among prostate cancer pT3b R0 patients at West-Tallinn Central Hospital

Treatment selection for men with metastatic prostate cancer who progress on upfront chemo-hormonal therapy.

Androgen deprivation therapy plus docetaxel (D-ADT) increases overall survival (OS) in men with high-volume, metastatic hormone-sensitive prostate cancer (mHSPC). Although the vast majority of men initially respond to D-ADT, most will progress and develop castration-resistant prostate cancer (CRPC). Little is known about the optimal treatment sequence for men with progressive disease on D-ADT. Retrospective analysis of consecutive mHSPC patients treated with ≥3 cycles of D-ADT at Cleveland Clinic and University of Wisconsin-Madison was undertaken. The primary end-points included radiographic progression free survival (rPFS) and OS with first-line treatment for metastatic CRPC (mCRPC). Final analysis included 136 patients, median age 65 (range 35-86), 77% GS ≥ 8, and 79% with high-volume disease who received ≥3 cycles of docetaxel. Undetectable PSA values at 12 and 24 months were observed in 32% and 25% of patients, respectively. Median time to CRPC (biochemical, clinical, or radiographic) was 19.6 months (16.6-22.6). Sixty patients (44%) received ≥1 treatment for CRPC: 48 patients (80%) received a second-generation hormonal therapy (sHT). Among these, 22 received abiraterone acetate, 20 enzalutamide, and six a novel CYP-17 inhibitor on trial (ASN-001). Five patients (8%) received sipuleucel-T; four (7%) radium-223, five (8%) chemotherapy (two carboplatin-based, two single agent cabazitaxel, one single agent docetaxel) and three other. Patients receiving sHT as the first treatment for mCRPC had a median rPFS of 9.0 months (95%CI, 6.9-11.2) compared with 3.0 months (95%CI, 1.5-4.5) for patients who received a non-sHT (P = 0.024). The choice of first therapy for mCRPC was independent of GS (P = 0.909), visceral disease (P = 0.690) and time to CRPC (P = 0.844). Longer OS correlated with time to CRPC (P = 0.010) and first treatment for CRPC with sHT (P = 0.005). For patients with progressive disease on D-ADT, subsequent treatment with a sHT is associated with a longer rPFS and OS.

Association of undetectable PSA with time to metastasis and survival after short-course androgen deprivation therapy for biochemically-recurrent prostate cancer patients.

e17073Background: Optimal utilization of novel therapies for advanced prostate cancer is challenging without a validated surrogate efficacy endpoint. Durable undetectable prostate-specific antigen ...

Who benefits most from early salvage radiation therapy after prostatectomy?

We are grateful for the opportunity to provide commentary on the recent work by Fossati et al ., entitled “Impact of Early Salvage Radiation Therapy in Patients with Persistently Elevated or Rising Prostate-specific Antigen After Radical Prostatectomy” (1). The optimal post-operative management of patients with prostate cancer who undergo radical prostatectomy (RP) is unclear. In general, there are two strategies for approaching radiotherapy. Adjuvant radiation therapy (ART) typically refers to post-operative radiation in the setting of high risk pathologic features but with an undetectable post-prostatectomy PSA, where the presence of residual prostate cancer is suspected but unknown. In this setting, radiation is typically delivered within a few months of surgery once there has been adequate recovery of urinary function. In contrast, salvage radiation therapy (SRT) refers to post-operative radiation in the setting of a rising or persistently detectable PSA, indicative of active prostate cancer and may be delivered several years after the initial RP (2). However, it is important to note that these definitions lack consensus.

Can post-operative prostate fossa radiation be omitted in patients with high-risk features using a genomic classifier?

101 Background: At our institution, based upon the AUA/ASTRO guidelines, discussion of adjuvant radiation therapy (ART) for patients with adverse pathologic features (APF) (pT3/positive margins) occurs in a multidisciplinary setting. We had previously offered ART to approximately 50% of these patients. We describe our evaluation of Decipher genomic testing to select patients to offer observation following prostatectomy (RP). Methods: Since March 2014, patients at Thomas Jefferson University with APF and undetectable post-operative PSA underwent Decipher genomic testing. Collectively, we decided to offer observation with salvage radiation therapy (SRT) for patients with low or intermediate risk Decipher scores. The primary outcome of this analysis was biochemical progression free survival (bPFS) with failure defined as a PSA ≥0.1 ng/mL. Results: From March of 2014 through September of 2016, 47 patients met the above criteria. The median patient age was 64 and median follow up was 16 months. Median pre-treatment PSA was 6.0 ng/mL (2.94 to 22.7 ng/mL). With regard to pathologic stage: 19% had T2c, 68% had T3a, and 13% had T3b disease. Pathologic Gleason grouping was 6%, 49%, 34%, 6%, and 4% for groups 1-5, respectively. 51% of patients had positive margins, 36% had lymph-vascular space invasion, and 53% had perineural invasion. Four patients received ART and 1 patient was lost to follow up after his initial visit. Of the remaining 42 patients, 3 patients experienced biochemical failure at 8, 27, and 44 months. Conclusions: This is the first prospective report utilizing Decipher genomic testing to stratify men with undetectable PSA and adverse pathologic features into an observation cohort following RP. Despite the stringency of our definition of biochemical failure, our observed bPFS was 87% at 3 years. Historically, in an unselected population the 3 year bPFS was 90% in those receiving ART and 65% in those receiving SRT. While these initial findings are promising, longer follow up is warranted. Our findings demonstrate the utility of genomic classifiers in patient selection and provide a safe approach to reducing over treatment in the post RP setting.