Charles J. Ryan

5057 Background: PET imaging of prostate specific membrane antigen (PSMA) has been shown to have a higher sensitivity and specificity compared to conventional imaging. The objective was to evaluate the impact of PSMA PET on the management of prostate cancer patients with biochemical recurrence following local therapy. Methods: In our initial Ga-68-PSMA-11 PET protocol (NCT02611882), 150 patients with biochemical recurrence were imaged. 63 patients were imaged using PET/CT (GE Discovery VCT) and 63 patients using PET/MRI (GE Signa 3.0T PET/MRI). 110 patients received Lasix injections. Referring clinicians filled out a pretreatment management form and a management form based on the imaging results. Changes in management were graded as major, minor, no change or unknown based upon the responses. Results: We received both pre and post imaging forms in 126 patients, for an 84% response rate. The average PSA in the population was 5.9 ± 5.4 ng/mL with an average doubling time of 9.7 ± 11.0 months, and 60 patients had a PSA of less than 2.0 at the time of imaging. The average time between prior treatment and imaging (RP and/or radiation) was 5.3 ± 5.4 years, with 46 patients imaged within two years of their most recent treatment. 43 patients had a prior prostatectomy, 41 prior radiation, and 33 patients had both. 103 patients (82%) had disease localized on PSMA imaging. Of the 126 patients, 67 (53%) of the imaging studies resulted in a major change in management. The most common major change was converting from active surveillance to radiation therapy (15 patients, 12%), changing from ADT to radiation therapy (16 patients, 13%), and converting from radiation therapy to either active surveillance (6 patients, 5%) or to ADT alone (3 patients, 2%). 10 patients (8%) had a minor change, 42 patients (33%) had no change, and 7 patients (6%) had an unknown change in management. Conclusions: The results of our surveys demonstrate a substantial impact of PSMA PET on the intended patient management. The majority of changes involved converting a targeted therapy to systemic treatment or systemic treatment to a targeted therapy. Prospective studies are warranted to determine whether directed treatment towards PSMA-avid lesions affects long-term disease outcomes. Clinical trial information: NCT02611882.

5067 Background: Higher baseline androgens have been previously shown to be associated with an improved overall survival (OS) in mCRPC patients treated with the androgen synthesis inhibitors, ketoconazole or abiraterone. The purpose of this analysis was to determine whether baseline serum androgen levels (Testosterone (T), Androstenedione (A) and DHEA (D) are associated with OS in mCRPC patients treated with docetaxel-based chemotherapy. Methods: Data from 1,050 men treated on CALGB 90401 with docetaxel, prednisone and either bevacizumab or placebo were used. Eligibility required progressive mCRPC and no prior chemotherapy. Pre-treatment serum assays for T, A and D were performed via tandem Liquid Chromatography-Mass Spectrometry (LC-MS/MS) at NMS labs. The proportional hazards model was used to assess the prognostic significance of T, A, and D in predicting OS adjusting for known prognostic factors. Results: Median values for T, A, and, D were 1.00, 13.00 and 8.12, ng/dL respectively.Values above the median were defined as low, above as high. Median OS for low vs high levels was 22.7 and 23.1 month for T, 22.4 and 21.7 month for A and 21.8 and 24.0 month for D, respectively, all NS. In multivariable analysis adjusting for 10 known prognostic values and prior keto use in mCRPC (Halabi JCO 2014), A (p-value = 0.013) levels were associated with OS. The HR for A was = 0.99 (95% CI = 0.98-0.99). Conclusions: In multivariate analysis, baseline androstenedione levels are prognostic factors for OS in mCRPC patients receiving chemotherapy. Low or undetectable levels of other androgens are associated with shorter OS, consistent with prior results in androgen synthesis inhibitor treated pts in both the chemotherapy naive and post chemotherapy settings. This relationship may reflect more aggressive tumor biology that evolves in an extreme androgen deprived milieu. Clinical trial information: NCT00110214.

5056 Background: Standard imaging in early stage PC has focused on detecting metastases (mets) within the abdomen and pelvis. The incidence of IT mets (lung, mediastinal, or supraclavicular) mets is unknown, but presumed to be negligible. Whole body ⁶⁸Ga-PSMA PET has greater sensitivity compared to conventional imaging, affording the opportunity to estimate the incidence of IT mets. Methods: Newly diagnosed or biochemically recurrent (BCR) PC patients (pts) with apparent localized disease on standard imaging were enrolled on a prospective study of ⁶⁸Ga-PSMA PET imaging between June 2015 and January 2017 and were analyzed for incidence of IT mets. Positive lesions were defined as uptake higher than blood pool. When appropriate, patients underwent confirmatory biopsy of the PSMA-avid IT lesions. Results: 364 pts underwent ⁶⁸Ga-PSMA PET imaging, including 121 (33%) pts with newly diagnosed PC and 243 (67%) pts with BCR. 145 pts (40%) had at least 1 PSMA-avid metastasis. PSMA-avid IT mets were detected in 20 pts (5.5% of overall cohort; 13.8% of those with ≥ 1 PET-positive mets), including 3 newly diagnosed (2.5%) pts and 17 (7.0%) pts with BCR. 9 of 20 pts (45%) had IT mets as the only detectable site of metastasis on PET. Biopsy of the PSMA-avid IT lesion was found to harbor PC in 5/5 patients (100%). Sites of detection included: supraclavicular node, n = 9 (2.5%); mediastinal node(s), n = 10 (3.6%), and visceral lung, n = 4 (1.0%). In the entire study cohort of 364 pts, 43% of pts had a Gleason Score ≥ 8 at diagnosis, median PSA was 4.87 ng/mL (range: 0.04 – 83.7), and the median PSA doubling time was 6.2 months (range: 0.4 – 78.3) in patients with BCR. There were no significant differences in PSA, PSA doubling time, Gleason grade, or stage between patients harboring IT metastases vs. those who did not. Conclusions: IT mets are detected by ⁶⁸Ga-PSMA PET imaging at an appreciable frequency in early stage PC with apparent localized disease by conventional imaging, which may significantly impact management in these cases. Further studies are warranted to validate these findings and determine the optimal strategy for the detection and treatment of supradiaphragmatic metastases in newly diagnosed and biochemically recurrent PC. Clinical trial information: NCT02918357.

3 Background: There is a clear need to develop a clinically relevant molecular subtyping approach for prostate cancer. We hypothesized that prostate cancer can be subtyped based on luminal versus basal lineage. Methods: We applied the PAM50 classifier, which is used clinically to identify luminal and basal cancers in breast cancer, to subtype a total of 3,782 prostate cancer samples using a high-density microarray platform run in a CLIA-certified laboratory. We examined the associations of these subtypes and clinical outcomes. Results: We demonstrate that PAM50 segregates prostate cancer into three reproducible subtypes in both retrospective cohorts and on prospective validation: luminal A (33.3%-34.3%), luminal B (28.5%-32.6%), and basal (34.1%-37.1%). Luminal B prostate cancers exhibited the worst clinical prognoses, followed by basal and luminal A subtypes (10-year biochemical recurrence-free survival: 29/39/41%; distant metastasis-free survival: 53/73/73%; prostate cancer-specific survival: 78/86/89%; overall survival: 69/80/82% respectively) on both univariable and multivariable analyses accounting for standard clinicopathologic prognostic factors. Known luminal lineage markers, such as NKX3.1 and KRT18, and the basal lineage CD49f signature, were enriched in luminal- and basal-like cancers respectively, demonstrating the connection between these subtypes and established prostate cancer biology. While both luminal-like subtypes were associated with increased AR expression and signaling, only luminal B prostate cancers were significantly associated with post-operative response to androgen deprivation therapy (ADT) in a subset analysis matching patients based on clinicopathologic variables (interaction p = 0.006, luminal B 10-year metastasis: 33% (treated) vs. 55% (untreated), non-luminal B: 37% (treated) vs. 21% (untreated)). Conclusions: These findings contribute novel insight into the biology of prostate cancer, and provide translatable clinical tools for personalizing post-operative ADT for patients with prostate cancer. Similar to breast cancer, these findings suggest that luminal/basal subtyping may be useful in treatment selection in prostate cancer.

193 Background: COU-AA-302 evaluated abiraterone acetate plus prednisone (AA) vs prednisone (P) in chemotherapy-naïve mCRPC pts, with overall survival (OS) and radiographic progression-free survival (rPFS) as co-primary end points. Per study criteria, pts with radiographic progression (RAD) only were allowed to continue treatment, while those with unequivocal clinical progression (UCP) only were not, and were censored for rPFS. We evaluated the clinical significance of survival outcomes for pts with UCP only vs RAD only from the prospective COU-AA-302 trial. Methods: UCP was defined per protocol as ≥ 1 of the following: initiation of chronic opiates, ECOG performance status (PS) decline to ≥ 3, or initiation of chemotherapy, palliative radiation therapy, or surgery. OS was evaluated for each type of progression using Cox proportional hazard models. Results: 500 (92%) pts in the AA arm and 540 (100%) in the P arm discontinued study treatment. Of the 736 pts who discontinued treatment for a protocol-defined reason, 280 (38%) discontinued for UCP only, 332 (45%) for RAD only, and 124 (17%) for both UCP and RAD. Clinical events cited as the reason for discontinuation for UCP (AA vs P arm) included pain requiring opiates (22% vs 25%), ECOG PS ≥ 3 (4% vs 5%), and initiation of chemotherapy (50% vs 53%), radiation therapy (36% vs 27%) and surgery (3% vs 5%). UCP only pts had shorter median OS compared with RAD only pts (Table). Conclusions: UCP is a criterion used as an indicator for a censored event, yet appears to confer inferior survival relative to RAD. The high frequency of UCP implies that it may be an important determinant of clinical outcome. The events that drive UCP should be defined as part of the development of more informative interim trial end points, in line with the PCWG3-proposed “no longer clinically benefitting” outcome measure, which captures pts with UCP. Clinical trial information: NCT00887198. [Table: see text]

154 Background: Interactions between metastatic prostate cancer cells, osteoblasts, osteoclasts, and other participants in bone metabolism are complex and result in pathologic bone physiology. Ra-223, a targeted alpha therapy, accumulates at sites of bone metastases and prolongs survival. Ra-223 and docetaxel (D), acting through different mechanisms of action, may have beneficial effects on bone pathophysiology and tumor microenvironment. Prior data suggest treatment with Ra-223 results in favorable alterations in bone biomarkers that are associated with survival. Methods: 53 patients with progressing CRPC and ≥ 2 bone metastases were randomized 2:1 to Ra-223 (55 kBq/kg q6wk × 5) + D (60 mg/m² q3wk × 10) versus D (75 mg/m² q3wk with step-down option to 60 mg/m²). Bone resorption (CTX-1, ICTP) and formation (P1NP, bALP) markers, tALP, and PSA were analyzed at wk 19 (after 3 Ra-223 injections) and 3 wk after end of treatment (EOT). Results: Mean % change at wk 19 and EOT are shown (Table). tALP, bALP, P1NP, and PSA declined early during treatment, reaching an average of > 30% decline from baseline by wk 19 in both arms. Mean % declines were greater in the Ra-223 + D versus the D-alone arm at wk 19 and EOT. Bone resorption markers CTX-1 and ICTP showed little decline at wk 19. Conclusions: Ra-223 + D patients had greater % decline in tALP and in bone formation markers bALP and P1NP. Due to small patient numbers and preliminary data, further analysis and correlation with clinical outcomes in a larger study is warranted. Clinical trial information: NCT01106352. [Table: see text]

153 Background: Chemohormonal therapy is standard of care for newly diagnosed metastatic prostate cancer (mPC) patients (pts) but is associated with significant adverse effects and negative metabolic changes. We performed a pilot study to investigate whether participation in a multi-disciplinary clinic to mitigate adverse effects of treatment is feasible. Methods: Pts with recently diagnosed mPC who were planning to start or had recently started chemohormonal therapy were prospectively enrolled in a multi-disciplinary clinic that included individualized monthly counseling from a physical therapist, oncology dietitian, and palliative care specialist on a rotating basis for 12 months. Patients were assessed quarterly for changes in % body fat, weight, serum levels of 25-OH vitamin D, fasting lipids/glucose/insulin, and quality of life (QOL). DXA bone density scans were performed at baseline and end of 12 months. The primary endpoint was the completion rate of scheduled visits. Results: 7 pts were enrolled between September 2015 and June 2016. All patients had extensive disease ( > 4 bone metastases and/or visceral metastases) at the time of study entry, and all 7 patients completed six cycles of docetaxel-based chemotherapy, and remained on hormone therapy for the duration of study. The percentage of completed visits was 98% (54/55 planned visits). The percentage of completed assessments including QOL questionnaires was 81%. No skeletal-related complications were observed. Median percent increase from baseline in body weight and % body fat was 3.51% and 20%, respectively. Four of the seven patients had osteopenia at baseline. Patient reported satisfaction was high and positive impact on psychosocial well-being was observed. Conclusions: Participation in a multi-disciplinary clinic by men receiving intensive chemohormonal therapy for metastatic prostate cancer was feasible. Patients are at risk for adverse metabolic and bone toxicity with therapy, underscoring the potential positive impact of a multi-disciplinary clinic. A randomized study to detect objective improvements in health outcomes is underway. Clinical trial information: NCT02168062.