4555 Background: Patients (pts) with biochemical (PSA) relapse after RP represent a rapidly rising population in whom appropriate standards of care remain undefined. Over the past several years we have focused on studying the natural history of these pts. Our previous report (Pound et al; JAMA 1999) suggests that the Gleason score, time of PSA relapse (>0.2 ng/ml) and PSADT are the strongest predictors of the probability of distant metastasis (DM) (Cox model). A recent update (Partin; AUA 2003, Eisenberger; ASCO 2003) suggests that PSADT overrides the other parameters in the prediction of DM. Our experience has been expanded (> 1000 additional pts and longer follow-up). We evaluate the relationship between PSADT and PCSS. Methods: 4,415 pts underwent a RP from 1982–2003 and 825 demonstrated evidence of PSA relapse. All pts were followed with yearly PSAs with no androgen deprivation given until development of DM. Cox-proportional hazards and Kaplan-Meier survival analyses were completed with time from PSA relapse to censoring (last follow-up) or death used as endpoint. Results: 825/4,415 demonstrated PSA relapse (mean time 8.4yrs), 170/825(20.6%) developed DM and 109/825(13%) have died of prostate cancer (PCa). PSADT was calculated on 411 pts (mean 9 PSAs /pt, range 2–33), ROC-AUC for PSADT prediction of PCSS was 0.77. Conclusions: PSADT is a potent predictor of the probability of DM and PCSS. Pts with PSADT ≤10 mos. are at significant risk for developing DM and dying of PCa. In this group, clinical trials should evaluate progression-free and overall survival with aggressive approaches. Pts with PSADT of >10 mos. may be observed or treated to delay onset of DM. (Supported by CAPCURE). No significant financial relationships to disclose.
4564 Background: The CYP17 inhibitor keto is active in mCRPC. The NLR, an index of systemic inflammation, is associated with prognosis in several types of cancer. We assessed the association between pre-tx NLR and outcome of mCRPC pts treated with keto. Methods: We performed an international multicenter retrospective study of pts with mCRPC, who were treated with keto. We analyzed the pre-tx NLR and previously described factors associated with keto tx outcome as prior response to hormonal tx, pre-tx PSADT, and extent of metastatic disease (limited vs extensive). Progression free survival (PFS) was determined by the Kaplan-Meier method. Multivariate analyses using Cox regression model were performed to determine their independent effect, and to form a predictive model. A survival tree analysis was used to find the best NLR cut-off value. Results: From 1999-2011, 156 mCRPR pts (median age 69) were treated with keto. 78/156 (50%) had ≥ 50% PSA decline. Overall median PFS was 8 months (mos) (range 1-144). Excluded from the analysis were 23 pts without available data on pre-tx NLR, and those with recent (≤1 mos) health event or tx (surgery, steroids, radiation) associated with a change of blood counts. 133 pts were included in the analysis. 62 (47%) had an elevated pre-tx NLR >3. Risk factors associated with PFS (table) were pre-tx NLR >3, prior response to GnRH-a <24 mos and to antiandrogen (AA) <6 mos, and pre-tx PSADT <3 mos. The number of risk factors was used to categorize patients into three risk groups (table): favorable (0-1 factors), intermediate (2 factors), and poor (3-4 factors). Conclusions: In mCRPC pts treated with keto, pre-tx NLR, prior response to hormonal tx, and pre-tx PSADT are associated with PFS, and may be used to categorize pts into risk groups. [Table: see text]
256 Background: Standard treatment options for patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) include docetaxel based chemotherapy, abiraterone, and radium 223. Octogenarian pts (age 80 and older) are often considered to be unfit for chemotherapy. However, recommendations for their management is limited by the paucity of clinical trials data in this population. In countries where abiraterone in the pre-chemotherapy setting has not been approved yet, or for pts who can’t afford it, the CYP 17 inhibitor ketoconazole is used as an alternative advanced hormonal tx. We aimed to study baseline characteristics and outcome of octogenarian versus young (age 60 or younger) pts with mCRPC treated with ketoconazole. Methods: We performed an international multicenter retrospective study of pts with mCRPC, who were treated with ketoconazole at four centers across two different countries. We compared baseline characteristics and outcome of octogenarian versus young pts. The effect of very old age on prostate-specific antigen (PSA) response, progression free survival (PFS), and overall survival (OS), was tested with adjustment of other known confounding risk factors using a chi-square test and partial likelihood test from Cox model. Results: Between 2004 and 2013, 35 octogenarians (median age 83) and 33 young pts with (median age 57) mCRPC were treated with ketoconazole. The groups were balanced regarding the following baseline clinicopathologic characteristics: extent of disease (limited-axial skeleton and/or nodal versus extensive-appendicular skeleton and/or visceral), combined gleason score, pre-treatment risk category (Keizman, Oncologist 2012; based on pre-tx neutrophil to lymphocyte ratio/prostate-specific antigen doubling time, and prior response to ADT), pain intensity, ECOG performance status, alkaline phosphatase level, hemoglobin level, PSA level. In octogenarian versus young pts, PSA response (greater than or equal to 50% decline from baseline) was 40% versus 61% (OR 3.5, p=0.04), median PFS 7 versus 8 months (HR 0.91, p=0.44), and median OS 31 versus 36 months (HR 0.66, p=0.31). Conclusions: In very old vs young mCRPC patients treated with ketoconazole, PSA response was lower. Baseline clinicopathologic characteristics, PFS, and OS were not significantly different between the groups.
4758 Background: Preclinical data suggested synergistic anti-tumor activity with the combination of D + E in AIPC. E is a GMP phosphodiesterase inhibitor administered orally. We designed a trial evaluating tumor response (↓PSA ≥50% lasting ≥4 wks) to D given on a weekly schedule + E daily. Methods: AIPC pts showing progressive disease after anti-androgen withdrawal were enrolled. Up to 2 prior chemotherapy (chemo) regimens were allowed. Planned treatment included 6 cycles of D 35 mg/m2 IV Q wk × 4 followed by 2 wks of rest. E 250 mg PO BID was initiated D 8. The statistical endpoint for this trial was the % of pts with ↓ in PSA ≥50% lasting ≥4 wks. A 2 stage trial was designed where the study would terminate if the % of pts meeting the endpoint was not convincingly >40%. If ≤3/14 pts responded in stage 1, this criterion would be met. During wks 1 and 3 serial plasma samples were obtained (last sample 168h). [D] were measured using a validated LC/MS/MS method and D pharmacokinetic (PK) parameters were determined by compartmental analysis. Results: From 3/29/02 - 11/11/03, fourteen pts were enrolled. Pt characteristics included median: age of 69.5 years (range 54–78), ECOG performance status of 1 (range 0–2), baseline prostate specific antigen of 76.65 ng/ml (range 28.3- 542.6), # prior hormonal manipulations of 2. Four pts had prior chemo and 1 had prior palliative RT. 85% had bone metastases; 50% had soft tissue (ST) measurable disease. Interim analysis revealed: 21% with a 50% decline in PSA level lasting ≥ 4 weeks; no ST disease responses. Significant toxicities (%) included: fatigue (14), nausea (28), diarrhea (7), abdominal pain (14), rash (7), syncope (21), pulmonary edema (7), CHF (14), superficial venous thrombosis (7) and elevations in transaminases (21), necessitating dose reductions and/or delays of D and E, in 71%, 64% of pts respectively. Paired D Pk data are available for 10 pts; mean ± SD clearance values were similar during wk 1 (45± 20 L/h) and wk 3 (40±25 L/h) (P≡0.07). Conclusions: This treatment does not compare favorably in efficacy or toxicity profile to other wkly single agent D regimens; nor does it compare favorably to the reported 58% PSA response with D given Q 3wks + daily E (Ryan et al., Semin in Oncol, 2001). Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis
e15547 Background: The VEGFR inhibitor sunitinib is a standard tx for metastatic clear cell RCC. Data on the activity of sunitinib in metastatic non clear cell RCC, is limited by small or heterogeneous (mixed histology or targeted therapies) studies, that revealed a lower antitumor activity than in patients with clear cell histology. We aimed to analyze the activity of sunitinib in a large international cohort of patients with metastatic papillary RCC, and to characterize patients who may benefit for this therapy. Methods: Records from metastatic papillary RCC patients treated with sunitinib in 10 centers across 3 countries were retrospectively reviewed. Univariate and multivariate analyses of association between clinicopathologic factors and clinical outcome were performed using Cox regression. Results: Between 2004-2013, 74 patients (median age 60, 68% male) with metastatic papillary RCC were treated with sunitinib. 78% had a prior nephrectomy. HENG risk was good 11%, intermediate 56%, and poor 33%. 21% were active smokers, and 31% users of angiotensin system inhibitors. 24% and 41% had liver and bone metastases, respectively. 55% had a pre-treatment neutrophil to lymphocyte ratio (NLR) >3. 40% had dose reduction/treatment interruption. Sunitinib induced hypothyroidism and hypertension (HTN) occurred in 30% and 43%, respectively. 70% achieved a clinical benefit (partial response + stable disease), while 30% had disease progression within the first 3 months of therapy. Median progression free survival (PFS) and overall survival (OS) were 5 and 12 months, respectively. 27% had a PFS ≥ 1 year, and 26% survived ≥ 2 years. Factors associated with PFS were sunitinib induced HTN (HR 0.31, p=0.002), pre-treatment NLR >3 (HR 5.3, p=0.001), and active smoking (HR 2.5, p=0.01). Factors associated with OS were sunitinib induced hypothyroidism (HR 0.4, p=0.024), past nephrectomy (HR 0.41, p=0.02), pre-treatment NLR >3 (HR 2.25, p=0.036), and active smoking (HR 2.3, p=0.027). Conclusions: Clinicopathologic factors may be used to identify patients with metastatic papillary RCC who may benefit from sunitinib tx. A prolonged PFS and OS were noted in 26-27% of patients.
