Fall In PSA Research Articles

EP-1514 Binary exponential model for the PSA fall after IMRT, dependency on initial PSA and Prostate volume

EP-1514 Binary exponential model for the PSA fall after IMRT, dependency on initial PSA and Prostate volume

Clinical validation of circulating cytokines as markers of prognosis and response to docetaxel in men with metastatic castration-resistant prostate cancer.

230 Background: Elevated circulating macrophage inhibitory cytokine -1 /growth differentiation factor 15 (MIC-1/GDF15), interleukins 4 (IL4) and 6 (IL6) levels were associated with poor prognosis and resistance to docetaxel chemotherapy in an exploratory cohort of men with metastatic castration resistant prostate cancer (mCRPC). To establish level 2 evidence of biomarker utility, these cytokines were tested in internal and external validation cohorts. Methods: Internal validation cohort: Plasma samples taken at baseline (BL) and preC2 docetaxel (n = 120). MIC-1/GDF15, IL-4 and IL-6 measured by ELISA assay. External validation cohort: Serum samples taken at BL and/or preC3 docetaxel in 430 men with mCRPC on phase III SYNERGY study (docetaxel +/- custirsen as 1st line chemotherapy in mCRPC with no OS benefit in the experimental arm). MIC-1/GDF15 measured by ELISA assay. Associations between cytokine levels, PSA response, time to PSA progression and OS were assessed by non-parametric tests and Cox Regression survival analyses. Results: Internal validation: At a median follow-up of 14 months, higher MIC-1/GDF15 levels at BL and preC2 were associated with shorter OS (BL; HR 1.2 95%CI 1.0-1.4; p = 0.03 and preC2; HR 1.3 95%CI 1.1-1.5; p = 0.004). Increase in MIC-1/GDF15 after chemotherapy correlated with lack of PSA response (p < 0.001). IL4 and IL6 did not correlate with survival or demonstrate additional value. External validation: At a median follow-up of 23 months, higher MIC-1/GDF15 levels at BL and preC3 predicted shorter OS (BL; HR 1.4 95%CI 1.2-1.6; p < 0.0001 and preC3; HR 1.6 95%CI 1.3-1.8; p < 0.0001). Higher pre C3 MIC-1/GDF15 levels were also associated with shorter time to PSA progression (HR 1.2 95% CI 1.0-1.4; p = 0.02). Rise in MIC-1/GDF15 from BL to preC3 correlated with lack of 50% PSA fall at 12 weeks (p < 0.001). Conclusions: Adherence to a biomarker development pipeline provides level 2 evidence of the prognostic value of circulating MIC-1/GDF15 in men with mCRPC receiving docetaxel. A prospective biomarker led study is now necessary to establish clinical utility.

Abstract IA18: Sensitivity and resistance biomarkers to PARP inhibitors in Mcrpc

A better understanding of the molecular underpinnings of prostate cancer renders the opportunity for more precise patient care by individualizing therapeutic strategies according to predictive biomarkers of benefit. Until now, clinical management of patients with prostate cancer, either localized or metastatic, has not yet incorporated precision medicine strategies. To pursue this, a new classification of the disease needs to be based on molecular features that are clinically relevant. Several studies have now confirmed genomic defects in the DNA damage response pathways (DDR), and primarily in the homologous recombination mediated repair pathway (HR), as a cornerstone of prostate cancer biology. This is particularly relevant in patients with metastatic castration-resistant prostate cancer (mCRPC). Among this population with lethal disease, around 20-25% of cases present genomic loss (by pathogenic mutations or by homozygous deletion) of at least one gene involved in HR, and in half of this cases the mutation is inherited, which makes these findings also relevant for patients’ relatives, considering how some of this events are linked to increased risk of prostate and others cancers. The HR gene most commonly lost in advanced prostate cancer is BRCA2 (8-12% in different series), followed by ATM (4-6%), CDK12 (3-5%), BRCA1, and PALB2 ( PARP-1 and 2 are key proteins in DNA single-strand break repair and a therapeutic target using a family of drugs (PARP inhibitors) already approved for the treatment of ovarian cancer associated to HR defects, primarily BRCA2 mutations. We completed a first stage of a phase II adaptive clinical trial evaluating the antitumor activity of the PARP inhibitor olaparib in mCRPC (TOPARP), as well as investigating predictive biomarkers associated with response to PARP inhibition. In a cohort of 49 evaluable patients who previously to docetaxel (49/49) and abiraterone and/or enzalutamide (48/49), 16 (32%) achieved a response to olaparib, using the trial preplanned definition of response (radiologic response by RECIST and/or 50% PSA fall and/or CTC conversion from >5 to On one hand, it is possible that different genes have a different weight in determining HR proficiency, and hence, synthetic lethality with PARP inhibition. It is possible that loss of some genes may be partially or totally compensated for by other proteins, whereas loss of some other genes may be more catastrophic for the tumor cell. On the other hand, it is also feasible that the presence of secondary biologic events in prostate cancer, such as AR aberrations, TP53/Rb1 loss, or others, may modulate the impact of HR defects. Analytical validation and clinical qualification of functional assays as predictive biomarkers of PARP inhibitor sensitivity would help towards integrating complex genomic, transcriptome, and epigenetics data with regards to defining the optimal predictive biomarkers for treatment stratification. The complex interaction between androgen receptor (AR) signaling and DDR may be relevant for PARP inhibition stratification. Preclinical studies suggest that blocking AR may render the cell sensitive to PARP inhibition; however, the impact of these findings on therapeutic strategies in the clinic is still not clear and further studies in localized and advanced disease are needed. Previously, a synthetic lethal interaction for PARP inhibition with PTEN loss or with the presence of ERG rearrangements in prostate cancer has been postulated from preclinical studies; to date, these data have not translated into clinical data supporting that these are optimal biomarkers to stratify patients for PARP inhibitors. It is possible these data are, however, very relevant to designing rational combination trials. Lastly, HR gene mutations are also relevant towards secondary resistance mechanisms to PARP inhibitors, which further supports their relevance in determining sensitivity. In a follow-up study we identified how in patients with germline or somatic BRCA2 and PALB2 mutations responding to olaparib, secondary genomic events (basically small fragment deletions) emerged in the region of the original mutation, reverting the gene reading frame to normal. These events occur in a polyclonal manner and may be restoring HR function. These have now been confirmed by other studies in prostate, breast, and ovarian cancer. Citation Format: Joaquin Mateo. Sensitivity and resistance biomarkers to PARP inhibitors in Mcrpc [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr IA18.

Metastases-directed therapy (MDT) for oligometastatic prostate cancer.

375 Background: Stereotactic ablative radiotherapy (SABR) is emerging as a treatment option for patients with oligometastatic prostate cancer. The primary aim of this approach is to prolong disease free survival and delay the initiation of systemic therapies. This retrospective study is aimed to analyse local control, biochemical progression-free survival (b-PFS), toxicity and systemic therapy-free survival in a cohort of patients treated by a single clinician. Methods: Eighteen patients (26 lesions) in patients with relapsed oligometastatic prostate cancer ( 1-3 sites) were treated with SABR, delivered using both cyberknife and VMAT. Doses used were 24 Gy in 2 or 3 fractions for spine and 30 - 40 Gy in 3 fractions for lymph nodes and other bony metastases. All patients had either a Choline or PSMA- PET scan prior to treatment. Response was assessed with PSA testing and repeat scanning when feasible. CTCAE acute and late toxicity was prospectively recorded. Results: Mean age was 68. Previous treatments for the primary prostate cancer included surgery (7 patients), surgery and salvage prostate bed radiotherapy (6 patients), radical radiotherapy (4 patients) and cryotherapy (1 patient). Twelve patients had a single metastatic site, four patients had 2 sites and two patients had 3 sites. Six patients patients were treated with a short course of androgen deprivation therapy (ADT) in addition to SABR. All patients had a fall in PSA with a mean reduction of 75%. Median pre-SABR PSA was 1.83μg/L and median post-SABR PSA was 0.28μg/L. At a median follow-up of 14 months (range 2 - 28.5), 14 patients (78%) remained systemic therapy free. Three patients with a single pelvic lymph node metastases achieved a sustained undetectable PSA level. All 8 patients who had a post-treatment PET scan showed no residual activity at the treated site. One patient experienced G2 acute bowel toxicity, otherwise there was no toxicity above G1. Conclusions: MDT using SABR for relapsed prostate cancer is a safe treatment with promising results in terms of local control, b-PFS and delaying the initiation of systemic therapies. This minimally invasive approach has the potential to improve patients' quality of life, but requires further evaluation in randomised clinical trials.

Influence of aggressive-variant prostate cancer (AVPC) features on outcome of metastatic hormone-sensitive prostate cancer (mHSPC) treated by chemohormonal therapy (CHT).

193 Background: Outcomes of patients (pts) undergoing CHT for mHSPC are heterogeneous, with some rapidly developing castration-resistance (CRPC). While AVPC ("anaplastic") features are described in CRPC, less is known in the mHSPC setting. In this multi-institutional cohort, we explored pre-treatment factors associated with poor outcome. Methods: De-novo mHSPC pts treated with CHT from June 2014 to July 2017 at The Ottawa Hospital Cancer Centre (TOHCC) and London Regional Cancer Centre (LRCC) were retrospectively identified. AVPC features (defined below) were collected and cumulatively scored (0, 1, or 2+), along with baseline, treatment and outcome data. Statistical comparisons utilized Cox regression analysis and Kaplan-Meier method for association with CRPC and survival. Results: 92 pts (58 TOHCC, 34 LRCC) met inclusion for study; 83 (90%) had "high-volume" disease (≥4 bone lesions; or ≥1 visceral metastasis), 69/73 (95%) prostate biopsies scored Gleason 8-10, and 55 (60%) had AVPC features: >5 cm nodal/pelvic mass (28), visceral metastases (21), lytic bone metastases (16), elevated LDH (12), low PSA (4), or neuroendocrine differentiation (2). Pre-docetaxel PSA fall of <50, 50-75, 75-90, and ≥90% baseline occurred in 12, 13, 19, and 56% respectively. Docetaxel was initiated a median of 66 days after androgen-deprivation, with 82% completing 5 or 6 cycles. 9 pts (10%) progressed during docetaxel, and 31 pts (34%) developed CRPC < 12 months. Median time to CRPC was 18.4, 14.0, and 11.0 months for 0, 1, and 2+ AVPC features (log rank p=0.009). CRPC was also associated with pre-docetaxel PSA fall <75% (p<0.001) and high alkaline phosphatase (p=0.016). At 18 months median follow-up, 16/55 (29%) with AVPC features have died versus 1/37 (3%) without (log rank p=0.001). In multivariable analysis, AVPC features and pre-docetaxel PSA fall were independently (p<0.05) associated with survival. Conclusions: In our study, mHSPC pts with AVPC features and suboptimal (<75%) pre-docetaxel PSA decline had poor prognosis. These features should be validated in larger cohorts to potentially identify mHSPC pts suitable for further study in clinical trials.

Post hoc analysis of a phase III study to test the association between circulating methylated glutathione s transferase (mGSTP1) DNA levels and response to docetaxel (DTX) in metastatic castration resistant prostate cancer (mCRPC).

5014 Background: GSTP1 inactivation is associated with CpG island hypermethylation in > 99% prostate cancers. Detection of circulating mGSTP1 DNA predicts response to DTX and overall survival (OS) in phase I/II mCRPC cohorts. This post hoc analysis of a phase III study aims to test the association between circulating mGSTP1 DNA levels and outcomes. Methods: The phase III SYNERGY study tested DTX +/- custirsen as 1st line chemotherapy in mCRPC (n = 1022) with no OS benefit in the experimental arm. Serum samples were taken at baseline (BL) and preC3 of DTX +/- custirsen from 600 patients (pts) enrolled on the SYNERGY study. mGSTP1levels in free DNA were measured using a sensitive methylation specific PCR assay and correlated with PSA response, time to PSA progression (TTP) and OS. Results: On interim analysis of 300 pts, serum mGSTP1 was detectable at BL in 80% and preC3 in 44%. Undetectable preC3 mGSTP1 correlated with a ≥30% fall in PSA within 3m of starting DTX (p < 0.001). Detectable BL and preC3 mGSTP1 predicted shorter TTP after DTX (BL; HR 1.6 95%CI 1.1-2.3; p = 0.01 and preC3 HR 2.2 95%CI 1.6-2.9; p < 0.001). Detectable mGSTP1 at both time points predicted shorter OS (BL; median OS 18.4 vs 33.1m, HR 2.4 95%CI 1.6-3.7; p < 0.001 and preC3; median OS 13.9 vs 29m, HR 2.7 95%CI 2.0-3.6; p < 0.001). In those with detectable BL mGSTP1, 50% had undetectable preC3 mGSTP1 predicting > 30% fall in PSA within 3m (p < 0.001), improved TTP (HR 0.40 95%CI 0.29-0.57; p < 0.001) and improved OS (25.2 vs 13.9 m HR 0.38 95%CI 0.28-0.51; p < 0.001). On multivariable analysis including Hb, Karnofsky PS, LDH, PSA and visceral metastases, detectable preC3 mGSTP1 independently predicted shorter TTP (HR 1.9 95%CI 1.4-2.6; p < 0.001). Detectable mGSTP1at both time points independently predicted OS (BL; HR1.8 95%CI 1.2-2.8; p = 0.006 and preC3; HR 2.2 95%CI 1.6-3.0; p < 0.001). Results from the full cohort of 600 pts will be available for presentation at the meeting. Conclusions: This study should validate circulating mGSTP1 DNA as a marker of therapeutic benefit and prognosis in men with mCRPC receiving DTX and could be utilized for clinical management.

CANCAP02: A study into the pharmacodynamic biomarker effects of vistusertib (AZD2014), an mTORC1/2 inhibitor, given prior to radical prostatectomy (RP).

97 Background: Additional systemic therapy given to unselected patients (pts) around RP has yet to improved pt survival. Further trials should use appropriate pt selection, i.e. men at highest risk of relapse, ideally biomarker stratified. Using novel drugs prior to RP allows direct study of effects in primary prostate cancer (PC) that may guide design of future trials. Altered PI3K/AKT/mTOR pathway signalling is associated with aggressive PC hence we have undertaken a study vistusertib, an oral, dual mTORC1/mTORC2 inhibitor prior to RP. Methods: Primary endpoint was to measure mTOR1/2 inhibition by immunohistochemistry (IHC). Secondary endpoints were feasibility, safety, tolerability and determining plasma concentrations of vistusertib. Exploratory objectives included measurement of anti-cancer effects. Men, due for RP, with high volume or aggressive PC consented and received vistusertib, 50mg bd, for 15 days prior to RP. Diagnostic biopsy and RP tissue were collected for IHC. Adverse events (AE) were graded according to CTCAE v4. Plasma was collected to determine vistusertib concentrations. Results: 21 men, median age 62 (range 50 – 69) included 11 intermediate and 10 high risk PC. 18/21 were evaluable for primary endpoint. On day of RP mean plasma vistusertib concentration at RP was 648 ng/mL (range 386-852) and 6-8 hr post dose 484 ng/mL (range 211-660). Majority of related AEs were Grade (Gr) 1, the most common being rash, thrombocytopenia, oral mucositis, diarrhoea, lymphopenia and fatigue. Six pts experienced Gr3 AEs (3 pt lymphopenia, 1 pt each rash, mucositis and ALT rise). Two pts discontinued due to AEs (mucositis, thrombocytopenia) and one withdrew consent. Surgery was delayed in one pt (Gr 1 thrombocytopenia). IHC confirmed at RP: 4EBP1 was reduced in 100% pt (75% no staining post vistusertib) and pS6 was reduced in 67%, not changed in 25% and increased in 8%. A fall in PSA occurred in 4/18 pts. Conclusions: 2 weeks of AZD2014 can be given prior to RP. Active plasma concentrations were achieved. mTOR pathway inhibition was confirmed on IHC and a PSA fall occurred in 22% of pt. Analysis is ongoing, to be informed by concomitant studies in a PTEN null PC model. Clinical trial information: NCT02064608.

Abstract CT322: DNA repair defects and antitumor activity with PARP inhibition: TOPARP, a phase II trial of olaparib in metastatic castration resistant prostate cancer

Abstract Introduction: Next generation sequencing (NGS) has identified genomic aberrations causing DNA repair defects in sporadic metastatic castration resistant prostate cancer (mCRPC). We hypothesized that single agent olaparib would have antitumor activity in a sub-population of mCRPC patients (pts) and that exome and transcriptome studies would identify this population. Methods: TOPARP is an open-label, investigator-initiated phase II trial with a novel multi-step adaptive design (CRUK/11/029). The first part of the study (TOPARP-A) has a two-stage design evaluating the antitumor activity of single agent olaparib in unselected mCRPC pts (p0 = 0.05; p1 = 0.20; α = 0.02; β = 0.10) with a preplanned analysis to identify a biomarker defined sensitive subgroup. Primary endpoint, response rate (RR), was defined as objective response by RECIST 1.1 and/or PSA fall ≥50% and/or confirmed circulating tumor cell (CTC) count falls from ≥5 to <5/7.5ml blood (VeridexTM). Secondary endpoints included safety, tolerability, progression-free survival (PFS) and overall survival (OS). Olaparib tablets (400mg bid) were administered to mCRPC pts progressing after 1-2 lines of chemotherapy. NGS and other studies from paired mandatory fresh CRPC biopsies, taken before and while on olaparib, evaluated putative predictive response biomarkers. Results: Fifty pts were enrolled from 7 UK centers; all had had prior docetaxel, 48 (96%) prior abiraterone and 29 (58%) prior cabazitaxel. Overall, 16 of 49 evaluable pts experienced a response (RR 32.7%, 95% CI: 20.0 to 47.5), with 11 and 4 pts having been on treatment for >6 and >12 months respectively at data cut-off. NGS identified homozygous deletions and/or putatively deleterious mutations in DNA repair genes in 15/49 (30.6%) evaluable pts. While a majority of these genomic aberrations occurred in BRCA2 and ATM, biallelic loss of other relevant genes, including members of the Fanconi Anemia complementation group and CHEK2, were also observed. Among these fifteen pts, 13 (86.7%) responded to olaparib. All seven pts with BRCA2 loss (somatic [4/7] or germline [3/7]) and 4/5 pts with ATM truncating mutations responded to olaparib. The specificity of the biomarker suite was 94% in this population. Conversely, PTEN loss and ERG rearrangements were not associated with response. Finally, consistent with previous studies of olaparib, anemia (10/50, 20%) and fatigue (6/50, 12%) were the most common grade>3 adverse events, with 13 (26%) pts requiring a dose reduction. Conclusions: Olaparib has durable antitumor activity in heavily pre-treated pts with sporadic mCRPC with a 32.7% overall response rate. Genomic defects in DNA repair genes associate with olaparib sensitivity in sporadic mCRPC, offering a possibility for the very first molecular treatment stratification of advanced prostate cancer. Citation Format: Joaquin Mateo, Shahneen Sandhu, Susana Miranda, Suzanne Carreira, Suneil Jain, Christy Ralph, Andrew Protheroe, Syed Hussain, Robert Jones, Tony Elliot, Ursula McGovern, Alexa Gillman, Claire Paulding, Helen Mossop, Nuria Porta, Diletta Bianchini, Zafeiris Zafeiriou, Gunther Boysen, Daniel Nava Rodrigues, Penelope Flohr, George Seed, Jane Goodall, Ines Figueiredo, Raquel Perez-Lopez, Nina Tunariu, Aurelius Omlin, Roberta Ferraldeschi, Lakshmi P. Kunju, Rosalind Eeles, Gerhardt Attard, Dan Robinson, Arul Chinnaiyan, Emma Hall, Johann S. de Bono. DNA repair defects and antitumor activity with PARP inhibition: TOPARP, a phase II trial of olaparib in metastatic castration resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT322. doi:10.1158/1538-7445.AM2015-CT322

Timing of PSA response to guide cessation of docetaxel in prostate cancer.

e16069 Background: Docetaxel plus prednisolone is an established treatment for men with advanced prostate cancer. Clinicians need to be able to identify men who are not benefiting from chemotherapy, and a key unanswered question is how many cycles of docetaxel should men receive before this assessment is made. We investigated the prognostic significance of a PSA response to docetaxel chemotherapy and the number of cycles after which an absence of PSA response could reliably predict future non-response. Methods: Data was collected for men who received one to ten cycles of docetaxel for castrate refractory prostate cancer between 2005 and 2011. PSA was monitored during treatment. All men were treated at a single centre, The Christie NHS Foundation Trust, UK. Survival is defined as the interval between the first dose of docetaxel and the date of death. Results: Data was available for 320 patients. At the commencement of chemotherapy, median age was 67 years (range 49-81yrs) and median PSA was 207ng/ml. All patients had a Karnofsky Performance Status ≥ 70%. There were 239 deaths and the median survival of the whole group was 403 days. 140 (44%) patients received 6 cycles of docetaxel and 23 patients (7%) received 10 cycles. Median survival was significantly longer in men who had any fall in PSA during chemotherapy compared to those whose PSA did not fall (462 days vs 268 days, p<0.001). Any PSA fall occurred during the first 4 cycles of docetaxel for 95.1% of men. Median survival was significantly longer in men who had a 50% fall in PSA during chemotherapy compared to those who did not (491 vs 357 days, p<0.001). The 50% fall in PSA occurred during the first 5/6 cycles of chemotherapy in 91.5% and 97.7% of men respectively. Conclusions: A patient’s clinical condition is of paramount importance when assessing them during docetaxel chemotherapy. Our data suggest that a fall in PSA following docetaxel is an indicator of improved overall survival. PSA response could help clinicians decide when to stop docetaxel; patients are unlikely to have a fall in PSA if it has not occurred during the first 4 cycles of chemotherapy and they fall into a poor prognostic group. These patients should be considered for alternative treatment in order to improve outcomes and spare them unnecessary toxicity.

Low doses of ketoconazole and prednisone in patients with castration resistant prostate cancer (CRPC): A retrospective study on 73 patients.

e16099 Background: The management of rising PSA in metastatic CRPC remains controversial. In Italy, abiraterone and enzalutamide are not at all approved in this setting of patients (pts). Ketoconazole is an inhibitor of adrenal androgen synthesis that has shown anti-tumor activity by interfering with C-17,20-lyase and could be used as secondary hormonal manipulation. In this retrospective study we report our experience with low doses of ketoconazole and prednisone in the treatment for CRPC. Methods: From March 2007 to March 2012, 73 pts with progressive CRPC who were previously treated with maximal androgen blockade received 200 mg ketoconazole orally 2 times daily, orally replacement prednisone (5 mg bid) and maintained LHRH-agonists. Overall, 40/73 (55%) pts had only bone metastases, 13/73 (18%) had nodal metastases, 20/73 (27%) both. Pts were monitored clinically and with serial PSA measurements every month. Partial biochemical response (PR) was defined as a >50% fall in PSA from baseline. Progressive disease (PD) was defined by objective disease progression or PSA increase of >50% above nadir or >25% above baseline. The endpoints of the study were biochemical response (BR), progression free survival (PFS), overall survival (OS) and adverse events assessment. Results: Median age was 74 (70-78) years; median baseline PSA was 33.09 (1.18-1348.8) ng/ml; median duration of the treatment was 5.05 (0-56.8) months. Twenty out 73 pts (27%) showed a decrease in PSA >50%, with a median duration of PSA response of 3.56 (1.17-33.58) months and 3 pts (4%) a PD. Fifty out 73 pts (68%) achieved a SD with an overall disease control (PR+SD) of 85%. PFS was 10 months for pts who achieved PR and 4 months for those with SD. Differences in PFS stratified according to site of metastases showed better prognosis in patients with only lymph nodes disease (p<0.05). Treatment with Ketoconazole was well tolerated and grades 3-4 toxicities occurred in only 3% of patients. Conclusions: Low-dose ketoconazole is an effective and well-tolerated treatment in pts with CRPC and should be considered in the subset of pts with low tumor burden and a rising PSA level despite maximal androgen blockade.

Outcome of Surgery for Benign Prostatic Hyperplasia-Is It Predictable?

The study was done to evaluate the pre-operative and intra operative factors which influence the post-operative outcome in patients undergoing surgery for Benign Prostatic Hyperplasia (BPH). It was carried out prospectively at a university college hospital in northern India. The study was carried out prospectively in 31 patients who underwent surgery for BPH (TURP - 50, Open Prostatectomy - 10). Various pre-operative and intra-operative parameters were studied by means of a detailed history and examination, IPS score, urodynamic evaluation & cystoscopic examination. Their effect on post-operative outcome was evaluated by measuring changes in IPSS, maximum and average flow rates, and fall in PSA values. Repeated measure ANNOVA was applied to calculate the significance of preoperative factors on post operative outcome (IPSS, Q max and Q av). All parameters studied in the patients improved significantly following surgery. Patients who had pre-operative urinary retention and catheter at the time of surgery had significant improvement in both subjective (IPSS ,p=.oo4) and objective (maximum & average flow rates p=.04) parameters studied. Patients with larger prostrate had a significantly better maximum flow rate (p=.03) and IPSS at 3 months post-operatively. Similarly, patients with larger bladder capacity (more than 150 ml), better compliance (more than 6 ml per cm of water) and lower post-voidal residue (less than 60ml) had better post-operative outcome. Patients with pre-operative urinary retention, shorter duration of bladder catheterization, lower post voidal residue, high IPSS score, larger prostrate, larger bladder capacity and compliance had a significantly better outcome following surgery for BPH as assessed by various parameters studied.

952 - Sequential Androgen Deprivation and Chemotherapy in Metastatic Prostate Cancer: Discordant Responses in Pilot Study Suggest an Opportunity for Individualized Therapy

ABSTRACT Background CRPC is fatal but with recent better survival based on new agents. Optimal sequential therapy remains a challenge. We undertook a phase II pilot study of Mitoxantrone (MTX) followed by docetaxel, estramustine, carboplatin (DEC). Methods CRPC pts who progressed on/after MTX were given estramustine 280mg TID x 5d, docetaxel 60mg/m2, carboplatin AUC = 5 q28 days; ASA & warfarin daily, max 8 cycles. Endpoints: RR >30% with PSA fall >30% & Results 20 pts: Med. age: 66 yrs (53-83), Med. Gleason 8, ECOG PS: 0-1, 12 pts with RP and 8 pts de novo mets, Sites: bone (18), lung (3), liver (4), LN (6). Pts received 2-11 MTX cycles. Prior RT: 12 pts. On DEC 13/20pts PR by PSA, 5: SD, 1: PD; 1: NE. Toxicity: 9pts gr 3/4 neutropenia - 1 with fever, 3: gr 3 neuropathy, 3: gr3 infection, 6: gr 3/4 Hgb, 1: gr3 plats, 1 DVT. Non-heme tox: 4pts gr3 fatigue, 3: gr 3 UTI, 1 gr3 dehydration & diarrhea. Med PFS MTX: 5.5 mos (1.2, 15.3), Med PFS DEC: 5.3 mos (1.2-14.5). OS from MTX start: 20.3 mos (9.1-37.5). OS from DEC start: 12.3 mos (1.2-31). Regression analysis identified visceral mets, alk phos & PFS on MTX (but not PSA, ECOG, Hb or Gleason score) as independent factors for OS from start of MTX. Response to MTX & DEC only partly overlapped. PSA response >30% drop in PSA to MTX or DEC & median OS were: responders to MTX only (n = 4; 20.3 mos (18.4-25.4)); to docetaxel only (n = 10; 14.6 mos (9.1-43.7); both (n = 5; 28.9 mos (22.7-40.3); neither (n = 1; 12.3 mos (Fisher's exact p = 0.3 for response MTX vs DEC, logrank p = 0.028 for OS). Based on pts ADT PSAn, we found longer PFS for DEC and MTX with higher PSAn (log-rank p = 0.048 & 0.019) & trend to better OS on MTX/DEC sequence with PSAn >4 (p = -0.14, med OS 20.1 vs 25.8 months). Fall in Hgb between ADT & start of DEC associated with shorter PFS on DEC (p = 0.05) with a trend to shorter OS (p = 0.08). Conclusions DEC was effective in patients with CRPC given MTX. Pts benefited if they responded to either or both agents but there was limited overlap in response (25%). High PSA nadir on ADT maybe associated with a longer PFS & OS to chemotherapy. Biomarkers linked to hormonal & chemotherapy effect for individual agents in PC could have significant utility. Study with larger cohorts of sequential therapy is ongoing Disclosure All authors have declared no conflicts of interest.

Efficacy of low-dose ketoconazole in the treatment of castration-resistant prostate cancer (CRPC): A single-institution experience.

e15133 Background: The management of rising PSA in CRPC remains controversial. Secondary hormonal manipulations are commonly used before starting chemotherapy. Ketoconazole, an antimycotic that affects the synthesis of androgens and other steroids, has shown direct cytotoxic effects in prostate cancer. This retrospective study describes our experience with low doses of ketoconazole and prednisone treatment for CRPC. Methods: From 4/2007 to 12/2011, 65 patients with progressive CRPC who were previously treated with maximal androgen blockade received 200 mg ketoconazole orally bid with orally replacement prednisone (5 mg bid) and maintained LHRH-agonists. Performance status of all patients was ECOG0. Overall, 34/65 (52.3%) patients had only bone metastases, 12/65 (18.5%) had nodal metastases, 17/65 (26.2%) both and only 2/65 (3.1%) had bone plus lung mets. All patients had low tumor burden and PSADT >6 months. Thirty-six out of 53 patients with bone mets received concomitant zoledronic acid. PSA response was defined as a >50% fall in PSA from baseline and PSA nadir was calculated. Progression was defined by objective disease progression or PSA increase of >50% above nadir or >25% above baseline. Patients were monitored clinically and with serial PSA measurements every 1-month. Results: Median age was 74.05 (range: 52.8-84.4) years; median baseline PSA was 29.95 (range: 1.18-1348.8) ng/ml; median duration of the treatment was 5.87 (range: 0.57-52.4) months. All pts were evaluable for PSA response. At a median F.U.of 15.4 mos. 19/65 patients (29.2%) showed a decrease in PSA >50%, with a median TTP of 17.23 mos for responders. Overall TTP was 5.86 mos and it was not affected by metastatic sites (p= 0.71).Toxicity was mild and no patients discontinued therapy because of side-effects. Five out of 65 patients had G2 (CTC.AE 4) nausea and moderate elevated transaminases. No acute hepatitis or adrenal insufficiency was observed. Conclusions: Our data confirm that low-dose ketoconazole is an effective and well-tolerated treatment in patients with CRPC and should be considered in the subset of patients with low-volume disease and a rising PSA level despite maximal androgen blockade.

A phase II trial of neoadjuvant metformin in prostatic adenocarcinoma with serum and tissue biomarker evaluation.

e15118 Background: Metformin is an inhibitor of the complex 1 in the respiratory chain, and is widely used in diabetes due to its effect on reducing insulin resistance. It has also been recently described to have effects via AMPK on inhibiting the mTOR kinase. Significant preclinical and epidemiological studies suggest its role in chemoprevention. These actions provide significant rationale to evaluate its utility in prostate cancer. We conducted a phase II single centre study of neoadjuvant metformin in localised prostate cancer. Methods: Men were required to have histologically confirmed prostate cancer involving at least 20% of at least 1 unfragmented biopsy core. Exclusion criteria included patients who on initial assessment are found to be on treatment with any drug used for the treatment of any form of diabetes, or patients that begin treatment for any form of diabetes during the course of the study. Pts were treated with up to 500mg tid of metformin. Primary objectives were to demonstrate safety and tolerability of neoadjuvant metformin administration in men with prostate cancer and document changes in phospho-AKT signalling indices. Results: 24 patients were enrolled with 22 evaluable; median age was 64 yrs (range, 45-70 yrs). Baseline characteristics included median PSA 6 ng/mL (range, 3.22-36.11ng/mL). Median duration of drug treatment was 41 days (range 18-81). No grade 3 adverse events were reported, all patients underwent subsequent radical prostatectomy with adverse effects related to metformin. Final Gleason scores ranged form 6-8, and final stage ranged from pT2a-pT3b. Significant pre-and post changes were noted in serum IGF1 (p=0.02), fasting glucose (p=0.03), BMI (p<0.01) and waist/hip ratio (p<0.01). There was a trend for a PSA reduction (p=0.08), with 6/22 patients experiencing a PSA fall of greater than 20%. There were no correlations between any metabolic, morphometric or cancer-related serum indices.Tissue results are pending. Conclusions: Neoadjuvant metformin is well tolerated prior to radical prostatectomy. Data to date indicates promising effects on metabolic parameters, tissue results will be presented including proliferation indices and signaling pathway assessments.

Influence of body mass index (BMI) on PSA kinetics in castrate-resistant prostate cancer (CRPC).

209 Background: Understanding of the role of host energetics in cancer outcomes has been increasing in recent years. In early stage prostate cancer trials obesity is associated with worse outcome. Its effect on treatment response and survival in advanced disease is largely unexplored. We sought to explore the relationship between BMI, the most validated measure of obesity, and biochemical response as well as overall survival in patients receiving first-line chemotherapy. Methods: We reviewed a prospectively-maintained institutional database identifying patients who received docetaxel (D) for CRPC. Demographics and PSA levels during treatment were extracted. Pts were divided into 2 BMI groups (> and < 30 kg/m2). We calculated biochemical responses as per historically validated surrogates: PSA decrease > 30% at 3months; overall decrease > 50%; time to PSA nadir and PSA half-life after 4 cycles, for each group. Results were compared with unpaired t-test and chi-square test. Results: 33 pts were identified between June ‘04 and Sept ‘10, 16 pts with BMI > 30 (hBMI) (range 30.1-34.2) and 17 with BMI < 30 (nBMI) (21.5-29.6). Median age for the entire cohort was 67.9 yrs (47.7-79.8), median Gleason score 8, median cycles of D received was 6 (3-20) with median duration of 3.7 months (1.4-8.7), p>0.05. Baseline PSA was 89.1 ng/ml (0.34-417) and 259.2 (16.1-1,589) for hBMI and nBMI respectively, p = 0.023. For hBMI group, only 56.3% (9/16) of patients demonstrated biochemical response, compared with 88.2% (15/17) in nBMI group(p = 0.039). Of the biochemical responders, 6/16 (38%) of hBMI and 9/7 (53%) of nBMI achieved >50% fall in PSA (p = 0.743) while 8/16 (50%) patients in hBMI group and 10/17 (59%) in nBMI group had a PSA drop >30% at 3 months (p = 0.61); Median time to PSA nadir was 3.4 months (0.7-4.9) and 2.7 (0.7-7.5), and median PSA half life was 56.4 days (16-138) and 46.1 days (16-302) for hBMI and nBMI groups, respectively, p > 0.05. Conclusions: Obese patients with CRPC have lower pre-D PSA levels. However, they also experience a lower rate of biochemical response to therapy. PSA kinetics in biochemical responders do not appear to be influenced by BMI. Survival data will be presented. No significant financial relationships to disclose.

Use of speed and extent of PSA response during the first three cycles of docetaxel chemotherapy in metastatic castrate-resistant prostate cancer to predict overall survival.

48 Background: Docetaxel chemotherapy has an established role in the management of metastatic castrate-resistant prostate carcinoma (CRPC). With an overall survival benefit demonstrated with second line agents, identifying non-responders to docetaxel at an early stage would allow timely consideration of therapy change.We wished to assess PSA response rates to sequential cycles of docetaxel chemotherapy to determine after which cycle men should be considered nonresponders.We also wished to assess if previous therapy with diethylstilbestrol (DES) influenced subsequent response to docetaxel. Methods: Retrospective case review of all men with CRPC receiving docetaxel chemotherapy between January 2007 and April 2010 at our institution was performed. PSA immediately prior to cycle 1 (baseline) and subsequent cycles were noted and evaluated for response compared to baseline PSA. Results: 86 men with a median age of 65 years (47-81) received an average of 5 cycles (1-10) of docetaxel chemotherapy. 67 (77%) had a documented fall in PSA below baseline during chemotherapy with 56 (65%) and 43 (50%) having a PSA response of >30% and >50% respectively. A PSA level lower than baseline was seen in 54%, 63% and 72% of men after cycles 1, 2 and 3 respectively. Limited PSA falls below baseline were seen in 3 (3.4%) and 2 (2.3%) men after cycles 4 and 5 respectively. All PSA responses of >50% had occurred by the start of cycle 4. Of the 14 men who had received DES prior to starting docetaxel, only 3 (21%) had >50% reduction in PSA. The median overall survival for men achieving a PSA response >50% below baseline was 20 mths and was significantly better than the median overall survival of 10mths for those with no PSA response >50% (p<0.0001). Site of metastatic disease also correlated with survival. Conclusions: In our population, men who fail to document a PSA response to the first 3 cycles of docetaxel chemotherapy are highly unlikely to do so after this time. Response defined as a fall below baseline and the extent of PSA decline below baseline are all correlated with survival. More modest PSA responses are seen in men pre-treated with DES than those who have not received DES. No significant financial relationships to disclose.

Low Dose Rate Brachytherapy for Prostate Cancer at the Northamptonshire Centre for Oncology — Outcomes and Bounces

Introduction: Patients with prostate cancer have been treated with low dose rate (LDR) I125 brachytherapy at the Northamptonshire Centre for Oncology since 2002. We evaluated biochemical relapse according to the Phoenix definition (nadir PSA +2 ng/ml) [1] and assessed the occurrence of PSA bounce. A PSA bounce is a rise and subsequent fall in PSA of more than 0.2 ng/ml. This is a recognised phenomenon and may lead to a mistaken diagnosis of relapse [2].

Oral vinorelbine as a fixed-weekly schedule in taxanes-refractory advanced HRPC: A single institution experience

e16084 Background: Vinorelbine (VRL) has been shown to be active in hormone-refractory prostate cancer (HRPC). Oral formulation of VRL represents a significant advance in the treatment of advanced cancer. The recommended doses are 60–80 mg/m2(d1–8 q3wks).We evaluated efficacy and toxicity of different VRL schedule administered as a fixed-weekly dose of 60 mg/m2. The purpose of this study was to evaluate the toxicity profile and efficacy of this schedule in terms of PSA response, objective response and clinical benefit (CB) response. Methods: Pts characteristics were: PS 0–2, adequate bone marrow, liver and renal functions. Oral VRL was adminestered at weekly dose of 60 mg/m2 until disease progression/intolerable toxicity. PSA response was defined as a >50% fall in PSA from baseline, confirmed by a second PSA value 4 or > weeks later. Pts with measurable soft tissue disease met traditional guidelines for tumour responses. Progression was defined by objective disease progression or PSA increase of >50% above nadir or >25% above baseline. Pts were monitored clinically and with serial PSA measurements every 1 week. Results: Thirty seven pts with progressive HR metastatic prostate cancer were evaluated. Mean (range) age was 67 years (50–88), median PSA level was 90 ng/ml (1- 4314), and median Gleason score was 7 (6–9). 23 (62%) pts had previous taxane chemotherapy and 14 pts (38%) were chemo-naive. Pts received a mean of 5.5 cycles (1cycle=3wks) (range:1–24). Median follow-up was 12 months. Thirty three of 37 Pts (97%) achieved a decline in serum PSA. CB response was achieved in 15 out of 37 pts(40%). The PSA response was observed in 13 pts (35%). Objective response was not observed and only 6 pts showed SD (16%). The relative dose-intensity was 94%. There were no reported grade 3–4 toxicities. Only 1 treatment discontinuation was observed (esopahgitis g2). Toxicities consisted primarily of g2 anemia (25%) and mild nausea (32%). Conclusions: Oral Vinorelbine administered as a fixed-weekly schedule of 60 mg/m2 is a safe regimen in pts with advanced HRPC. This regimen of oral vinorelbine is an effective and well-tolerated treatment in this setting, despite a major dose-intensity administered. Further studies will be evaluated in chemo-naive and/or elderly population. No significant financial relationships to disclose.

Efficacy of low-dose ketoconazole in hormone refractory prostate cancer patients (HRPC): A single institution experience

16117 Background: The management of HRPC remains controversial. Among the options, second-line hormonal therapy is commonly used. Ketoconazole, an antimycotic which affects the synthesis of androgens and other steroids, has shown direct cytotoxic effects in prostate cancer. This study describes our experience with low-dose ketoconazole treatment for HRPC. Methods: All eligible pts had histologically proven adenocarcinoma of the prostate, and all pts had progressive castration resistant prostate cancer by consensus criteria and had received no prior hormonotherapy. Pts received 400 mg ketoconazole orally 3 times daily, and orally replacement hydrocortisone. PSA response was defined as a >50% fall in PSA from baseline, confirmed by a second PSA value 4 or > weeks later. Pts with measurable soft tissue disease met traditional guidelines for tumour responses. Progression was defined by objective disease progression or PSA increase of >50% above nadir or >25% above baseline. Pts were monitored clinically and with serial PSA measurements every 1 month. Results: Data for 73 pts were analysed. Median age was 73 years(57–89), median PSA was 67.8 ng/ml (range: 7.5–347.0), with a median performance status of 90%(range: 70–90%). Of the 70 pts (PSA data missing in 3 pts), 33 (47.0%) showed a decrease in PSA >50% (95% CI 37.5%-61.4%) with a median duration of 7.8 months (range 4–41 months). We observed objective responses in 12 of 34 pts(35%) with measurable soft tissue disease and bone metastasis. Age, PSA at diagnosis, Performance status, Gleason score and bone scan result were not significantly associated with response to ketoconazole treatment in univariate or multivariate analyses. A longer duration of primary androgen deprivation therapy (ADT) and total duration of previous hormonal therapy was associated with a longer time to progression.Toxicity was mild with 5 of 73 patients(7.0%) discontinued therapy because of gastrointestinal side-effects or moderate elevated transaminases. No acute hepatitis or adrenal insufficiency was observed. Conclusions: Low-dose Ketoconazol is an effective and well-tolerated treatment in pts with HRPC and should be considerate in a subset of pts with low-volume disease and a rising PSA level despite ADT. No significant financial relationships to disclose.

Suivi pratique d’un patient traité par finastéride pour le dépistage de cancer de prostate

The following conclusions can be made on the practical follow up of a patient receiving finasteride in screening for prostate cancer from an analysis of the literature and, particularly, the Prostate Cancer Prevention Trial (PCPT). Prostate volume fells by an average of 17 to 19%. The average fall in PSA after one year of finastéride treatment was 50%. This fall continued over time, at an average of 5% per year. An adjustment factor of x 2 at 1 year was used to return to a PSA value of a group of untreated men. The ratios of free PSA/total PSA and complexed PSA/total PSA remained unchanged and were interpreted as usual. The risk of cancer was low if the PSA fell by > or = 50% and raised if it fell by < 33%. Prostate cancer was associated with an average 15% rise in PSA on finasteride. This change still needs to be validated. The sensitivity of PSA and rectal examination was greater in detecting all grades of cancer in people receiving finasteride than on placebo. These findings have the benefit of reducing the indications for biopsy during follow up. Finasteride does not appear to cause high grade cancers. Despite the 25% reduction in the risk of cancer on finasteride there was insufficient information, particularly on the impact on mortality to allow chemoprevention to be proposed. Patients started on finasteride to treat BPH must be informed of the possible benefits, side effects and follow up arrangements to screen for prostate cancer.