A phase II trial of 17-allylamino-17-demethoxygeldanamycin (17-AAG) in patients with hormone-refractory metastatic prostate cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15553-15553 ◽  
Author(s):  
E. I. Heath ◽  
D. Hillman ◽  
U. Vaishampayan ◽  
S. Sheng ◽  
F. H. Sarkar ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Biology ◽  
Progression Free Survival ◽  
Fold Increase ◽  
Median Number ◽  
Serum Markers ◽  
Primary Objective ◽  
Psa Response ◽  
Hormone Refractory ◽  
Prior Systemic Therapy

15553 Background: 17-Allylamino-17-Demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin antibiotic with anti- proliferative activity in several mouse xenograft models including prostate cancer models. Serum IL-6, IL-8, and maspin are potentially important markers of prostate cancer biology. Methods: Patients (pts) with metastatic, hormone-refractory prostate cancer progressing on at least one prior systemic therapy with rising PSA were eligible. All pts received 17-AAG at a dose of 300 mg/m2 IV weekly for three out of four weeks. Primary objective was to assess the PSA response (50% decrease in PSA). Secondary objectives included Adverse Events (AEs) and correlative serum markers including IL-6, IL-8 and maspin levels. A Simon two-stage design required a total of 25 pts with early termination if < 2 responses occurred among the 1st 16 eligible patients. Results: Seventeen pts were enrolled of which 15 were deemed eligible. Median age was 68 and median PSA was 252 ng/mL. Pts received 17-AAG for a median number of 2 cycles. No pt had a PSA response. No grade 4/5 AEs occurred. Grade 3 AEs included fatigue (4 pts), lymphopenia (2 pts) and back pain (2 pts). The median PSA progression free survival was 1.8 months (95% CI: 1.3–3.4 months). The six-month overall survival was 61% (95% CI: 37%-100%). Due to the lack of PSA response, accrual was stopped per study design. At day 15, the median IL-6 and IL-8 increase from baseline was 0.4 pg/ml (p=0.57) and 3 pg/ml (p=0.73), respectively. Maspin levels had day 15 increase of 6-fold (p=0.44). At treatment failure (TF), the median IL-6 increase from baseline was 4.47 pg/ml (p=0.03) and IL-8 decrease was 1.8 pg/ml (p=0.31). Maspin levels had a 29-fold increase at TF (p=0.09). Conclusions: 17-AAG did not show any activity with regards to PSA response. Serum IL-6 was significantly increased at the time of TF. Further evaluation of 17-AAG at a dose of 300 mg/m2 IV weekly in this patient population is not warranted. No significant financial relationships to disclose.

High response to docetaxel (D)/carboplatin (C) based chemotherapy as salvage therapy in patients with docetaxel-resistant metastastic hormone-refractory prostate cancer (HRPC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16041-e16041
Author(s):  
C. Reuter ◽  
P. Ivanyi ◽  
M. Morgan ◽  
A. Ganser ◽  
T. Winkler ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Retrospective Analysis ◽  
Performance Status ◽  
Neuron Specific Enolase ◽  
Median Number ◽  
Optimal Regime ◽  
Common Grade ◽  
Psa Response ◽  
Hormone Refractory ◽  
Grade 3

e16041 Background: Presently, there is no standard treatment for prostate cancer (PC) patients who are resistant to docetaxel therapy. While previous reports support the use of C in combination with D in these patients (pts), the optimal regime is still unknown. Methods: Metastatic HRPC pts with clinical and/or radiographic evidence of progression while on docetaxel were included in our retrospective analysis. Between February 2005 and December 2008, 30 pts received treatment with C AUC 5 q3wks in combination with D 75 mg/m2 q3wks or D 35 mg/m2 d1, d8, d15 q4wks. All pts were assessed for PSA response and clinical outcome. Results: 27 pts were evaluable for response. Median age was 69 years (range 56–77) and median baseline performance status was ECOG 1 (range 0–2). The median number of prior therapies was 1 (range 1–3) with a median of 7 cycles of D therapy (range 3–34) administered. Median PSA at baseline was 297.15 ng/ml (range 12.33–6,446). Serum chromogranin A and neuron-specific enolase (NSE) were elevated in 24/24 and 8/25 cases, respectively. The median follow-up was 8.9 months (range: 0–38) with a median number of 6 cycles DC administered (range: 2–35). PSA declines of ≥50% (= PSA-response) was achieved in 14 of 27 pts (52%, 95% C.I. 0.32, 0.71) and PSA stabilization in 9 pts (33%). 4 pts (15%) progressed without PSA response. 6 PSA responders had a PSA reduction of >90%. The median duration of PSA response was 20.7 wks (95% C.I. 18.4, 59 wks). TTP was significantly longer in PSA responders vs. PSA non-responders (64.7 wks vs 15 wks, p<0.0001). 10 of 16 pts with measureable disease were evaluable for response. 3 of 6 PSA responders had a PR and 3 SD, while 2/4 pts with PSA non-response had PD and 2 SD. At the time of analysis, 2 PSA responders and 7 PSA non-responders have died. Median OS of all patients was 69.7 weeks with 79.9 wks for PSA responders vs. 38 wks for PSA non-responders (p=0.0034). The most common grade 3/4 toxicities were neutropenia in 42%, anemia in 23% and thrombocytopenia in 15% of pts. 17 of 30 pts had blood transfusions due to anemia. Conclusions: This retrospective analysis supports the usefulness of C plus weekly D chemotherapy as ≥second-line chemotherapy in docetaxel-resistant PC patients. No significant financial relationships to disclose.

Pilot study of veliparib (ABT-888) with temozolomide (TMZ) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 224-224 ◽  
Author(s):  
Maha Hussain ◽  
Michael Anthony Carducci ◽  
Susan F. Slovin ◽  
Jeremy Paul Cetnar ◽  
Jiang Qian ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Type I Error ◽  
Objective Response ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Type I ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Psa Response ◽  
Clinically Significant

224 Background: Castration-resistant PC tumors exhibit increased PARP activity (critical enzymes for DNA damage repair). Veliparib is a novel, oral, potent inhibitor of PARP-1 and PARP-2. Preclinically, resistance to oral TMZ treatment in the PC3-Luc prostate cancer mouse model was reversed when mice were treated with veliparib. Based on the synergistic interaction, we evaluated the efficacy and safety of veliparib + TMZ in mCRPC pts. Methods: Eligible pts had mCRPC, PSA>2 ng/mL, progressed on at least one docetaxel based therapy and adequate organ function. Pts received veliparib 40 mg BID Days (D) 1-7 and TMZ D1-5 in 28D cycle (C) until disease progression (PD) or unacceptable toxicities. Tumor response was assessed every 8 weeks. Primary objective: Efficacy based on rate of PSA decline of 30% or greater. Secondary objectives: safety, RECIST objective response rate, progression-free survival (PFS), overall survival (OS) and biomarker analyses. A sample size of 25 pts provided 76% power to differentiate between PSA response rates of 5 and 20% at 1-sided type I error rate of 0.1. Results: 26 pts were enrolled; median age 67 years [55, 81]; median baseline PSA 107 ng/ml (6.9, 4584.4); 7/26 (27%) had 2 prior therapies. Median Cs of veliparib + TMZ received were 2 (range 1–9). Most frequent treatment related adverse events (AE) were fatigue (50%), nausea (38%) and constipation (23%). Grade 3/4 AEs in >10% of pts was thrombocytopenia (15%). All pts are off therapy. 25 pts were PSA response evaluable; 2 pts had a confirmed PSA response; 1 pt had a 37% decrease in PSA while the other pt had a 96% decrease in PSA and a 40% reduction in tumor size. 4/25 pts had stable disease for a minimum of 4 months (m). Median PFS was 2.1 m [95% CI: 1.8, 3.9]; 11/26 pts have died with median OS of 9.1 m [95% CI: 5.5, 11.7]. There was a negative correlation between change from baseline in circulating tumor cells and PFS. Conclusions: Veliparib + TMZ were well tolerated with evidence of some activity. Due to lack of activity of TMZ in CRPC,veliparib-induced potentiation of TMZ may not be clinically significant. Other combinations will be explored with higher doses of veliparib. Biomarker data will be presented.

Ixabepilone (Epothilone B Analogue BMS-247550) Is Active in Chemotherapy-Naive Patients With Hormone-Refractory Prostate Cancer: A Southwest Oncology Group Trial S0111

2005 ◽  
Vol 23 (34) ◽  
pp. 8724-8729 ◽  
Author(s):  
Maha Hussain ◽  
Catherine M. Tangen ◽  
Primo N. Lara ◽  
Ulka N. Vaishampayan ◽  
Daniel P. Petrylak ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Performance Status ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Hematologic Toxicity ◽  
Hormone Refractory Prostate Cancer ◽  
Grade 5 ◽  
Psa Response ◽  
Hormone Refractory ◽  
Grade 3

Purpose The epothilones are a new class of tubulin-polymerizing agents with activity in taxane-sensitive and resistant tumor models. We evaluated ixabepilone (BMS-247550) in patients with metastatic hormone-refractory prostate cancer (HRPC). Methods Eligible patients had chemotherapy-naive metastatic HRPC, a Zubrod performance status of 0 to 2, and adequate organ function. All patients received BMS-247550 at 40 mg/m2 over 3 hours every 3 weeks. The primary end point was proportion of patients achieving a prostate-specific antigen (PSA) response. Results Forty-eight patients with metastatic HRPC were registered. Forty-two patients were eligible, with a median age of 73 years and a median PSA level of 111 ng/mL; 78% had bone-only or bone and soft tissue metastases, and 88% had objective radiologic disease progression at registration. Grade 3 and 4 adverse events (AEs) occurred in 16 and three patients, respectively. All grade 4 toxicities were neutropenia or leukopenia. The most frequent grade 3 AEs were neuropathy (eight patients), hematologic toxicity (seven patients), flu-like symptoms, and infection (five patients each). There were no grade 3/4 thrombocytopenia or grade 5 AEs. There were 14 confirmed PSA responses (33%; 95% CI, 20% to 50%); 72% of PSA responders had declines greater than 80%, and two patients achieved an undetectable PSA. The estimated median progression-free survival is 6 months (95% CI, 4 to 8 months), and the median survival is 18 months (95% CI, 13 to 24 months). Conclusion Ixabepilone has demonstrated activity in patients with chemotherapy-naive metastatic HRPC. Major toxicities were neutropenia and neuropathy. Further testing to define its activity relative to standard therapy is warranted.

Abi Race: A prospective, multicenter study of black (B) and white (W) patients (pts) with metastatic castrate resistant prostate cancer (mCRPC) treated with abiraterone acetate and prednisone (AAP).

2018 ◽  
Vol 36 (18_suppl) ◽  
pp. LBA5009-LBA5009 ◽  
Author(s):  
Daniel J. George ◽  
Elisabeth I. Heath ◽  
A. Oliver Sartor ◽  
Guru Sonpavde ◽  
William R. Berry ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Multicenter Study ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
Abiraterone Acetate ◽  
Primary Objective ◽  
Prospective Multicenter Study ◽  
Psa Response ◽  
Castrate Resistant ◽  
The Impact

LBA5009 Background: Pivotal trials of AAP for patients with mCRPC enrolled few B pts, a population with a higher mortality from prostate cancer. Retrospective data suggests B pts may have higher PSA response rates than W pts treated with AAP for mCRPC. Therefore, we prospectively investigated AAP in B vs. W pts with mCRPC. Methods: Abi Race (NCT01940276) is a prospective, multicenter, parallel group study of AP in 100 men (50 B, 50 W) with mCRPC, self-identified by race. All pts received AA 1000 mg/D and P 10 mg/D (AAP) until disease progression or unacceptable adverse events (AE). The primary objective was radiographic progression-free survival (rPFS); key secondary endpoints include PSA kinetics and safety. Exploratory analyses include SNP, metabolomics and hormonal differences by race. Results: Baseline characteristics among pts were similar. The median rPFS for B and W pts was 16.8 months (mo) in each. However, PSA PFS varied by race; median PSA PFS for B and W pts were 16.6 and 11.5 mo [Table]. B pts also had numerically higher rates of ≥30%, ≥50% and ≥90% PSA decline [Table]. AEs were similar in frequency and severity by race including hypertension (42 vs 40%); however, fatigue was higher in W pts (40 vs 26%), and hypokalemia was higher in B pts (36 vs 18%). SNP profiling revealed differences in key genes involved in androgen metabolism and transport. Conclusions: This is the first prospective multicenter study by race of secondary hormonal therapy in mCRPC. B pts may have greater and more durable PSA response to AAP than W pts. SNP patterns vary by race and will be evaluated for prognostic significance. Further prospective studies in B pts are possible and needed to understand the impact of racial determinants on outcome of new hormonal regimens. Clinical trial information: NCT01940276. [Table: see text]

A phase II study of paclitaxel and vinorelbine (Pacl-Vin) in hormone-refractory metastatic prostate cancer (HRPC): Double tubulin targeting

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14559-14559
Author(s):  
S. Sewak ◽  
S. Kosmider ◽  
V. Ganju ◽  
A. Woollett ◽  
B. Le ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Objective Response ◽  
Progression Free Survival ◽  
Bisphosphonate Therapy ◽  
Combination Methods ◽  
Psa Response ◽  
Hormone Refractory ◽  
Grade 3 ◽  
Ecog Ps

14559 Background: Phase 2 trials of Paclitaxel+corticosteroid or Vinorelbine+corticosteroid have shown 20–40% PSA responses. Preclinical models have shown synergy between Paclitaxel and Vinorelbine. A phase I trial showed this to be a tolerable combination. Methods: The aim of this study was to determine the efficacy and safety of Paclitaxel and Vinorelbine. 30 castrate pts with progressive, metastatic prostate cancer were enrolled. Previous radiotherapy, strontium therapy, 1 line of chemotherapy, and concurrent bisphosphonate therapy were allowed. Pts were treated with Paclitaxel 40 mg/m2 (1 hr), and Vinorelbine 20 mg/m2 iv on day-1 & day-8 of a 21-day cycle. All pts received standard premedication for Paclitaxel including dexamethasone. Results: Baseline pt characteristics were: median ECOG PS of 1 (range 0–2), median age 71, mean PSA 413ng/mL, mean Hb 11.9 g/dL. For 10 pts with measurable disease the partial response rate was 20%, with 70% of pts achieving stable disease (SD). Of 23 assessable pts, 9% had 50% decline in PSA, and 78% had SD, maintained for at least 4 weeks. Median overall survival was 7.3 months. Median progression free survival was 3.3 months. All pts completed quality of life (QOL) questionnaires. There was an improvement over baseline after 3 cycles of therapy in pts pain, appetite, constipation, voiding and overall wellbeing (p = non-significant). Grade 3/4 toxicities were: anemia 3%, neutropenia 8%, infection 2%, febrile neutropenia 4%, lethargy 1%, and somnolescence 1%. 1 pt died as a result of sepsis and neutropenia. Conclusions: In this poor prognostic cohort of pts the combination of Paclitaxel and Vinorelbine is a tolerable regimen, which has demonstrated minor PSA response, with the majority of pts achieving PSA stability. There was some objective response to this regimen and importantly it stabilized disease in a majority of pts. Important QOL parameters such as pain were improved.This is a useful regimen to test in poor prognosis HRPC pts. No significant financial relationships to disclose.

Prostate Cancer: Biology, Incidence, Detection Methods, Treatment Methods, and Vaccines

2020 ◽  
Vol 20 (10) ◽  
pp. 847-854
Author(s):  
Ronald Bartzatt
Keyword(s):  
Prostate Cancer ◽  
Cancer Treatment ◽  
Prostate Specific Antigen ◽  
Cancer Biology ◽  
Early Stage ◽  
Specific Antigen ◽  
Detection Methods ◽  
Hormone Refractory Prostate Cancer ◽  
High Risk Prostate Cancer ◽  
Hormone Refractory

Cancer of the prostate are cancers in which most incidences are slow-growing, and in the U.S., a record of 1.2 million new cases of prostate cancer occurred in 2018. The rates of this type of cancer have been increasing in developing nations. The risk factors for prostate cancer include age, family history, and obesity. It is believed that the rate of prostate cancer is correlated with the Western diet. Various advances in methods of radiotherapy have contributed to lowering morbidity. Therapy for hormone- refractory prostate cancer is making progress, for almost all men with metastases will proceed to hormone-refractory prostate cancer. Smoking cigarettes along with the presence of prostate cancer has been shown to cause a higher risk of mortality in prostate cancer. The serious outcome of incontinence and erectile dysfunction result from the cancer treatment of surgery and radiation, particularly for prostate- specific antigen detected cancers that will not cause morbidity or mortality. Families of patients, as well as patients, are profoundly affected following the diagnosis of prostate cancer. Poor communication between spouses during prostate cancer increases the risk for poor adjustment to prostate cancer. The use of serum prostate-specific antigen to screen for prostate cancer has led to a greater detection, in its early stage, of this cancer. Prostate cancer is the most common malignancy in American men, accounting for more than 29% of all diagnosed cancers and about 13% of all cancer deaths. A shortened course of hormonal therapy with docetaxel following radical prostatectomy (or radiation therapy) for high-risk prostate cancer has been shown to be both safe and feasible. Patients treated with docetaxel-estramustine had a prostate-specific antigen response decline of at least 50%. Cancer vaccines are an immune-based cancer treatment that may provide the promise of a non-toxic but efficacious therapeutic alternative for cancer patients. Further studies will elucidate improved methods of detection and treatment.

UnCHAARTED territory: The role of docetaxel rechallenge following chemohormonal therapy for metastatic castrate-sensitive prostate cancer.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 117-117
Author(s):  
Mary Mahler ◽  
Esmail Mutahar Al-Ezzi ◽  
Noa Shani Shrem ◽  
Eric Winquist ◽  
Christina M. Canil ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Lymph Node ◽  
Median Time ◽  
Median Number ◽  
Time To Progression ◽  
Chemohormonal Therapy ◽  
Radium 223 ◽  
Psa Response ◽  
Number Of Cycles

117 Background: Since docetaxel has been advanced to the metastatic castrate-sensitive prostate cancer (mCSPC) setting, there is a lack of evidence guiding its re-introduction upon castrate-resistant (CR) progression. We sought to identify clinical characteristics and outcomes of patients subjected to docetaxel rechallenge (DR) following prior docetaxel exposure in the mCSPC realm. Methods: Patients rechallenged with docetaxel following treatment in the mCSPC setting were identified from three academic centres in Ontario, Canada. Retrospective chart reviews were performed to identify clinical, treatment and outcome variables. Results: Of the 45 patients with DR initiated between 06/2015 and 07/2020, the median age was 65, 60% had a Gleason score of ≥8, and 64% had an ECOG of ≤1. 56% had bone only metastasis, 4% lymph node only metastasis, 29% bone and lymph node metastasis, and 11% had visceral metastasis. In the mCSPC setting, 98% of patients received 6 cycles of docetaxel with 13% requiring dose delays. Of 43 informative patients, all had a PSA response to chemohormonal therapy. 91% achieved at least a 50% PSA response (PSA50), of which 40% had a 50-89% PSA reduction and 51% had a ≥90% PSA reduction. 29% of patients obtained a PSA nadir of < 0.2 ng/mL. 16% had CR progression in < 6 months, 56% in 6-12 months, and 28% in > 12 months. DR was initiated after a median of 20.8 months (range 6.0-40.4) following the last dose of docetaxel for mCSPC, and was given as first line treatment for CR disease to 7%, second line to 51%, third line to 40%, and fourth line or beyond to 2% of patients. 69% of patients had received an androgen-receptor axis targeted therapy prior to DR, 18% radium 223, and 7% had received a trial drug. Notably, no patients had received cabazitaxel prior to DR. The median number of cycles of docetaxel received at rechallenge was 5 (range 1-11) with 18% of patients requiring treatment delays. 64% of patients stopped treatment due to progression, 16% due to side effects, 7% at the patient’s request, 7% due to completion of the planned number of cycles, and 6% due to death or other causes. Among 44 informative patients, 23% achieved at least a PSA50, with 18% having a 50-90% PSA reduction, and 5% having a ≥90% PSA reduction. The median time to progression (biochemical, radiographic, or death) was 2.3 months (95%CI 1.7-4.4) and the median overall survival was 11.0 months (95%CI 8.5-14.3). Conclusions: DR following exposure to docetaxel in the mCSPC setting resulted in a PSA50 in only around one quarter of patients. Both the median time to progression and overall survival were found to be short. With future investigations, we hope to identify clinical variables that will help predict which patients might benefit most from DR.

PSA flare-up in patients with hormone-refractory prostate cancer (HRPCA) receiving docetaxel-based chemotherapy: Incidence and differentiation from progressive disease

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14523-14523
Author(s):  
D. Sahi ◽  
C. H. Ohlmann ◽  
I. Cordia ◽  
U. Engelmann ◽  
A. Heidenreich
Keyword(s):  
Prostate Cancer ◽  
Progressive Disease ◽  
Initial Increase ◽  
Hormone Refractory Prostate Cancer ◽  
Common Phenomenon ◽  
Maximum Increase ◽  
Psa Response ◽  
Hormone Refractory ◽  
Initiation Of Therapy ◽  
Doubling Times

14523 Background: Docetaxel-based chemotherapy displays the standard therapy for patients with hormone-refractory prostate cancer. A subset of patients will experience an initial PSA increase after initiation of therapy followed by a subsequent PSA decrease. The aim of our study was to investigate the incidence of this phenomenon and to identify factors that differentiate the flare-up from progressive disease. Methods: We retrospectively analyzed the patient records of 46 patients who received docetaxel as monotherapy or in combination with either mitoxantron or estramustine for hormone-refractory prostate cancer. PSA flare-up was defined as an initial PSA increase of more than 25% after initiation of therapy over baseline followed by a PSA decrease of at least 75% compared to the maximum increase over baseline. Progressive disease was defined as a PSA increase of at least 25% over baseline in patients with no PSA response which had to be confirmed four weeks later. Results: Of 46 patients who received docetaxel-based chemotherapy 16 (34.8%) showed a PSA decrease of at least 50%, 6 (13.0%) between 30–50%, 17 (37.0%) had stable disease and 7 (15.2%) patients experienced progressive disease. An initial PSA increase followed by a subsequent PSA decrease was seen in 6 (13.0%) of the patients. Median PSA increase compared to baseline was 81.0% (25–239). The median following PSA decrease was 110.5% (77–160) compared to the initial increase. Median PSA doubling times of patients with PSA flare up or progressive disease were 113.3 and 100.7 days (p = 0.7941), respectively. Conclusions: PSA flare-up seems to be a common phenomenon in patients being treated with docetaxel-based chemotherapy for hormone-refractory prostate cancer. In order not to prevent those patients from a subsequent PSA decrease by early cessation of therapy it would be useful to discriminate them from patients with progressive disease. According to the results of our study PSADT does not differ between patients with flare-up or progressive disease and can therefore not be used to distinguish between the two. No significant financial relationships to disclose.

Mifepristone (RU-486) in androgen independent prostate cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14508-14508
Author(s):  
J. H. Hayes ◽  
W. K. Oh ◽  
P. W. Kantoff ◽  
J. B. Manola ◽  
M. R. Smith ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Biology ◽  
Critical Role ◽  
Adrenal Androgens ◽  
Ru 486 ◽  
Testosterone Levels ◽  
Potential Efficacy ◽  
Psa Response ◽  
Grade 3 ◽  
Gi Bleed

14508 Background: The androgen receptor (AR) plays a critical role in the development and progression of prostate cancer, and available antiandrogens do not turn off AR transcription completely. Mifepristone (RU-486) is a potent inhibitor of AR and acts by both competing with dihydrotestosterone (DHT) and binding with the AR co-repressor nuclear receptor co-repressor (NCoR), converting AR from a transcriptional activator to a transcriptional repressor. Methods: 22 patients with AIPC, PSA ≥5 ng/mL, and documented bone metastases were treated with mifepristone 200 mg PO QD until disease progression. Correlative studies include measurement of testosterone, cortisol, androstenedione, DHT, DHEA (dehydroepiandrosterone), and DHEA sulfate levels at baseline and during therapy. Results: Patients were treated a median of 84 days (range 10–182 d). Median PSA at time of enrollment was 41.9 ng/mL (range 5.2–1930.9 ng/mL). No patients demonstrated a PSA response. 13 patients have discontinued treatment, 12 for progressive disease (11 PSA progression and 1 bony progression) and 1 for grade 3 toxicity (GI bleed after 10 d on treatment). 6 patients are still on therapy with stable disease after a median 98 d. In 11 patients, baseline testosterone levels were mean 28.4 ng/dL (range <20–49 ng/dL). After one month of therapy, testosterone increased to mean 66.6 ng/dL (range 16–104 ng/dL) (p = 0.001). Compared to baseline, one month androstenedione and DHEAS levels were elevated in the majority of patients. Conclusions: Mifepristone demonstrated limited activity in AIPC patients. Potential efficacy was most likely limited by a rapid elevation in testosterone levels. We hypothesize that inhibition of glucocorticoid receptor led to an increase in ACTH with subsequent elevation of adrenal androgens and conversion to DHT. These preliminary data suggest that even moderate increases in systemic testosterone levels may stimulate tumor growth. These data also emphasize the continued importance of adrenal androgens and AR transcription in prostate cancer biology. No significant financial relationships to disclose.

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