A randomized phase II trial of abiraterone, olaparib or abiraterone + olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair defects.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS5086-TPS5086 ◽  
Author(s):  
Zachery Reichert ◽  
Benedito A. Carneiro ◽  
Stephanie Daignault-Newton ◽  
Amanda Sullivan ◽  
Felix Yi-Chung Feng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Dna Repair ◽  
Excision Repair ◽  
Single Agent ◽  
Specific Antigen ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Psa Response ◽  
Brca1 Brca2

TPS5086 Background: Approximately 20% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor mutations in genes encoding DNA repair proteins (e.g. ATM, BRCA1, BRCA2, PALB2, RAD51, CHEK2, FANCA). These mutations impact base excision repair and alternative end-joining, which rely on the activity of poly(ADP-ribose) polymerase (PARP). Olaparib (olap) inhibits PARP and showed activity in a post hoc analysis in mCRPC patients with DNA repair defects (DRD). In a subgroup analysis of the NCI 9012 trial evaluating abiraterone (abi) +/- veliparib (a PARP inhibitor), patients with DRD in both treatment groups had a > 80% prostate-specific antigen (PSA) response rate and prolonged progression free survival (PFS) (13.8 mos vs. 7.8 mos; P = 0.01). Preclinical data suggests interactions between androgen signaling and PARP activity. These observations provide the rationale to evaluate the efficacy of olap, abi or the combination in patients with DRD. Methods: This is a prospective, randomized, open-label phase 2 clinical trial with a primary endpoint of objective PFS (radiographic + clinical). Secondary endpoints: objective disease and PSA response rates. Analysis of tumor specimens, circulating tumor cells/DNA will be performed. Eligible patients with progressive mCRPC, no prior mCRPC therapy with tumor loss of ATM, BRCA1 or BRCA2 (based on known germline loss, prior CLIA certified tumor analysis or new metastatic biopsy) will be stratified by germline vs. somatic mutational status and randomized 1:1:1 to abi (1000 mg daily) + prednisone (5 mg bid), olap (300 mg daily) or olap + abi + prednisone (same doses). Patients in single agent arms may cross over to opposite single agent therapy at progression. An exploratory cohort of patients with DNA repair defects besides ATM, BRCA1, BRCA2 may receive olap. Statistical analysis will provide median, 12-month, and 24-month product-limit estimates of PFS by treatment arm. The study is recruiting 60 randomized patients at sites in the US. The trial is coordinated by the Prostate Cancer Clinical Trials Consortium, LLC and funded by AstraZeneca. Clinical trial information: NCT03012321.

Abiraterone in patients with metastatic castration-resistant prostate cancer progressing after docetaxel and MDV3100.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4554-4554 ◽  
Author(s):  
Ecaterina Ileana ◽  
Yohann Loriot ◽  
Laurence Albiges ◽  
Christophe Massard ◽  
Aurore Blesius ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Specific Antigen ◽  
Patient Characteristics ◽  
Preliminary Evidence ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Symptom Response ◽  
Psa Response ◽  
Metastatic Sites

4554 Background: Chemotherapy with docetaxel is the standard first-line treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). In patients progressing after docetaxel, both abiraterone and MDV3100 have yielded improved survival for patients with mCRPC. The efficacy of abiraterone in patients pre-treated with MDV 3100 is unknown. Methods: We investigated abiraterone-prednisone in 24 patients with cancer progression after docetaxel followed by MDV3100. All patients received abiraterone 1000 mg/day plus prednisone 10mg/day. Prostate-specific antigen (PSA) response, symptom response, and time to progression were assessed. Results: Patient characteristics were as follows: median age: 74 years (53-84), median PSA: 108 ng/mL (2-2541), metastatic sites: bone: all 24 patients, liver/lung: 6 patients (25%), and lymph nodes : 9 patients (38%). Five patients (21%) had a PSA decrease on abiraterone-prednisone. Three patients (13%) achieved a PSA response, defined as a decrease of >50% in PSA, confirmed after≥ 4 weeks. The duration of PSA response was 2, 3 and 4.5 months. Six patients (29%) had a symptomatic response on the pain score and analgesic consumption was decreased. Treatment was well tolerated. Abiraterone-prednisone was discontinued in one patient due to edema and hypokaliemia. Conclusions: This study shows preliminary evidence that abiraterone-prednisone yields activity in patients with mCRPC pretreated with docetaxel and MDV3100.

The effect of prior abiraterone (Abi) use on the activity of enzalutamide (Enza) in men with mCRPC.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 18-18 ◽  
Author(s):  
Heather H. Cheng ◽  
Rosa Nadal ◽  
Roman Gulati ◽  
Arun Azad ◽  
Przemyslaw Twardowski ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Specific Antigen ◽  
Subsequent Treatment ◽  
Significant Response ◽  
Castration Resistant Prostate Cancer ◽  
Steroid Use ◽  
Castration Resistant ◽  
Disease Characteristics ◽  
Psa Response ◽  
Time Of Presentation

18 Background: Enzalutamide (Enza) and abiraterone (Abi) are next generation hormonal agents for metastatic castration resistant prostate cancer (mCRPC). Whether these agents can be effectively sequenced is not yet well understood. Results of retrospective analyses of Abi after prior Enza have demonstrated modest responses of brief duration, suggesting common resistance pathways. Here, we retrospectively analyze response to Enza with or without prior Abi treatment. Methods: We retrospectively reviewed 195 patients from seven academic centers treated with Enza between January 2009 and August 2013. Data were collected on disease characteristics, prior therapies, and prostate-specific antigen (PSA) values at baseline and while on treatment. Logistic regression was used to evaluate association between 30% or greater PSA decline on Enza and either prior Abi treatment or 30% or greater PSA decline on prior Abi after accounting for potential confounders. Results: One hudred eighty three patients had non-missing PSA starting and nadir values on Enza, with starting PSA median 102.0 (range 1.1–5007.0) ng/mL. Overall, 42% (76 of 183) of Enza-treated patients achieved a 30% or greater PSA decline, with 39% (58 of 150) response among prior Abi-treated patients and 55% (18 of 33) response among Abi-naïve patients. Of 79 patients who lacked significant response to prior Abi, 30% (25 of 79) achieved a 30% or greater PSA decline and 19% (15 of 79) achieved a 50% or greater PSA decline with subsequent Enza. Odds of achieving a 30% or greater PSA response on Enza was 2.3 times higher for Abi-naïve patients versus prior Abi-treated patients (95% CI 1.0–5.5, P=0.06) and 1.9 times higher for Abi-responders vs Abi-non-responders (95% CI 1.0–3.7, P=0.06) after adjusting for prior docetaxel and concurrent steroid use. Conclusions: In this multi-center retrospective study, 39% of patients achieved a 30% or greater PSA decline with Enza after prior Abi treatment. While the activity of Enza appears to be blunted in the post-Abi setting, PSA declines still occur in a meaningful proportion of patients. Notably, 30% of patients without significant response to prior Abi responded to subsequent treatment with Enza, suggesting a subset of men with distinct biological resistance pathways. Data will be updated at the time of presentation.

Efficacy of abiraterone and enzalutamide in patients who had disease progression within twelve months of completing docetaxel for metastatic castration sensitive prostate cancer.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 241-241
Author(s):  
Gang Chen ◽  
David James VanderWeele ◽  
Fatima Karzai ◽  
Marijo Bilusic ◽  
Munjid Al Harthy ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Specific Antigen ◽  
Response Duration ◽  
Optimal Timing ◽  
Castration Resistant Prostate Cancer ◽  
Duration Of Treatment ◽  
Psa Response ◽  
Psa Progression ◽  
Low Volume

241 Background: Docetaxel is a standard of care for mCSPC. Enzalutamide and abiraterone have been proven to improve survival in metastatic castration-resistant prostate cancer (mCRPC) patients. Little is known about patients who have been treated with docetaxel for mCSPC and subsequent therapeutic responses. This retrospective analysis is to evaluate the response duration of abiraterone and enzalutamide in patients who previously received docetaxel for mCSPC but developed mCRPC within 12 months. Methods: Clinical Trial NCT02649855 enrolled patients with newly diagnosed mCSPC who were treated with standard androgen deprivation therapy (ADT) and docetaxel (75 mg/m2 every 3 weeks for 6 cycles) sequenced with immunotherapy (PROSTVAC) from February 2016 to present. Patients who had progression (based on consecutive PSA rises or imaging) within 1 year of completing docetaxel and went on to subsequent abiraterone/enzalutamide were evaluated. (Note these are different PSA progression criteria than used in CHAARTED, Sweeney, NEJM, 2015). Results: Of the 46 patients evaluated regardless of immunotherapy sequence, 15 (33%) went on subsequent therapy after progression on docetaxel for mCSPC, with 12 patients starting abiraterone/enzalutamide (6 each with high and low volume disease). The median age was 62 (41-83) years. 7/12 patients (58.3%) initiated enzalutamide and 5/12 patients (41.7%) initiated abiraterone. The median duration of treatment for both was 7.12 (1.53–16.0) months, the median time to prostate-specific antigen (PSA) progression was 5.54 (0–15.83) months; 5/12 (41.7%) of patients did not have PSA response. Of note, patients with low volume disease had a median treatment duration of 5.88 months, 3 of them did not have PSA response. Conclusions: These data from a small cohort suggest that patients who have progression within 12 months of completing docetaxel for mCSPC have limited subsequent benefit from enzalutamide or abiraterone. Additional studies are required to determine optimal timing and treatment sequence for patients with mCSPC who rapidly develop mCRPC. Clinical trial information: NCT02649855.

KEYNOTE-046 (Part B): Effects of ADXS-PSA in combination with pembrolizumab on survival in metastatic, castration-resistant prostate cancer patients with or without prior exposure to docetaxel.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 126-126 ◽  
Author(s):  
Mark N. Stein ◽  
Lawrence Fong ◽  
Anthony E. Mega ◽  
Elaine Tat Lam ◽  
John W. Heyburn ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Phase 1 ◽  
Specific Antigen ◽  
Prior Exposure ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Clinical Trial Information

126 Background: ADXS-PSA, an attenuated Listeria monocytogenes-based immunotherapy targeting prostate-specific antigen (PSA), is currently being evaluated in combination with pembrolizumab as a treatment for progressive metastatic castration-resistant prostate cancer (mCRPC) in the phase 1/2 KEYNOTE-046 trial (Part B). Methods: A total of 37 patients received 1x109 CFU + 200 mg pembro IV every 3 wks, for up to 2 yrs or until progression/toxicity. Results: At entry, patients were ~70 yrs with median a Gleason score of 9, and bone predominant disease (70%). MSI-High was negative in 36 pts who were able to be tested. Eighteen (48.6%) patients had received prior docetaxel, 15 pts of whom (83.3%) had also received 1-2 next generation hormonal agents (NGHAs). Nineteen (51.3%) had not received prior docetaxel and 16 of these pts (84.2%) had received 1-2 NGHAs. Overall, 16 out of 37 pts (43%) had a decreased PSA post-BL with 6/37 (16%) pts achieving a confirmed PSA reduction ≥50% from baseline. The median OS (months) for the whole group (37 pts) was 33.6 m (95% CI, range 15.4-33.6 months). The mOS for pts with and without prior exposure to docetaxel was 16 m (5.9 -33.6) and NR at 30 months of follow-up (15.4-NR), respectively. Prolonged survival was observed in pts regardless of prior therapies, microsatellite stable (MSS) status or PSA delta <50% or ≥50%. Conclusions: Results with ADXS-PSA in combination with pembrolizumab in mCRPC, with or without prior docetaxel, show promising clinical activity to be further assessed in randomized studies. Clinical trial information: NCT02325557.

scholarly journals Pretreatment neutrophil-to-lymphocyte ratio and Mean Platelet Volume in castration-resistant prostate cancer patients treated with first-line docetaxel

2019 ◽  
Author(s):  
Barbaros Başeskioğlu ◽  
Berna Bozkurt Duman ◽  
Bülent Yıldız ◽  
Timuçin Çil ◽  
Murat Dinçer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Mean Platelet Volume ◽  
Specific Antigen ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Platelet Volume ◽  
Neutrophil Lymphocyte Ratio ◽  
Lymphocyte Ratio ◽  
Castration Resistant ◽  
Psa Response

Abstract Background:Patients who have evidence of disease progression (eg, increase in serum prostate-specific antigen [PSA], new metastases, progression of existing metastases) while being managed with androgen deprivation therapy (ADT) are considered to have castration-resistant disease. Docetaxel (75 mg/m2) given every three weeks in combination with daily prednisone (5 mg twice a day) significantly prolonged overall survival compared with mitoxantrone plus prednisone in the TAX 327 phase III trial [3]. Based upon those results, docetaxel plus prednisone has become the standard initial regimen when chemotherapy is indicated for CRPC Methods: Inflammation-based markers, such as the Neutrophile/Lymphocyte Ratio (NLR), are widely available and inexpensive measurements that are easy to integrate into pretreatment evaluation. Mean platelet volume (MPV) is a marker of activated platelets is associated some types of cancer including ovarian, gastric cancer. We retrospectively evaluated the predictive impact of neutrophil-lymphocyte ratio (NLR) and MPV as a marker for in men with progressive metastatic castration resistant prostate cancer (mCRPC) following docetaxel.Results: A significant correlation was not observed between NLR and PSA response. A significant correlation was not also observed between MPV and PSA response.There no correlation was found between MPV and NLR with total PSA level and response (p:0.355, p:0.673 respectively)Conclusion: . In our study; We didn’t show any correlation between MWP level, NLR ratio and response to Docetaxel therapy A significant correlation was not also observed between NLR , MPV and PSA response.

scholarly journals A phase II single-arm study of pembrolizumab with enzalutamide in men with metastatic castration-resistant prostate cancer progressing on enzalutamide alone

2020 ◽  
Vol 8 (2) ◽  
pp. e000642 ◽  
Author(s):  
Julie N Graff ◽  
Tomasz M Beer ◽  
Joshi J Alumkal ◽  
Rachel E Slottke ◽  
William L Redmond ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Specific Antigen ◽  
Subsequent Treatment ◽  
Castration Resistant Prostate Cancer ◽  
Entire Cohort ◽  
Castration Resistant

BackgroundCheckpoint inhibitors can induce profound anticancer responses, but programmed cell death protein-1 (PD-1) inhibition monotherapy has shown minimal activity in prostate cancer. A published report showed that men with prostate cancer who were resistant to the second-generation androgen receptor inhibitor enzalutamide had increased programmed death-ligand 1 (PD-L1) expression on circulating antigen-presenting cells. We hypothesized that the addition of PD-1 inhibition in these patients could induce a meaningful cancer response.MethodsWe evaluated enzalutamide plus the PD-1 inhibitor pembrolizumab in a single-arm phase II study of 28 men with metastatic castration-resistant prostate cancer (mprogressing on enzalutamide alone. Pembrolizumab 200 mg intravenous was given every 3 weeks for four doses with enzalutamide. The primary endpoint was prostate-specific antigen (PSA) decline of ≥50%. Secondary endpoints were objective response, PSA progression-free survival (PFS), time to subsequent treatment, and time to death. Baseline tumor biopsies were obtained when feasible, and samples were sequenced and evaluated for the expression of PD-L1, microsatellite instability (MSI), mutational and neoepitope burdens.ResultsFive (18%) of 28 patients had a PSA decline of ≥50%. Three (25%) of 12 patients with measurable disease at baseline achieved an objective response. Of the five responders, two continue with PSA and radiographic response after 39.3 and 37.8 months. For the entire cohort, median follow-up was 37 months, and median PSA PFS time was 3.8 months (95% CI: 2.8 to 9.9 months). Time to subsequent treatment was 7.21 months (95% CI: 5.1 to 11.1 months). Median overall survival for all patients was 21.9 months (95% CI: 14.7 to 28 .4 months), versus 41.7 months (95% CI: 22.16 to not reached (NR)) in the responders. Of the three responders with baseline biopsies, one had MSI high disease with mutations consistent with DNA-repair defects. None had detectable PD-L1 expression.ConclusionsPembrolizumab has activity in mCRPC when added to enzalutamide. Responses were deep and durable and did not require tumor PD-L1 expression or DNA-repair defects.Trial registration numberclinicaltrials.gov (NCT02312557).

A study of two ODM-201 formulations with a safety and tolerability extension phase in patients with metastatic chemotherapy-naive castration-resistant prostate cancer (CRPC).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 115-115 ◽  
Author(s):  
Christophe Massard ◽  
Teuvo L. J. Tammela ◽  
Egils Vjaters ◽  
Vilnis Lietuvietis ◽  
Petri Bono ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Response Rate ◽  
Specific Antigen ◽  
Castration Resistant Prostate Cancer ◽  
Capsule Formulation ◽  
Castration Resistant ◽  
Psa Response ◽  
Effect Of Food ◽  
Extension Period ◽  
Clinical Trial Information

115^ Background: This open phase I trial assessed the bioavailability, and the effect of food on the bioavailability of ODM-201 600mg tablets compared to a 600mg capsule formulation. Efficacy, safety, and tolerability of ODM-201 were studied in the extension period. Methods: The study had two parts: a pharmacokinetic (PK), and a safety and tolerability part. Dosing was 600mg bid with or without food. In the PK part, three single doses of ODM-201 were given over 3 weeks. In the extension part patients could continue treatment until disease progression or until an intolerable adverse event or condition that prevented further dosing of ODM-201. Results: Thirty men with metastatic chemotherapy-naïve castration-resistant prostate cancer (CRPC) were enrolled, the median age was 68. The median prostate-specific antigen (PSA) was 18.2 ng/mL and testosterone 23.1 ng/dL at baseline. Food interaction was observed when ODM-201 formulations were administered after a high fat content breakfast compared to administration at fast. AUC and Cmaxvalues were about 50% lower after fast. Twenty nine patients have completed the 4-week visit. The PSA response rate (50% or more PSA decline) was 86%, with a median PSA decrease of -66% (-96, 5) at week 4 (N=18/21). Most commonly reported adverse events so far are fatigue, abdominal pain, diarrhea, hematuria, and nausea. Conclusions: ODM-201 600mg bid as tablets has comparable PK to capsules used in the phase II ARADES trial. It is well tolerated and has good PSA response in chemotherapy-naïve patients with CRPC . Clinical trial information: NCT01784757.

Clinical activity of abiraterone acetate in patients with castration-resistant prostate cancer who received prior ketoconazole therapy.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 99-99 ◽  
Author(s):  
Bo Zhao ◽  
Jorge A. Garcia ◽  
Timothy D. Gilligan ◽  
Brian I. Rini ◽  
Robert Dreicer
Keyword(s):  
Prostate Cancer ◽  
Specific Antigen ◽  
Underlying Mechanism ◽  
Abiraterone Acetate ◽  
Clinical Activity ◽  
Drug Discontinuation ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Psa Response ◽  
Psa Progression

99 Background: Studies have shown activity of Abiraterone acetate (AA) in patients (pts) with castration-resistant prostate cancer (CRPC) who have received prior ketoconazole. Prostate-specific antigen (PSA) response to AA in relation to previous PSA response to ketoconazole was investigated. Methods: A retrospective analysis was conducted to determine the clinical activity of AA in men with CRPC who have received prior ketoconazole therapy at our institution. Time to PSA progression (PSA TTP) was defined by PCWG2 criteria, a PSA reduction of 50% or more was considered as PSA response. Results: Thirty four pts were identified. Nineteen pts (56%) had previous PSA responses on ketoconazole, with a median PSA TTP of 11 months (95% confidence interval [CI] 6.8-19.9). Subsequently, 11 of 34 (33%) of pts achieved a PSA response on AA, with a median PSA TTP of 6 months (95% CI 4.9-9.5). Among the 19 pts having a PSA response on ketoconazole, only four (21%) pts subsequently had PSA response to AA. Two of these pts had transient PSA response with PSA TTP less than 3 months on kKetoconazole, one patient discontinued Ketoconazole due to side effects, one patient had intermittent non-castrate testosterone levels. In contrast, 7 of 15 (46.7%) pts without prior PSA response to ketoconazole subsequently achieved PSA response on AA (p=0.11). Of note, PSA reduction of less than 50% on AA was observed in 9 of 34 pts (26%), which was associated with a longer median PSA TTP compared to pts who had PSA-progressive disease (5.9 months [95% CI 3.5-7.3] vs.1.5 months [95% CI 1.0-3.5], p=0.028). Five of these nine patients had a prior PSA response to ketoconazole but required drug discontinuation for reasons other than disease progression. Conclusions: PSA response to prior ketoconazole therapy is associated with lower PSA response rate to subsequent AA. The observation suggests that there is a biologically distinct subset of patients who are ketoconazole-resistant but abiraterone-sensitive, the underlying mechanism needs to be further investigated.

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