Determining biomarkers of response to docetaxel for patients with metastatic castration-resistant prostate cancer (mCRPC) using circulating cell-free tumor DNA (ctDNA).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 260-260
Author(s):  
Daniel Khalaf ◽  
Cameron Herberts ◽  
Gillian Vandekerkhove ◽  
Matti Annala ◽  
Kevin Beja ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Performance Status ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Pten Loss ◽  
Discernible Effect ◽  
Pten Deletion ◽  
Psa Response ◽  
Psa Progression ◽  
Ctdna Analysis

260 Background: Docetaxel is associated with improved outcomes for mCRPC. There are currently no predictive molecular biomarkers for docetaxel to assist with patient selection. Methods: Patients commencing docetaxel for mCRPC between November 2015 and August 2017 were enrolled on a prospective cohort study evaluating circulating biomarkers. A plasma sample for ctDNA analysis was collected before initiation of docetaxel. Targeted sequencing of 73 prostate cancer-relevant genes was performed on leukocyte DNA (germline) and plasma cell-free DNA. Patient records were reviewed for baseline clinical characteristics, PSA response (≥ 50% decline from baseline), and time to PSA progression (TTPP) (PCWG3 criteria). Results: There were 33 patients enrolled; all patients had received prior abiraterone or enzalutamide and none had received prior taxanes. At baseline, the median age was 69.9 years, 30.3% had ECOG performance status 2, 66.7% had bone metastasis and 9.1% had liver metastases. The PSA response rate (RR) was 39.4% and 33.3% had a TTPP less than 3 months. 82% of patients had a ctDNA fraction >5%. Deleterious BRCA2 or ATM defects were present in 12.1% (4/33) of patients (3 somatic and 1 germline). TP53 alterations were identified in 39.4% (13/33), RB1 loss in 21.2% (7/33), PTEN loss in 21.2% (7/33), and Androgen Receptor (AR) amplification in 42.2% (14/33). PTEN deletion was associated with a trend toward inferior RR and TP53 had no discernible effect on PSA RR (Table). BRCA2/ATM defects were associated with a trend toward a lower rate of PSA progression within 3 months (Table). Conclusions: In this preliminary analysis, TP53 alterations had no discernible effect on efficacy of docetaxel chemotherapy. Accrual is ongoing in order to further clarify whether there is an association between PTEN, RB1, AR and BRCA2/ATM alterations and benefit from docetaxel. [Table: see text]

ARN-509 in men with high-risk nonmetastatic castration-resistant prostate cancer (CRPC).

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 7-7 ◽  
Author(s):  
Matthew Raymond Smith ◽  
Emmanuel S. Antonarakis ◽  
Charles J. Ryan ◽  
William R. Berry ◽  
Neal Shore ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Phase I ◽  
Phase Ii ◽  
Nuclear Translocation ◽  
Performance Status ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Psa Response ◽  
Psa Progression

7 Background: ARN-509 is a novel second-generation anti-androgen that binds directly to the ligand-binding domain of the androgen receptor, impairing nuclear translocation and DNA binding. The Phase II portion of a multicenter Phase I/II study is evaluating the activity of ARN-509 in 3 distinct patient populations of men with CRPC (high risk non-metastatic CRPC, metastatic treatment-naïve CRPC, and progressive disease after abiraterone acetate). Preliminary results for the cohort of patients with high-risk non-metastatic CRPC are presented here. Methods: All patients had CRPC, no radiographic evidence of metastases (pelvic lymph nodes <3 cm below the iliac bifurcation were allowed), and high risk for disease progression based on PSA value ≥ 8 ng/mL within 3 months of enrollment and/or PSA doubling time ≤ 10 months. Patients received ARN-509 at the recommended Phase II dose of 240 mg/day, previously established in Phase I (Rathkopf et al, GU ASCO 2012). The primary endpoint was PSA response rate at 12 weeks according to the Prostate Cancer Working Group 2 Criteria. Secondary endpoints included safety, time to PSA progression and 1-year metastasis-free survival. PSA assessments were collected every 4 weeks and tumor scans were performed every 16 weeks. Results: Forty-seven patients were enrolled between November 2011 and May 2012. The median age was 71 years (range 51 to 88) and at baseline, patients presented with ECOG performance status 0 (77%), Gleason Score 8-10 (32%), and median PSA of 10.7 ng/mL. All patients received prior treatment with a LHRH analog with or without a first-generation anti-androgen. At a median treatment duration of 20 weeks, three patients discontinued the study. The most common treatment-related adverse events (AE) were fatigue (30%), diarrhea (28%), nausea (17%), rash (13%), and abdominal pain (11%). The incidence of Grade 3 AEs was 6.4%, and no seizures have been observed to date. The 12-week PSA response was 91% and the time to PSA progression has not been reached. Conclusions: In men with high-risk non-metastatic CRPC, ARN-509 is safe and well tolerated with promising preliminary activity based on high PSA response rates. Clinical trial information: NCT01171898.

A phase Ib/II trial of indomethacin and enzalutamide to treat castration-resistant prostate cancer (CRPC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS394-TPS394 ◽  
Author(s):  
Chong-xian Pan ◽  
Primo Lara ◽  
Christopher P. Evans ◽  
Mamta Parikh ◽  
Ralph de Vere White ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Response Rate ◽  
Performance Status ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Phase Ib ◽  
Androgen Synthesis ◽  
Psa Response

TPS394 Background: Enzalutamide (Enza) and abiraterone (Abi) are commonly used to treat CRPC. Resistance is the most common cause of treatment failure. We discovered that a critical steroidogenic enzyme AKR1C3 was significantly elevated and contributed to intratumoral androgen synthesis in Enza-resistant prostate cancer cells and tumors. Overexpression of AKR1C3 induced androgen receptor variant 7 (AR-V7) expression, while inhibition of AKR1C3 downregulated AR-V7. We then discovered that indomethacin (Indo) inhibited AKR1C3 activation and sensitized resistant CRPC cells to Enza and Abi. One patient accidentally took Indo and achieved biochemical as well as radiological response of his prostate cancer. These findings prompted us to design a clinical trial to test the combination of Indo with Enza for the treatment of CRPC and to study the underlying mechanisms of action and resistance. Methods: This investigator-initiated single-arm Phase Ib/II trial enrolls patients with progressive CRPC after Abi, adequate vital organ function, ECOG performance status 0-2, and serum testosterone < 50 ng/dl. Major exclusion criteria include prior Enza treatment, brain metastasis and history of seizure. In the Phase Ib cohort, patients receive Enza 160 mg po qd and Indo 50 mg po tid to determine toxicity. The Phase II expansion will enroll 26 patients with 21 evaluable patients. This sample size provides 90% power to detect, at the 0.05 level (1-sided), the difference between a PSA response rate of 50% expected with the study treatment and a historical control of 20% with Enza alone. Co-primary endpoints are safety and PSA response of ≥50% decrease. Secondary endpoints include overall response rate as determined by the Prostate Cancer Working Group 2 criteria (PCWG2), progression-free survival and overall survival. Molecular correlative studies are exploratory endpoints. Serum and intratumoral androgen levels, full-length AR, AR-V7 and AKR1C3 will be measured to assess the effect of the combination therapy. To date, 4 patients have been enrolled to the trial (clinicaltrials.gov Identifier No: NCT02935205; this trial is funded by DoD Prostate Cancer Research Program IMPACT award). Clinical trial information: NCT02935205.

Durable radiologic and clinical disease stability beyond PSA progression in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4553-4553
Author(s):  
Diletta Bianchini ◽  
Shahneen Kaur Sandhu ◽  
Amy Mulick Cassidy ◽  
Andrea Zivi ◽  
Janusz Mezynski ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Performance Status ◽  
Specific Antigen ◽  
Abiraterone Acetate ◽  
Clinical Disease ◽  
Castration Resistant Prostate Cancer ◽  
Clinical Progression ◽  
Ecog Performance Status ◽  
Conversion Rates ◽  
Psa Progression

4553 Background: AA, a potent oral CYP17A1 inhibitor is approved for treatment of mCRPC with a survival advantage of 4.9 months. In clinical practice, response evaluation remains challenging for pts with mCRPC. CTC conversion from CTC ≥ 5 to CTC < 5 with treatment predicts for improved overall survival in mCRPC. We hypothesized that pts continue to have durable disease stability beyond PSA progression on AA. Methods: Prostate Specific Antigen (PSA) responses, radiological responses and CTC conversion rates were retrospectively analysed in pts treated on AA at our institution. CTCs, PSA and imaging were obtained at predefined time points during these studies. Radiological and PSA progression were defined by standard Prostate Cancer Working Group Criteria II. Clinical progression consisted of worsening disease related pain, skeletal events or declining performance status.Pearson’s chi-squared test and the Kaplan-Meier method were used for this analysis. Results: 141 patients [ECOG Performance Status 0-2; Median Age: 69.7 (range 44.7-87.1); 85 post-docetaxel, 56 pre-docetaxel] received AA. The median duration of clinical and radiological stable disease (SD) was 16.8 months (n=55) and 5.6 months (n=75) in patients with a baseline CTCs count of ≤ 5 cells/7.5mls and ≥ 5 cells/7.5 mls respectively. In the 105 patients with documented PSA progression on AA there was a median 5.7-month delay in detecting radiological and/or clinical progression (95% CI: 4.2, 8.4; range 0.3, 35.6 months). Radiological and clinical SD of ≥ 1 year, ≥ 2 years and ≥ 3 years on AA was observed in 43/141 (30.5%), 21/141 (14.9%) and 12/141 (8.5%) respectively. Conclusions: Radiological and clinical disease stabilization beyond PSA progression is maintained in a high proportion of mCRPC patients treated with AA. Future studies should evaluate whether continued AA treatment beyond PSA and radiological progression can impact outcome.

βIII-tubulin expression as a predictor of docetaxel resistance in metastatic castrate-resistant prostate cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15174-e15174
Author(s):  
Bertha E. Sanchez ◽  
Nilesh Gupta ◽  
Meredith Mahan ◽  
Evelyn R Barrack ◽  
Prem-veer Reddy ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Gleason Score ◽  
Clinical Decision Making ◽  
Performance Status ◽  
Ecog Performance Status ◽  
Docetaxel Resistance ◽  
Psa Response ◽  
Castrate Resistant Prostate Cancer ◽  
The Mean ◽  
Castrate Resistant

e15174 Background: Docetaxel is a tubulin-targeting cytotoxic that remains first-line therapy in metastatic castrate-resistant prostate cancer (mCRPC) patients (pts) even though half of pts are reported to be non-responders. A predictive marker to identify those who will benefit from docetaxel-therapy will assist clinical decision making. High βIII-tubulin (TUBB3) expression has previously been reported to correlate with lack of response to taxanes in other cancers. We evaluated TUBB3 expression as a predictor of docetaxel-resistance in mCRPC. Methods: mCRPC pts treated with at least 3 cycles of docetaxel between 1990 and 2011 were identified retrospectively. TUBB3 immunostaining was performed on archival formalin-fixed, paraffin-embedded tissue. Stain intensity was scored from 0 to 3; 2 and 3 were interpreted as positive. Rates of PSA response were compared between pts with positive (+) and negative (-) TUBB3 expression. Two definitions of PSA response were evaluated (any PSA decline and at least 50% decline). Overall survival (OS) distribution between TUBB3+ and TUBB3- pts was estimated by the Kaplan-Meier method. Results: Of 73 pts, 26 (35%) expressed TUBB3. At diagnosis, the mean age was 65.7 years and the median Gleason score was 8. At the time of docetaxel therapy, the mean age was 71.2 years, the median PSA level was 70.9 (range, 0.2-5253) and 76% had ECOG performance status ≤1. The median number of docetaxel cycles was 7 (range, 3-18). The total dose of docetaxel was not different between groups (p=0.705). The median OS was 19.2 mo. TUBB3 expression was not correlated with any clinical or pathological characteristic (age, Gleason score, stage, ECOG, PSA, LDH, alkaline phosphatase, hemoglobin, visceral disease or chemotherapy before docetaxel). 65% of TUBB3+ pts had any PSA decline compared to 89% of pts with TUBB3- (p=0.0267). 52% of TUBB3+ pts had a PSA decline of ≥ 50% compared to 70% of TUBB3- pts (p=0.0144). Median OS for TUBB3+ pts was 16.8 mo compared to 20.4 mo in TUBB3- pts (p=0.039). Conclusions: High TUBB3 expression was associated with shorter OS and lower PSA response rates in mCRPC pts treated with docetaxel. These findings need to be validated prospectively.

Results from a phase I study of enzalutamide in combination with docetaxel in men with prostate cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5066-5066
Author(s):  
Mark T. Fleming ◽  
Dana E. Rathkopf ◽  
Jackie Gibbons ◽  
Amy C. Peterson ◽  
Alison Hannah ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Phase I ◽  
Phase I Study ◽  
Performance Status ◽  
Safety Data ◽  
Primary Therapy ◽  
Castration Resistant Prostate Cancer ◽  
Ecog Performance Status ◽  
Combination Methods

5066 Background: Enzalutamide (ENZA) is a novel androgen receptor (AR) inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) who had received prior docetaxel (DOC). DOC also prolongs survival in mCRPC and also appears to have anti-tumor effects mediated through the androgen-receptor axis, providing a compelling rationale for combining the two agents. CYP3A4 plays a role in DOC clearance and is induced by ENZA. We therefore conducted a phase I study to explore the PK and safety profiles of this combination. Methods: This study (NCT01565928) evaluated the safety and pharmacokinetics (PK) of DOC co-administered with ENZA in men with mCRPC on androgen deprivation therapy. Pts received DOC (75 mg/m2) by 1-h infusion every 3 weeks with corticosteroids. ENZA (160 mg/d) was started 24 h after the first DOC infusion. Plasma PK samples were collected for 24 h after Cycle (C) 1 and C2 DOC infusions to enable within-subject comparisons of DOC PK ± ENZA. A sample size of 18 pts able to receive ≥ 2 full doses of DOC was specified for PK analyses. Results: Twenty-two pts were enrolled, 4 did not receive 2 full doses of DOC. As of 21 Sept 2012, preliminary PK and C1 and C2 safety data were available from 15 pts. The median age was 65 (range 46-80 yrs); 11 had ECOG performance status 1 (vs 0). Prior primary therapy included surgery (n=2), radiation (n=4) or both (n=5); median PSA was 44.7ng/mL (1.9-585). ANC<1000/mm3 was reported in 14 pts (1 febrile neutropenia), other adverse events in ≥4 pts included fatigue (11), dyspnea (6), alopecia (5), peripheral neuropathy (5), anemia (4) and dysgueusia (4). No seizures were reported. Preliminary PK data (n=15) show similar DOC exposure (within 20%) for DOC in combination with ENZA vs. DOC alone.Final PK and updated tolerability and efficacy data beyond Cycle 2 will be presented. Conclusions: In mCRPC pts, ENZA does not appear to affect tolerability of DOC or have a clinically meaningful impact on DOC PK. Clinical trial information: NCT01565928.

Activity of gemcitabine-oxalipaltin (GemOx) plus prednisolone in patients with castration-resistant prostate cancer (CRPC) for whom docetaxel-based chemotherapy failed.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 108-108
Author(s):  
Jae-Lyun Lee ◽  
Yesul Kim ◽  
Jin-Hee Ahn ◽  
MeeKyung Choi ◽  
Seung-Woo Hong ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Synergistic Effects ◽  
Drug Effects ◽  
Fixed Dose ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Psa Response ◽  
Psa Progression ◽  
Grade 3

108 Background: We assessed the cytotoxic effects of the gemcitabine in combination with oxaliplatin (GemOx) in prostate cancer cell lines and evaluated the efficacy and safety of GemOx in patients with metastatic castration-resistant prostate cancer (CRPC) who failed docetaxel based chemotherapy. Methods: Gemcitabine and oxaliplatin were preclinically tested for their cytotoxic activity in LNCaP, PC3 and DU145 cell lines. The combined drug effects were evaluated using the Chou and Taladay analysis. Clinically, patients with CRPC who failed prior docetaxel chemotherapy were treated with gemcitabine 1,000 mg/m2 at fixed-dose rate (10 mg/m2/min) and oxaliplatin 100 mg/m2 intravenously every 2 weeks and prednisolone 5 mg orally twice daily. Unless disease progression or intolerability develops, treatment could be continued until 12 cycles. Primary endpoint was PSA response rate (PCWG 1.0 criteria). Results: The IC50of gemcitabine and oxaliplatin were, respectively, 1.25 μM and 0.69 μM for LNCaP cells; 50.00+ μM and 12.81 μM for PC3 cells; and 11.23 μM and 11.04 μM for DU145 cells. The GemOx combination displayed synergistic effects in all 3 cell lines. In phase II study, 31 patients were accrued. At the time of this analysis 7 patients were still continuing treatment. The median age was 67 years (range 57 ~ 81) and the median dose of docetaxel exposure was 525 mg/m2. A total of 231 cycles administered with a median of 9 cycles per patient. PSA responses were observed in 52% (95% CI, 34~69) and partial responses were observed in 7 of 10 patients with measurable disease. Out of 23 patients, 10 patients achieved pain response (44%). With a median FU duration of 8.0 months, the median time to PSA progression was 6.4 months (95% CI, 3.5~9.2). Peripheral neuropathy developed in 78% of patients but remained of grade 1 ~2 intensities. Frequently observed grade 3 or 4 toxicities were neutropenia (10%), thrombocytopenia (10%), anemia (3%), and diarrhea (3%). Conclusions: GemOx is active and well tolerated in patients with CPRC after docetaxel failure and deserves further investigation in this setting (NCT 01487720). Clinical trial information: NCT01487720.

Enzalutamide in combination with docetaxel in men with prostate cancer (PC): Preliminary results from a phase I study.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 63-63 ◽  
Author(s):  
Mark T. Fleming ◽  
Dana E. Rathkopf ◽  
Jackie Gibbons ◽  
Amy C. Peterson ◽  
Alison Hannah ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Nuclear Translocation ◽  
Performance Status ◽  
Safety Data ◽  
Phase Iii ◽  
Primary Therapy ◽  
Castration Resistant Prostate Cancer ◽  
Current Standard ◽  
Ecog Performance Status ◽  
To Receive

63 Background: Enzalutamide (ENZA), a novel oral androgen receptor (AR) inhibitor, inhibits AR signaling via inhibition of androgen binding to the AR, AR nuclear translocation, and nuclear AR-DNA binding. ENZA demonstrated a survival benefit in men with metastatic castration-resistant prostate cancer (mCRPC) who had received prior docetaxel (Scher et al, NEJM 2012; 367:1187). A Phase III study in men with progressive chemotherapy-naïve disease (PREVAIL), is ongoing. Docetaxel (DOC) is the current standard first-line chemotherapy for mCRPC. CYP3A4, which plays a role in DOC clearance, is induced by ENZA. Patients (pts) eligible to receive DOC may benefit from continued AR inhibition with ENZA, provided the combination is well tolerated with no unacceptable drug-drug interactions. Methods: This study evaluated the safety and pharmacokinetics (PK) of DOC co-administered with ENZA in men with mCRPC on androgen deprivation therapy. Pts received DOC (75 mg/m2) by 1-h infusion every 3 weeks, with corticosteroids. ENZA (160 mg/d) was started 24 h after the first DOC infusion. Plasma PK samples were collected for 24 h after Cycle (C) 1 and C2 DOC infusions to enable within-subject comparisons of DOC PK ± ENZA. A sample size of 18 pts able to receive ≥ 2 full doses of DOC was specified for PK analyses. Results: As of 21 Sept. 2012, 22 pts have been enrolled, 3 did not complete both C1 and C2; PK and C1 and C2 safety data are currently available from 15 pts reported here. The median age was 65 (range 46-80 yrs); 11 had ECOG performance status 1 (vs 0). Prior primary therapy included surgery (n=2), radiation (n=4) or both (n=5); median PSA was 44.7ng/mL (1.9-585). ANC<1000mm3 was reported in 14 pts (1 febrile neutropenia), other adverse events in ≥4 pts included fatigue (11), dyspnea (6), alopecia (5), peripheral neuropathy (5), anemia (4) and dysgueusia (4). No seizures were reported. Preliminary PK data (n=15) show similar DOC exposure (within 20%) for DOC in combination with ENZA vs. DOC alone. Conclusions: This is the first evaluation of ENZA given in combination with DOC.In mCRPC pts ENZA does not appear to affect tolerability of DOC or have a clinically meaningful impact on DOC PK. Clinical trial information: NCT01565928.

ARASENS: A phase 3 trial of darolutamide in combination with docetaxel for men with metastatic hormone-sensitive prostate cancer (mHSPC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS383-TPS383 ◽  
Author(s):  
Matthew Raymond Smith ◽  
Fred Saad ◽  
Maha Hussain ◽  
Cora N. Sternberg ◽  
Karim Fizazi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase 1 ◽  
Performance Status ◽  
Physical Symptoms ◽  
Castration Resistant Prostate Cancer ◽  
Opioid Use ◽  
Phase 3 ◽  
Ecog Performance Status ◽  
Double Blind ◽  
Disease Extent

TPS383 Background: The addition of either docetaxel or abiraterone acetate plus prednisone to androgen deprivation therapy (ADT) improves overall survival (OS) compared with ADT alone in men with mHSPC. It is hypothesized that other androgen receptor (AR)-targeted therapies could be combined with docetaxel for mHSPC. Darolutamide (ODM-201) is an investigational oral AR antagonist with a unique chemical structure and negligible blood-brain barrier penetration that inhibits tumor growth by binding to AR and AR mutants (eg, W742L and F877L) with high affinity and specificity. In phase 1/2 ARADES and phase 1 ARAFOR trials, darolutamide demonstrated antitumor activity and was well tolerated in men with metastatic castration-resistant prostate cancer (mCRPC). ARASENS will evaluate the addition of darolutamide to standard ADT and docetaxel in men with mHSPC. Methods: This international, randomized, double-blind, placebo-controlled phase 3 trial (NCT02799602) is being conducted at > 300 sites in 23 countries. ~1300 men with newly diagnosed mHSPC will be randomized 1:1 to darolutamide (600 mg orally twice daily) or matching placebo. All patients will receive standard ADT + docetaxel (6 cycles). Patients will be stratified by disease extent and alkaline phosphatase level. Key inclusion criteria: histologically or cytologically confirmed PC with documented metastases, started ADT ± first-generation antiandrogen therapy ≤12 weeks before randomization, and ECOG performance status 0-1. The primary end point is OS. Secondary end points include time to mCRPC, initiation of subsequent anticancer therapy, symptomatic skeletal event (SSE)-free survival, time to first SSE, first opioid use, pain progression, and worsening of physical symptoms. Safety will be assessed. ARASENS is actively enrolling at > 280 sites across 23 countries. Clinical trial information: NCT02799602.

Abiraterone acetate plus prednisone (AA+P) without continuing LHRH-therapy in patients with metastatic chemotherapy: Naive castrations-resistant prostate cancer—Results from the SPARE-trial (NCT02077634).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5046-5046 ◽  
Author(s):  
Carsten Henning Ohlmann ◽  
Christoph Ruessel ◽  
Roger Zillmann ◽  
Eva Hellmis ◽  
Henrik Suttmann ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Objective Response ◽  
Serum Testosterone ◽  
Abiraterone Acetate ◽  
Castration Resistant Prostate Cancer ◽  
Testosterone Levels ◽  
Psa Response ◽  
Secondary Endpoints ◽  
Psa Progression ◽  
Lhrh Therapy

5046 Background: The value of continuation of androgen deprivation therapy (ADT) in metastatic castration-resistant prostate cancer (CRPC) remains controversial and clear evidence is lacking. Especially upon treatment with the life-prolonging cytochrome P450 17-alpha-hydroxylase/C17,20 lyase (Cyp17)-inhibitor, abiraterone acetate (AA), which in combination with prednisone (P), has the ability to further suppress serum testosterone levels over ADT alone, continuation of ADT seems to be negligible. Methods: The exploratory phase II trial randomized CRPC patients to receive continued ADT plus AA+P versus AA+P alone (NCT02077634), funded by Jansen-Cilag GmbH, Germany. The primary endpoint was rate of rPFS at month 12, not powered for a direct comparison between treatment arms. Secondary endpoints included PSA response rate, objective response, time to PSA progression and safety. Results: Altogether, 67 patients were randomized between 08/2014 to 04/2017. Median testosterone-levels (T) remained far below castrate-levels throughout treatment in all patients. However, in 6 patients (18%) from Arm B, T-levels increased above castrate levels within 28 days after cessation of AA+P treatment. Median treatment duration is shorter in Arm A. Safety analysis is underway and results will be presented. Conclusions: Results of this exploratory study suggest that treatment with AA+P without ADT may be effective in patients with mCRPC and that ADT may not be necessary in patients receiving AA+P. In some patients, serum-testosterone levels may rise rapidly upon treatment discontinuation so that the levels should be monitored closely. Clinical trial information: NCT02077634. [Table: see text]

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.

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