Quality of life (QOL) for the treatment sequence of abiraterone acetate plus prednisone (AAP) followed by enzalutamide (ENZ) versus the opposite sequence for metastatic castration-resistant prostate cancer (mCRPC): Results from a phase II randomized clinical trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5578-5578
Author(s):  
Daniel J Khalaf ◽  
Katherine Sunderland ◽  
Bernhard J. Eigl ◽  
Daygen L. Finch ◽  
Conrad D. Oja ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Treatment Time ◽  
Well Being ◽  
Rank Test ◽  
Line Treatment ◽  
Treatment Sequence ◽  
Castration Resistant Prostate Cancer ◽  
Opposite Sequence ◽  
Psa Progression

5578 Background: A randomized cross-over phase II trial (Lancet Oncol 20(12):1730, 2019) showed the sequence of AAP followed by ENZ is associated with a better time to PSA progression compared with the opposite sequence and superior 2nd line activity of ENZ. It is unknown whether one treatment sequence is associated with better QOL than the other. Methods: 202 Patients were randomized (1:1) to receive either AAP followed by ENZ at PSA progression (arm A) or the opposite sequence of ENZ followed by AAP (arm B). FACT-P questionnaires were completed at baseline, cross-over and every 4 weeks on treatment. Time to QOL deterioration (TTQOLD) for the treatment sequence was determined from start of 1st line treatment to first questionnaire with a clinically meaningful decrease from baseline and compared between arms using the log-rank test. TTQOLD was also determined for 1st line and 2nd line separately. The proportion of patients with QOL deterioration for total FACT-P score and FACT-P subscores from baseline to week 12 of 1st and 2nd line treatment was compared between arms using X2 test. Results: Median follow-up for 1st and 2nd line and whole sequence were 9.3, 6.6 and 22.0 months (mos) respectively and questionnaire completion rate was 81%. TTQOLD for total FACT-P score for the whole sequence for arm A vs B was 10.5 mo (95% CI 5.0-15.5) vs 10.8 mo (5.5-13.1), p = 0.74. For 1st-line AAP vs ENZ, median TTQOLD was 15.5 mo (5.5-21.2) vs 11.0 (5.5-13.3) respectively (p = 0.23). For 2nd line ENZ vs ABI, median TTQOLD was 3.7 mo (2.0-5.4) vs 5.8 (2.8-12.1), p = 0.13. There was a higher rate of deterioration in physical well-being (PWB) for 1st line ENZ (arm B) and 2nd line ENZ (arm A) (Table). Conclusions: There was no difference in TTQOLD between the two treatment sequences of AAP and ENZ. Although treatment with second line ENZ has been associated with greater anti-cancer effects, ENZ was associated worse PWB QOL scores. Clinical trial information: NCT02125357 . [Table: see text]

Encouraging activity of bicalutamide and everolimus in castration-resistant prostate cancer (CRPC): Early results from a phase II clinical trial.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 157-157
Author(s):  
C. Pan ◽  
P. Ghosh ◽  
P. Lara ◽  
D. Robles ◽  
L. Beckett ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Disease Progression ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Tumor Formation ◽  
Mtor Pathway ◽  
Phase Ii Clinical Trial ◽  
Castration Resistant Prostate Cancer ◽  
Early Results ◽  
Psa Response

157 Background: Multiple signaling pathways are involved in the development of CRPC. We previously showed that the mTOR pathway is activated in CRPC cell lines while inhibition of this pathway results in upregulation of androgen receptor (AR) signaling (Wang et al, Oncogene. 2008). Simultaneous blockade of the mTOR and AR pathways synergize in inducing PCa cell death and delaying tumor formation in mouse models. We hypothesize that simultaneous blockade of the AR and mTOR pathways in CRPC patients with bicalutamide and everolimus will result in improved efficacy compared to bicalutamide alone. Methods: A phase II clinical trial with a lead-in safety phase was designed to determine the efficacy and tolerability of the bicalutamide and everolimus combination in CRPC patients compared with bicalutamide alone. Patients must have histologically confirmed disease and demonstrated disease progression (either by PSA or radiographically) while on androgen deprivation therapy. At the lead-in phase, all patients receive both agents. At the phase II stage, patients are randomized to bicalutamide +/− everolimus. The primary endpoint is PSA response. The second endpoints include progression-free survival, time-to-treatment failure, overall survival and toxicity. Here, we report the results of the lead-in phase. Results: Eight patients were recruited at the lead-in phase. The bicalutamide/everolimus combination was well tolerated with no unexpected toxicities. Six of 8 patients have had PSA response after at least 8 weeks of therapy and the remaining two patients had stable PSA response. The median time to disease progression was 6.8 months. Nine patients have been recruited at the phase II stage so far. This clinical trial is being subcontracting to the other sites of the California Cancer Consortium. Tumor and blood specimens are being collected for molecular correlative studies of mTOR pathway markers. Conclusions: The rational combination of bicalutamide and everolimus appears to have promising anti-tumor activity and an acceptable toxicity profile. The randomized phase of the clinical trial is currently ongoing and will be reported. Supported by Novartis. [Table: see text]

Predictors for response to cetuximab in a prospective clinical trial (E2303) of patients with head and neck squamous cell carcinoma (HNSCC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5576-5576 ◽  
Author(s):  
Amanda Psyrri ◽  
Ju-Whei Lee ◽  
Eirini Pectasides ◽  
Maria Vassilakopoulou ◽  
Barbara Burtness ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Cox Regression ◽  
Objective Response ◽  
Eastern Cooperative Oncology Group ◽  
Disease Stage ◽  
Rank Test ◽  
Free Survival ◽  
Cox Regression Analysis ◽  
Event Time

5576 Background: Theidentification of resistance mechanisms to Epidermal Growth Factor Receptor (EGFR) inhibitors remains critical lack in the management of HNSCC. We sought to determine predictors for response to cetuximab in a phase II clinical trial. Methods: 63 patients (pts) with operable stage III/IV HNSCC participated in E2303, an Eastern Cooperative Oncology Group (ECOG) phase II trial of induction chemotherapy with weekly cetuximab, paclitaxel and carboplatin x 6 followed by chemoradiotherapy with the same regimen. A tissue microarray was constructed and EGFR, ERK1/2, Met, pAkt and STAT protein expression levels were assessed using AQUA. The objectives of analysis were to determine association of biomarkers with E2303 efficacy outcomes (best objective response (OR), overall survival (OS), progression-free survival (PFS), and event-free survival (EFS)). The logistic regression model was used to examine relationship between marker measurements (on a continuous scale) and OR. The univariate and multivariate Cox proportional hazards models were used to evaluate the relationship between markers and event-time distributions. Fisher’s exact test was used to evaluate differences in response rate between groups (high vs. low AQUA scores). Event-time distributions were estimated by the Kaplan-Meier method and compared by the log-rank test. Results: Cytoplasmic ERK1/2 levels weresignificantly associated with PFS and OS (p=0.03 and 0.01, respectively). Nuclear ERK1/2 levels were significantly associated with OS (p=0.02) and tended towards significance for PFS (p=0.09). The multivariate Cox regression analysis shows that cytoplasmic and nuclear ERK1/2 are significantly associated with OS and PFS after controlling for primary site and disease stage, respectively There was no significant association between cytoplasmic or nuclear ERK1/2 status and OR (p-values 0.98 and 0.41, respectively).No association was found between expression of any of other biomarkers and outcome measures. Our data analysis was based on 35 pts with marker data available. Conclusions: Ras/MAPK/ERKpathway may be associated with resistance to cetuximab in HNSCC.

ProCAID: A phase I clinical trial to combine the AKT inhibitor AZD5363 with docetaxel and prednisolone (DP) chemotherapy for metastatic castration resistant prostate cancer (mCRPC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 228-228 ◽  
Author(s):  
Simon J. Crabb ◽  
Alison J. Birtle ◽  
Karen Martin ◽  
Nichola Downs ◽  
Megan Bowers ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Protein Kinase ◽  
Phase I ◽  
Disease Progression ◽  
Phase Ii ◽  
Performance Status ◽  
Research Network ◽  
Castration Resistant Prostate Cancer ◽  
Akt Inhibitor ◽  
Clinical Resistance

228 Background: DP extends survival in mCRPC. However emergent clinical resistance is effectively inevitable. Serine/threonine protein kinase AKT (protein kinase B) pathway activation is highly prevalent in mCRPC contributing to disease progression and DP therapeutic resistance. AZD5363 is a potent oral pan-AKT inhibitor. Pre-clinical data suggest activity in mCRPC and synergy with docetaxel. This phase I trial was to develop a DP/AZD5363 combination in mCRPC. Methods: Eligibility included chemotherapy naive histologically/cytologically proven measurable/evaluable mCRPC, PSA or radiographic disease progression, ECOG performance status 0 or 1, serum testosterone <1.7 nmol/L. Treatment comprised DP up to 10 cycles (75 mg/m2, IV, day 1; prednisolone 5 mg BID, PO, day 1–21) and AZD5363 to disease progression. Planned AZD5363 dose levels were 320 mg (DL1), 400 mg (DL2) and 480 mg (DL3), BID, PO, 4 days on/3 days off, from cycle 1, day 2. We utilised a conventional 3+3 dose escalation to determine a recommended phase II dose (RP2D) for AZD5363 combined with DP according to defined dose limiting toxicity (DLT) using CTCAEv4. Results: 10 patients were recruited (4 DL1, 6 DL2), median age 67.5 (Range: 56-72). A median of 6.5 cycles (Range: 3-10) of DP and 4 cycles (Range: 1-13) of AZD5363 were administered. No DLTs were seen in DL1. 2 patients in DL2 experienced DLTs (G3 rash, G3 diarrhoea). 7 pts (70%) had at least one G3/4 IMP-related AE with neutropenia (n=3) and maculo-papular rash (n=3) the most common. G3/4 AEs considered related to AZD5363 occurred in 3 patients (0 DL1, 3 DL2) including maculo-papular rash, diarrhoea and neutropenia. Transient hyperglycaemia occurred in all patients (Random glucose C1D2 pre dose mean 6.0 mmol/L, 2 hour mean 8.7 mmol/L, 4 hour mean 9.5 mmol/L, 8 hour mean 6.5 mmol/L). Conclusions:The RP2D for AZD5363 is 320 mg bd 4 days on/3 days off in combination with full dose DP for mCRPC. A placebo controlled randomised phase II trial for this approach has commenced recruitment. This work was supported by CRUK [C9317/A16029]. CRUK Reference: CRUK/12/042. This research was conducted with support from the Investigator-Sponsored Study Collaboration between AstraZeneca and the National Cancer Research Network. Clinical trial information: NCT02121639.

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.

Blood platelet volume to predict treatment-specific outcomes of metastatic castration-resistant prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 242-242
Author(s):  
Wataru Fukuokaya ◽  
Takahiro Kimura ◽  
Fumihiko Urabe ◽  
Shoji Kimura ◽  
Kojiro Tashiro ◽  
...  
Keyword(s):  
Radiographic Progression ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Line Treatment ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Castration Resistant ◽  
Psa Progression ◽  
Pre Treatment ◽  
First Line Treatment

242 Background: In the present guidelines for the management of metastatic castration-resistant prostate cancer (CRPC), it is unclear who benefits from androgen receptor axis-targeted agents (ARATs) or docetaxel as a first-line treatment. Methods: We conducted a single-institutional retrospective study to explore treatment-specific biomarkers for treatment response of metastatic CRPC. A cohort of 211 patients with metastatic CRPC treated with either ARAT (abiraterone acetate or enzalutamide) or docetaxel as a first-line treatment was evaluated. In addition to well-established biomarkers such as hemoglobin, neutrophil-to-lymphocyte ratio, alkaline phosphatase, and lactate dehydrogenase, we also assessed red cell distribution width, platelet count, and mean platelet volume (MPV). Laboratory measures were assessed within 1 month before starting treatment. Prostate-specific antigen progression-free survival (PSA-PFS) and radiographic progression-free survival (RPFS) were evaluated. Multivariable Cox regression models were used to assess the association between biomarkers and the risk of events. We also studied the statistical interaction between biomarkers and clinical outcomes. Results: Of all blood-based biomarkers, multivariable Cox regression models identified pre-treatment MPV (≤9.0 fL) as an independent prognostic factor of both PSA progression (hazard ratio [HR]: 2.62, 95% confidence interval [CI]: 1.25-5.48, P = 0.011) and radiographic progression (HR: 4.46, 95% CI: 1.79-11.1, P = 0.001). In addition, these models showed a lower risk of PSA progression (HR: 0.38, 95% CI: 0.15-0.96, P = 0.041) and radiographic progression (HR: 0.16, 95% CI: 0.05-0.50, P = 0.002) with docetaxel compared with ARAT when pre-treatment MPV was small. Conclusions: The present study identified MPV as a significant treatment-specific prognostic factor of PSA progression and radiographic progression in patients with metastatic CRPC treated with a first-line treatment. Furthermore, our results suggested that small MPV was associated with superior survival benefit on docetaxel over ARAT.

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