Publications by authors named "Daniel J Khalaf"

4 Publications

  • Page 1 of 1

Effectiveness of first-line abiraterone versus enzalutamide among patients ≥80 years of age with metastatic castration-resistant prostate cancer: A retrospective propensity score-weighted comparative cohort study.

Eur J Cancer 2021 Jul 12;152:215-222. Epub 2021 Jun 12.

Department of Medicine, Medical Oncology Division, BC Cancer, Vancouver Centre, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Background: Metastatic castration-resistant prostate cancer (mCRPC) disproportionately affects the elderly. There is limited data assessing the efficacy and tolerability of abiraterone acetate (AA) versus enzalutamide in this population.

Objective: To compare the clinical efficacy and tolerability of AA versus enzalutamide in patients ≥ 80 years with mCRPC.

Design, Setting And Participants: A retrospective propensity-weighted comparative cohort study of first-line AA versus enzalutamide among patients with mCRPC aged ≥80 years.

Outcome Measurements And Statistical Analysis: Inverse probability treatment weights based on propensity scores were generated to assess the treatment effect of AA versus enzalutamide on time to PSA progression (TTPP), time to progression (TTP) (first of PSA/radiographic/clinical progression) and overall survival using a weighted Cox proportional hazards model. PSA response rate (PSA RR) was compared between groups using Χ.

Results And Limitations: One hundred fifty-three patients received AA, and 125 received enzalutamide. Enzalutamide was associated with higher PSA RR (61.6% vs 43.8%, P < 0.004), and TTP (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.50-0.88, P = 0.01) but not TTPP (HR 0.73, 95% CI 0.53-1.01, P = 0.06). There were significantly more dose reductions with enzalutamide (22.9% vs 44.8%, P > 0.001) but there was no interaction between median proportion of full dose received and TTPP or TTP for either drug. Rates of treatment discontinuation (for reasons other than progression) were also significantly different between AA and enzalutamide (28.8% vs 40.8%, respectively, P = 0.04). The most common reason for dose reductions and discontinuation of enzalutamide was fatigue (30.4% and 5.6%, respectively).

Conclusions: Despite more dose reductions and a higher treatment discontinuation rate, enzalutamide was associated with a higher PSA RR and longer time to progression, than AA. Given that clinical outcomes were not adversely impacted by decreased treatment exposure, dose modification may be a useful treatment strategy to balance toxicity and tolerance.
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http://dx.doi.org/10.1016/j.ejca.2021.05.003DOI Listing
July 2021

Evolution of Castration-Resistant Prostate Cancer in CtDNA during Sequential Androgen Receptor Pathway Inhibition.

Clin Cancer Res 2021 Jun 3. Epub 2021 Jun 3.

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.

Purpose: Cross-resistance renders multiple lines of androgen receptor (AR) signaling inhibitors increasingly futile in metastatic castration-resistant prostate cancer (mCRPC). We sought to determine acquired genomic contributors to cross-resistance.

Experimental Design: We collected 458 serial plasma cell-free DNA samples at baseline and progression timepoints from 202 patients with mCRPC receiving sequential AR signaling inhibitors (abiraterone and enzalutamide) in a randomized phase II clinical trial (NCT02125357). We utilized deep targeted and whole-exome sequencing to compare baseline and posttreatment somatic genomic profiles in circulating tumor DNA (ctDNA).

Results: Patient ctDNA abundance was correlated across plasma collections and independently prognostic for sequential therapy response and overall survival. Most driver alterations in established prostate cancer genes were consistently detected in ctDNA over time. However, shifts in somatic populations after treatment were identified in 53% of patients, particularly after strong treatment responses. Treatment-associated changes converged upon the gene, with an average 50% increase in copy number, changes in mutation frequencies, and a 2.5-fold increase in the proportion of patients carrying AR ligand binding domain truncating rearrangements.

Conclusion: Our data show that the dominant genotype continues to evolve during sequential lines of AR inhibition and drives acquired resistance in patients with mCRPC.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1625DOI Listing
June 2021

Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial.

Lancet Oncol 2019 12 11;20(12):1730-1739. Epub 2019 Nov 11.

Division of Medical Oncology, BC Cancer, Vancouver, BC, Canada; Vancouver Prostate Centre, Vancouver, BC, Canada. Electronic address:

Background: Abiraterone acetate plus prednisone and enzalutamide are both used for the treatment of metastatic castration-resistant prostate cancer. We aimed to determine the best sequence in which to use both drugs, as well as their second-line efficacy.

Methods: In this multicentre, randomised, open-label, phase 2, crossover trial done in six cancer centres in British Columbia, Canada, we recruited patients aged 18 years or older with newly-diagnosed metastatic castration-resistant prostate cancer without neuroendocrine differentiation and Eastern Cooperative Oncology Group performance status 2 or less. Patients were randomly assigned (1:1) using a computer-generated random number table to receive either abiraterone acetate 1000 mg orally once daily plus prednisone 5 mg orally twice daily until PSA progression followed by crossover to enzalutamide 160 mg orally once daily (group A), or the opposite sequence (group B). Treatment was not masked to investigators or participants. Primary endpoints were time to second PSA progression and PSA response (≥30% decline from baseline) on second-line therapy, analysed by intention-to-treat in all randomly assigned patients and in patients who crossed over, respectively. The trial is registered with ClinicalTrials.gov, NCT02125357.

Findings: Between Oct 21, 2014, and Dec 13, 2016, 202 patients were enrolled and randomly assigned to either group A (n=101) or group B (n=101). At the time of data cutoff, 73 (72%) patients in group A and 75 (74%) patients in group B had crossed over. Time to second PSA progression was longer in group A than in group B (median 19·3 months [95% CI 16·0-30·5] vs 15·2 months [95% CI 11·9-19·8] months; hazard ratio 0·66, 95% CI 0·45-0·97, p=0·036), at a median follow-up of 22·8 months (IQR 10·3-33·4). PSA responses to second-line therapy were seen in 26 (36%) of 73 patients for enzalutamide and three (4%) of 75 for abiraterone (χ p<0·0001). The most common grade 3-4 adverse events throughout the trial were hypertension (27 [27%] of 101 patients in group A vs 18 [18%] of 101 patients in group B) and fatigue (six [10%] vs four [4%]). Serious adverse events were reported in 15 (15%) of 101 patients in group A and 20 (20%) of 101 patients in group B. There were no treatment-related deaths.

Interpretation: Enzalutamide showed activity as a second-line novel androgen receptor pathway inhibitor, whereas abiraterone acetate did not, leading to a longer time to second PSA progression for the sequence of abiraterone followed by enzalutamide than with the opposite treatment sequence. Our data suggest that using a sequencing strategy of abiraterone acetate followed by enzalutamide provides the greatest clinical benefit.

Funding: Canadian Cancer Society Research Institute, Prostate Cancer Canada, Movember Foundation, Prostate Cancer Foundation, Terry Fox New Frontiers Program, BC Cancer Foundation, Jane and Aatos Erkko Foundation, Janssen, and Astellas.
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http://dx.doi.org/10.1016/S1470-2045(19)30688-6DOI Listing
December 2019

Health-related Quality of Life for Abiraterone Plus Prednisone Versus Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer: Results from a Phase II Randomized Trial.

Eur Urol 2019 06 24;75(6):940-947. Epub 2018 Dec 24.

Department of Medical Oncology, BC Cancer Vancouver Centre, Vancouver, BC, Canada; Department of Urological Sciences, The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Background: Abiraterone and enzalutamide are associated with side effects that may impair health-related quality of life (HRQoL).

Objective: To assess patient-reported HRQoL, depression symptoms, and cognitive function for abiraterone versus enzalutamide.

Design, Setting, And Participants: We randomized 202 patients in a phase II study of abiraterone versus enzalutamide for first-line treatment of metastatic castration-resistant prostate cancer (ClinicalTrials.gov: NCT02125357).

Intervention: Patients completed Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Patient Health Questionnaire-9 (PHQ-9) questionnaires, and Montreal Cognitive Assessment (MoCA) cognitive assessments at baseline and on treatment.

Outcome Measurements And Statistical Analysis: To compare the change in FACT-P scores over time between treatment arms, we used a mixed model for repeated measures (MMRM). For FACT-P domains where there was an interaction between the treatment arm and age, we constructed separate models for patients aged <75 and ≥75yr. We compared the proportion of patients with clinically meaningful change from baseline for FACT-P, and the proportion of patients with an abnormal score and median change from baseline for PHQ-9 and MoCA using Fisher's exact test and Mann-Whitney U test.

Results And Limitations: In the MMRM analysis, there was a positive test for interaction in the treatment arm by age for total FACT-P (p=0.048). FACT-P change from baseline over time was better for abiraterone than for enzalutamide in the ≥75-yr model (p=0.003), with no difference in the <75-yr model (p>0.9). A higher proportion of patients experienced clinically meaningful worsening with enzalutamide for the physical and functional well-being domains (37% vs 21%, p=0.013; 39% vs 23%, p=0.015). The distribution of change in PHQ-9 scores from baseline favored abiraterone at weeks 4, 8, and 12. These analyses were not prespecified, and results should be considered to be hypothesis generating.

Conclusions: Patient-reported outcomes favored abiraterone compared with enzalutamide with differences in FACT-P HRQoL and PHQ-9 depression scores. Differences in the total FACT-P scores were seen only in the elderly patient subgroup.

Patient Summary: In this report, we examined the change in patient-reported quality-of-life scores from the start of treatment over time for patients treated with abiraterone versus enzalutamide for metastatic castration-resistant prostate cancer. We found that elderly patients treated with abiraterone had better quality of life over time, with no difference between treatments for the younger subgroup of patients.
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http://dx.doi.org/10.1016/j.eururo.2018.12.015DOI Listing
June 2019
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