In a phase III trial (PROfound) reported in The New England Journal of Medicine, Johann de Bono, MB, ChB, PhD, of the Institute of Cancer Research and Royal Marsden Hospital, London, and colleagues found that olaparib significantly improved progression-free survival vs hormonal therapy in patients with metastatic castration-resistant prostate cancer and alterations in BRCA1, BRCA2, or ATM who had disease progression on a new hormonal therapy.¹ A progression-free survival benefit was also observed in the combined population of patients with these alterations and those with alterations in other genes involved in homologous recombination repair.

Johann de Bono, MB, ChB, PhD

Study Details

In the trial, men with disease progression who were receiving enzalutamide or abiraterone as a new hormonal agent were randomly assigned 2:1 within two cohorts between April 2017 and November 2018 to receive olaparib at 300 mg twice daily or the physician’s choice of enzalutamide at 160 mg once daily or abiraterone at 1,000 mg once daily plus prednisone at 5 mg twice daily (control group). Cohort A comprised 162 patients in the olaparib group and 83 in the control group who had at least one alteration in BRCA1, BRCA2, or ATM. Cohort B comprised 94 patients in the olaparib group and 48 in the control group who had alterations in any of 12 other prespecified genes involved in homologous recombination repair.

The primary endpoint was imaging-based, progression-free survival in cohort A upon blinded independent central review. A major secondary endpoint was progression-free survival in the combined cohorts.

In cohort A, for the olaparib vs control groups, the median age was 68 vs 67 years (67% vs 72% aged ≥ 65 years). In both groups, 23% had metastatic disease at initial diagnosis, and 67% had a Gleason score ≥ 8. Median prostate-specific antigen was 62 vs 113 µg/L, 59% vs 55% had measurable disease, 35% vs 28% had bone-only metastasis, and 28% vs 39% had liver or lung metastasis. Eastern Cooperative Oncology Group performance status was 0 or 1 in 93% vs 96%. Previous new hormonal treatment was enzalutamide alone in 42% vs 48%, abiraterone alone in 38% vs 35%, and both in 20% vs 17%, and 65% vs 63% had prior taxane treatment.

Progression-Free Survival

In cohort A, median progression-free survival was 7.4 months in the olaparib group vs 3.6 months in the control group (hazard ratio [HR] = 0.34, P < .001). Objective response rate among evaluable patients was 33% vs 2% (odds ratio = 20.86, P < .001). Median time to pain progression was significantly prolonged in the olaparib group (HR = 0.44, P = .02; 84% vs 67% progression-free at 6 months). Among evaluable patients (153 and 77), prostate-specific antigen (PSA) response (≥ 50% reduction) was observed in 43% vs 8%. Among evaluable patients (97 and 44), clearance of circulating tumor cells was observed in 30% vs 11%.

Overall, 81% of patients with disease progression in the control group crossed over to receive olaparib. An interim analysis showed a median overall survival of 18.5 months vs 15.1 months (HR = 0.64, P = .02). A sensitivity analysis adjusting for switching to olaparib treatment yielded a hazard ratio of 0.57 (95% confidence interval [CI] = 0.34–0.96).

In the combined populations of cohorts A and B, median progression-free survival was 5.8 months in the olaparib group vs 3.5 months in the control group (HR = 0.49, P < .001). Objective response rate among evaluable patients was 22% vs 4%. At 6 months, 85% vs 75% were free of pain progression. Among evaluable patients (243 and 123), PSA response was observed in 30% vs 10%. Among evaluable patients (153 and 68), clearance of circulating tumor cells was observed in 27% vs 10%.

A total of 82% of control group patients crossed over to olaparib at disease progression. Interim analysis showed a median overall survival of 17.5 months vs 14.3 months (HR = 0.67, 95% CI = 0.49–0.93). A sensitivity analysis adjusting for switching to olaparib treatment yielded a hazard ratio of 0.60 (95% CI = 0.40–0.90).

An exploratory analysis of outcomes in cohort B showed a median progression-free survival of 4.8 months in the olaparib group vs 3.3 months in the control group and a median overall survival of 14.2 months vs 11.5 months.

Adverse Events

In the total population, the median duration of assigned treatment was 7.4 months in the olaparib group and 3.9 months in the control group. Among all patients, grade ≥ 3 adverse events occurred in 51% of the olaparib group vs 38% of the control group, with the most common in the olaparib group being anemia (21%) and fatigue/asthenia (3%).

The most common adverse events of any grade were anemia (46% vs 15%), nausea (41% vs 19%), and fatigue/asthenia (41% vs 32%) in the olaparib group and fatigue/asthenia in the control treatment. Pulmonary embolism occurred in 11 patients (4%) in the olaparib group and in 1 patient in the control group; no fatalities were reported.

Adverse events led to treatment interruption in 45% vs 18%, dose reduction in 22% vs 4%, and treatment discontinuation in 18% vs 8%. Adverse events led to death in 4% of patients in each group, with one death in the olaparib group (due to lung infection) and one in the control group (due to pleural effusion/respiratory insufficiency) considered related to study treatment.

No cases of myelodysplastic syndromes or acute myeloid leukemia were observed. New primary cancers were reported in one patient in the olaparib group (glioma) and two patients in the control group (gastric cancer and transitional cell carcinoma).

The investigators concluded: “In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival and better measures of response and patient-reported endpoints than either enzalutamide or abiraterone.” 

DISCLOSURE: The study was funded by AstraZeneca and Merck Sharp & Dohme. Dr. de Bono has received honoraria from Astellas Pharma, AstraZeneca, Bio X Cell, Daiichi Sankyo, Genentech/Roche, Janssen Oncology, Menarini Silicon Biosystems, Pfizer, Sanofi, and Sierra Oncology; has served as a consultant or advisor to Astellas Pharma, AstraZeneca, Bayer, Bio X Cell, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eisai, Genentech/Roche, Genmab, GlaxoSmithKline, Janssen Oncology, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma GmbH, Pfizer, Sanofi, Sierra Oncology, and Taiho Pharmaceutical; has received institutional research funding from Astex Pharmaceuticals, AstraZeneca, Bayer, Celgene, CellCentric, Daiichi Sankyo, Genentech, GlaxoSmithKline, MedImmune, Medivation, Merck Serono, Merck Sharp & Dohme, Orion Pharma GmbH, Sanofi, Sierra Oncology, and Taiho Pharmaceutical; holds a variety of institutional patents or other intellectual property; and has been reimbursed for travel, accommodations, or other expenses by Astellas Pharma, AstraZenenca, Genmab, GlaxoSmithKline, Orion Pharma GmbH, Sanofi, Taiho Pharmaceutical, Qiagen, and Vertex.

REFERENCE

1. de Bono J, Mateo J, Fizazi K, et al: Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med 382:2091-2102, 2020.