Olaparib trial reveals ‘first personalized treatment strategy for prostate cancer’
BARCELONA, Spain — Olaparib significantly improved radiographic PFS compared with horomone therapy for men with metastatic castration-resistant prostate cancer who had homologous recombination repair gene alterations and received prior treatment with new hormonal agents, according to results of the randomized phase 3 PROfound study presented at European Society for Medical Oncology Congress.
Researchers also observed a favorable trend for OS with olaparib (Lynparza, AstraZeneca) — a poly(ADP-ribose) polymerase (PARP) inhibitor — despite crossover.
“This is the first personalized treatment strategy for prostate cancer,” researcher Maha Hussain, MD, FACP, FASCO, deputy director of Robert H. Lurie Comprehensive Cancer Center at Northwestern University, told HemOnc Today. “Prostate cancer has lagged behind all solid tumors. We have seen molecularly targeted treatments for breast, ovarian and lung cancers, even gallbladder cancer, but there has been nothing for prostate cancer.
“The androgen receptor continues to be very dominant in this disease, but we don’t even measure the androgen receptor because so many patients respond to it,” added Hussain, a HemOnc Today Editorial Board Member. “It is delightful to see a molecularly targeted therapy work in prostate cancer.”
In the past decade, researchers have determined metastatic castration-resistant prostate cancer can have deleterious alternations in a variety of genes. Loss-of-function alterations in homologous recombination repair genes — including BRCA1, BRCA2 and ATM — are associated with response to PARP inhibition, according to study background.
Hussain and colleagues conducted the open-label PROfound study to evaluate the efficacy and safety of olaparib vs. physician’s choice of enzalutamide (Xtandi; Astellas, Pfizer) or abiraterone acetate (Zytiga, Janssen) for 387 men (median age, 68 years; range, 47-91) with metastatic castration-resistant prostate cancer. Approximately one-quarter of men had de novo metastatic disease, more than 60% had received prior chemotherapy and more than 20% had received two lines of chemotherapy.
All men had alterations in any of 15 predefined genes with direct or indirect roles in homologous recombination repair, and all experienced disease progression on prior front-line therapy for metastatic disease with a new hormonal agent.
Researchers randomly assigned men 2:1 to olaparib 300 mg twice daily or physician’s choice of abiraterone or enzalutamide.
The study consisted of two cohorts. Cohort A included 245 men with BRCA1, BRCA2 or ATM mutations (olaparib, n = 162; physician’s choice, n = 83). Cohort B included 142 men with alterations in other homologous recombination repair genes (olaparib, n = 94; physician’s choice, n = 48).
Men assigned to the physician’s choice group who experienced progression as determined by blinded independent central review were allowed to cross over to olaparib.
Radiographic PFS in cohort A served as the primary endpoint. Radiographic PFS among all study patients, as well as three additional outcomes in cohort A — confirmed objective response rate, time to pain progression and OS — served as key secondary endpoints.
Median treatment duration was 7.4 months with olaparib and 3.9 months with physician’s choice.
Results showed olaparib-treated men in cohort A achieved significantly longer median radiographic PFS (7.39 months vs. 3.55 months; HR = 0.34; 95% CI, 0.25-0.47). They also were more likely to be progression free by radiographic criteria at 6 months (59.7% vs. 22.6%) and 12 months (28.1% vs. 9.4%).
“I consider this not only statistically significant but also clinically significant,” Hussain said. “We see separations of the curve occurring very early in the process and continuing beyond a year.”
The benefit with olaparib persisted when investigators analyzed radiographic PFS for both cohorts (median, 5.82 months vs. 3.52 months; HR = 0.49; 95% CI, 0.38-0.63).
Analysis of secondary endpoints showed olaparib conferred benefit to men in cohort A with regard to confirmed ORR (33.3% vs. 2.3%; OR = 20.86; 95% CI, 4.18-379.18), time to pain progression (median, not reached vs. 9.92 months; HR = 0.44; 95% CI, 0.22-0.91) and interim OS (median, 18.5 months vs. 15.11 months; HR = 0.64; 95% CI, 0.43-0.97).
“OS data for both cohorts are not mature. We anticipate outcomes next year, but this is a very promising early signal,” Hussain said.
Olaparib’s safety profile appeared consistent with that observed in prior studies.
The most common adverse events — irrespective of whether treating physicians considered them related to treatment — included anemia (46.1% for olaparib vs. 15.4% for physician’s choice), nausea (41.4% vs. 19.2%), decreased appetite (30.1% vs. 17.7%) and fatigue (26.2% vs. 20.8%).
Most adverse events were mild with the exception of anemia (21.5% for olaparib vs. 15.4% for physician’s choice).
Men assigned olaparib appeared almost twice as likely to discontinue treatment due to adverse events (16.4% vs. 8.5%).
The PROfound trial is the first positive phase 3 biomarker-selected study that evaluated a targeted treatment for men with metastatic castration-resistant prostate cancer.
“Is it perfect? Not yet,” Hussain told HemOnc Today. “But when you think about the rate of separation of the curves and the trends in third-line or fourth-line therapy, this is really exciting. This also opens the door for more combination trials and efforts to move this forward into earlier stages where the impact can be bigger.” – by Mark Leiser
Reference: Hussain M, et al. Abstract LBA12_PR. Presented at: European Society for Medical Oncology Congress; Sept. 27-Oct. 1, 2019; Barcelona, Spain.
Disclosures: AstraZeneca and Merck Sharpe & Dohme funded this study. Hussain reports honoraria from Aptitude Health, Astellas, Epics, Genentech, PER, Research to Practice and Sanofi Genzyme; consultant/advisory fees from Bayer, Genentech and Pfizer; and travel/accommodation support from Astellas, AstraZeneca, Bayer, Genentech, Pfizer and Sanofi Genzyme. Please see the abstract for all other authors’ relevant financial disclosures.