Olaparib trial reveals ‘first personalized treatment strategy for prostate cancer’
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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.
Perspective
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Eleni Efstathiou, MD, PhD
There are five requirements for a study to be truly practice changing. It must address an unmet need. It must follow a design that actually compares an experimental arm to a ‘standard’ practice. There must be positive outcomes that are clinically meaningful. The data must be reproducible. Finally, the practices must be accessible to the community.
This study certainly meets an unmet need. We need to move away from “all-comers” study outcomes because we know disease outcome variability is largely driven by underlying molecular heterogeneity. The challenge remains identifying causal pathways of disease progression that can be targeted.
The study design criteria is met because sequential treatment with androgen signaling inhibitors is standard practice in a lot of community practices, and even some academic settings. The investigators made sure to allow crossover to olaparib upon progression, leaving very minimal window for complaints or ethical considerations. This also is a heavily pretreated population with no real alternatives. Two-thirds had prior taxanes, all had prior abiraterone or enzalutamide, 20% had received both, and 20% had both docetaxel and cabazitaxel (Jevtana, Sanofi Genzyme). Look at the population and think of your clinic. A patient comes in the door and he has received [every viable therapy] you have. He has extensive visceral disease — more than likely lung or liver — and a great performance status. This exactly the type of person for whom we want to prolong life and prolong lack of symptoms.
What about positive outcomes? The primary endpoint was met, with a doubling of radiographic PFS in the BRCA1/BRCA2/ATM cohort. Time to pain progression is a very valuable endpoint. OS data are immature but still we see a clear trend, even with 80% crossover.
This is the first phase 3 trial of a targeted therapy for prostate cancer to deliver positive outcomes. We shouldn’t expect reproducibility, but yet we do. If we look at data from trials of other BRCA-driven solid tumors, approvals of PARP inhibitors largely have been driven by PFS. If we look at ongoing and completed phase 2 trials in prostate cancer, there is absolute concordance favoring BRCA2 responsiveness.
Now, the big issue. We have all seen reports in diseases where we have approved targeted agents that 50% of patients are not receiving the right targeted therapies. There is limited access to validated genomic analysis assays, there is a high cost associated with their use, and they are not available internationally. There are concerns with in-house assays because they are not really validated or certified, and some of us have limited understanding of reporting. Then there is the little elephant in the room: What are we going to do with platinum-based treatment? It has not been tested in this setting and there are no data, but hopefully we will get there at some point.
Taken together, this truly is a practice-changing study, not just for our patients but also for study design. It is assay-specific, resulting in a validated genomic testing tissue-based assay that successfully identified candidates for olaparib treatment. Among patients with metastatic castration-resistant prostate cancer and alterations in DNA damage response and repair (DDR) genes — primarily BRCA2 — olaparib provided a statistically significant, clinically meaningful improvement with an acceptable safety profile. In terms of therapeutic strategy for prostate cancer, we are starting to enter the targeted therapy era, and maybe we will abandon the sequential use of novel androgen signaling inhibition.
So where do we go from here? We go into full-throttle, marker-driven clinical research. That will allow us to move into molecular classification so we can link outcomes to targeting causal pathways of progression and have a means of identifying them.
When we think about DDR alterations specifically, there’s only one way to augment our outcomes. We need to move earlier in the disease, and we need to make decisions about which genes we are going to target. Of course, ease of and access to education is important to ensure practice uptake of novel therapeutic strategies. Our goal is progress, not perfection. This trial moves the field forward.
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Ignacio Duran, MD, PhD
This work is relevant for two important reasons. First, it demonstrated superiority in terms of efficacy. Olaparib clearly was superior to the regimens used in the control arm. Second, this study has proved a new concept in prostate cancer, as it demonstrated the disease can be treated with a targeted therapy approach. Not all men with prostate cancer have the same types of tumors, and this is the first time we have been able to identify that we can more precisely characterize the molecular biology and genetic background of tumors. That knowledge will help us better determine the best way to treat them.
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