Treatment with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib delayed disease progression and appears to improve survival, compared with newer hormonal agents in men with pretreated metastatic castration-resistant prostate cancer and homologous recombinant repair (HRR) genetic alterations—specifically BRCA1, BRCA2, and ATM.

Data from the PROfound study, reported at the 2019 ESMO Congress,¹ showed that disease progression was delayed by about 4 months in patients who received olaparib vs newer hormonal agents, and survival was prolonged by more than 3 months at this early time point.

Maha H.A. Hussain, MD, FACP, FASCO

“In metastatic castration-resistant prostate cancer that has progressed on front-line hormonal therapy with abiraterone or enzalutamide, olaparib provides statistically significant and clinically meaningful progression-free survival in patients with metastatic castration-resistant prostate cancer and BRCA1, BRCA2, or ATM genetic alterations,” said lead author Maha H.A. Hussain, MD, FACP, FASCO, of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago.

All men enrolled in the study had to have alterations in DNA repair genes (HRR). “PROfound is the first positive biomarker-selected phase III study evaluating a molecularly targeted therapy in men with metastatic castration-resistant prostate cancer and the largest to have central HRR mutation testing,” she emphasized. “This study highlights the importance of genomic testing in this population. A recurring theme is that precision medicine trials are feasible in metastatic castration-resistant prostate cancer,” Dr. Hussain stated.

Olaparib is approved for the treatment of ovarian cancer harboring BRCA mutations. PROfound is the first phase III study of PARP inhibition in prostate cancer with these and other DNA repair (HRR) genetic mutations.

“Over the past decade, we have come to realize that metastatic castration-resistant prostate cancer can have deleterious alterations in a variety of DNA repair genes. The intent of our study was to target those genes to prevent the cancer from repairing itself,” Dr. Hussain explained.

PROfound Study Details

Among patients screened for the trial, about 30% had BRCA1 or BRCA2 genetic alterations. Dr. Hussain explained that these alterations are associated with a more aggressive phenotype and that this was a preselected population, so the prevalence of these genes is probably somewhat lower in a general population of men with prostate cancer.

PROfound enrolled 387 men with metastatic castration-resistant prostate cancer and HRR genetic alterations and randomly assigned them 2:1 to treatment with olaparib at 300 mg twice daily or physician’s choice of enzalutamide or abiraterone acetate plus prednisone. Enrollment criteria specified alterations of any of 15 predetermined HRR genes with a direct or indirect role in progressive disease on prior new hormonal agents.

Cohort A included 245 patients with alterations in BRCA1, BRCA2, or ATM; cohort B included 142 men with any of 12 other HRR alterations (ie, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RA51D, or RAD54L).

For cohort A, the primary endpoint was progression-free survival as assessed by imaging. Cohort B had other endpoints as well. Crossover to olaparib was allowed at disease progression. The median age of patients was 68 years.

Notably, men in their late 80s and early 90s were eligible, Dr. Hussain said. About 20% of patients had de novo metastatic disease, which is associated with a poor prognosis, she noted.

The patient population was relatively heavily pretreated. All had to experience disease progression on at least one line of prior androgen-deprivation therapy; about 60% had prior chemotherapy; 25% had two prior lines of chemotherapy.

Key Findings

The median radiographic progression-free survival in cohort A was 7.39 months vs 3.5 months in the comparator arm—representing a 66% reduction in disease progression (P < .0001). “This was not only statistically significant but clinically significant. The separation of curves continues beyond a year,” stated Dr. Hussain.

Among all patients enrolled in the trial, the median progression-free survival was 5.82 months with olaparib vs 3.52 months with the comparator, for a 51% reduction in the risk for disease progression (P < .0001). All secondary endpoints favored olaparib as well, including objective response rate, time to pain progression, and overall survival.

In cohort A, the objective response rate was 33% vs 2.3%, respectively (P < .0001). Time to pain progression was not reached in patients in cohort A who received olaparib vs 9.92 months for those in the comparator arm (P = .0192). The median overall survival was not reached in either arm but trended toward improvement with olaparib at this early time point.

Overall, olaparib was generally well tolerated. The median duration of treatment was 7.4 months with olaparib and 3.9 months with the control. Although higher rates of adverse events were reported with olaparib, the majority were mild. Grade 3 or higher anemia occurred in 21% of olaparib-treated patients. Treatment discontinuation due to adverse events occurred in 16.4% of the olaparib group compared with 8.5% of the comparator arm.

“Overall, the adverse-event profile of olaparib was consistent with that seen in other settings,” Dr. Hussain said.

Future Directions

At a press conference, Dr. Hussain stated that she believes that results would be even better in the front-line setting. More study is needed, and currently several studies are looking at PARP inhibitors as first-line therapy in prostate cancer. Phase II studies are comparing PARP inhibitors with androgen receptor–directed therapies or in combination in preselected populations. A phase III study is evaluating front-line treatment with olaparib plus abiraterone, she said.

“There are a lot of questions and more trials will happen,” she added.

Genetic testing is necessary to select patients for olaparib, but such testing has not been standard practice in the United States. Dr. Hussain said that with education and more data, molecular testing will become more widespread for patients with prostate cancer. There is still debate about germline vs somatic testing.

“The issue of germline testing and the implications for family members is important. The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology are right now opening the door for molecular testing,” she noted.

Ignacio Duran, MD

Additional Commentary on PROfound Trial

Press conference moderator Ignacio Duran, MD, of the Hospital Universitario Marqués de Valdecilla, Santander, Spain, called PROfound “a highly relevant study.” Dr. Duran continued: “The study proved olaparib is superior to standard therapy in patients with metastatic castration-resistant prostate cancer harboring HRR genetic alterations. Now prostate cancer can be treated with a targeted therapy approach. Prostate tumors are heterogeneous. For the first time, we can identify a target that we can hit with more precision.”

“This is a double-hit win: superior efficacy for olaparib and proof of a new concept in treating prostate cancer,” he stated. 

DISCLOSURE: The PROfound trial was supported by AstraZeneca. Dr. Hussain reported financial relationships with Sanofi/Genzyme, Genentech, Aptitude Health, Epics, AstraZeneca, Bayer, PER, and Astellas. Dr. Duran reported financial relationships with Roche, Merck Sharp & Dohme, Novartis, Ipsen, and Pharmacyclics.

REFERENCE

1. Hussain M, Mateo J, Fizazi K, et al: PROfound: Phase 3 study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations. 2019 ESMO Congress. Abstract LBA12_PR. Presented September 30, 2019.