Treatment with olaparib delayed disease progression, and early survival data suggest a positive trend in favor of olaparib compared with newer hormonal agents in men with pretreated metastatic castration-resistant prostate cancer and homologous recombinant repair genetic alterations—specifically BRCA1, BRCA2, and ATM.

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

Maha Hussain, MD, FACP, FASCO

“In patients with metastatic castration-resistant prostate cancer with BRCA1, BRCA2, or ATM genetic alterations that has progressed on front-line hormonal therapy with abiraterone or enzalutamide, olaparib provides statistically significant and clinically meaningful improvement in progression-free survival,” said lead author Maha 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. “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 [homologous recombinant repair] 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.

PROfound is the first phase III study of PARP inhibition in prostate cancer with BRCA alterations and other DNA repair 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, with the hope of impacting patient outcomes,” Dr. Hussain explained.

Study Details

Among patients screened for the trial, about 30% had qualifying DNA repair genetic alterations. Dr. Hussain explained that these alterations are associated potentially 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 homologous recombinant repair 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 DNA repair genes with a direct or indirect role in the homologous recombinant repair pathway, and progressed on prior new hormonal agent treatment.

Cohort A included 245 patients with alterations in BRCA1, BRCA2, or ATM; cohort B included 142 men with any of 12 other DNA repair gene 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 blinded independent centrally reviewed imaging. There were other secondary endpoints as well. Crossover to olaparib was allowed at disease progression in both cohorts. The median age of patients was 68 years.

Notably, men in their late 80s and early 90s were enrolled, 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 65% 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 the risk of disease progression or death (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, translating into a 51% reduction in the risk for disease progression or death (P < .0001). All key 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). Median 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). In cohort A, the median overall survival for the olaparib arm was 18.50 months vs 15.11 months in the new hormonal agent arm despite over 80% crossover from the control arm to olaparib therapy.

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 low grade. 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 in the earlier disease setting of advanced prostate cancer. Phase II studies are comparing PARP inhibitors with androgen receptor–directed therapies or combination in preselected populations. A phase III study is evaluating front-line treatment with olaparib plus abiraterone, she said.

“There are many questions to be answered, and thus, more trials will likely be conducted,” 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 providing guidance for genetic testing,” she noted.

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

Ignacio Duran, MD

metastatic castration-resistant prostate cancer harboring [homologous recombinant repair] 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.

TRITON2 Trial

Also presented at the ESMO Congress 2019, preliminary results of the phase II TRITON2 trial supported the use of a PARP inhibitor (rucaparib) in men with metastatic castration-resistant prostate cancer with a BRCA1 or BRCA2 mutation.² In that trial, rucaparib achieved a 43.9% objective response rate in 57 Response Evaluation Criteria in Solid Tumors–evaluable patients and a confirmed prostate-specific antigen response in 98 evaluable patients. No responses were seen in men with ATM or CDK12 mutations. The safety profile of rucaparib was consistent with studies of ovarian cancer and other solid tumors. These data will be submitted for a planned supplemental new drug application to expand the indications for rucaparib to include BRCA-mutated prostate cancer. ■

DISCLOSURE: The PROfound trial was supported by AstraZeneca. Dr. Hussain reported financial relationships with Sanofi/Genzyme, Genentech, Aptitude Health, Epics, AstraZeneca, Bayer, Pfizer, PER, and Astellas. Dr. Duran reported institutional financial relationships with AstraZeneca and Roche; served as an advisor/board member for Roche, BMS, MSD, Pharmacyclics, Janssen, Ipsen, and Novartis; has received honoraria from Roche, BMS, MSD, Janssen, Ipsen, Novartis, and Astellas; and has received travel/accommodation expenses from Ipsen and AstraZeneca.

REFERENCES

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.

2. Abida W, Campbell D, Patnaik A, et al: Preliminary results from the TRITON2 study of rucaparib in patients with DNA damage repair-deficient metastatic castration-resistant prostate cancer: Updated analyses. 2019 ESMO Congress. Abstract 846PD. Presented September 29, 2019.