Olaparib Improves Radiographic PFS in HRR-Mutant mCRPC

Jose Baselga, MD

José Baselga, MD

Olaparib (Lynparza) demonstrated a statistically significant and clinically meaningful improvement in radiographic progression-free survival (rPFS) compared with enzalutamide (Xtandi) or abiraterone acetate (Zytiga) in patients with metastatic castration-resistant prostate cancer (mCRPC) who harbor a homologous recombination repair (HRR) gene mutation and have progressed on prior therapy with either androgen receptor (AR) inhibitor, meeting the primary endpoint of the phase III PROfound trial (NCT02987543).¹

The safety and tolerability profile of the PARP inhibitor was found to be consistent with what has been observed in prior studies, stated AstraZeneca, the company jointly developing olaparib with Merck (MSD), in a press release. Full data from PROfound are expected to be presented at an upcoming medical meeting.

“For men with metastatic castration-resistant prostate cancer the disease remains deadly, especially in those who have failed on a new hormonal anticancer treatment. This trial is the only positive phase III trial of any PARP inhibitor in metastatic castration-resistant prostate cancer, where the need for new, effective therapies is high,” José Baselga, MD, PhD, executive vice president, Oncology R&D, of AstraZeneca, stated in the press release. “The PROfound trial also demonstrates the potential value of genomic testing in this at-risk patient population. We look forward to discussing these results with global health authorities soon.”

The prospective, multicenter, open-label, phase III PROfound trial included 340 patients with mCRPC who progressed on prior hormonal anticancer therapy. Investigators randomized patients in a 2:1 ratio to receive olaparib or either enzalutamide or abiraterone. Patients must have had a mutation in 1 of 15 genes that are involved in the HRR pathway, which include BRCA1/2, ATM, and CDK12.

Olaparib was administered at 300 mg twice daily, enzalutamide was given at 160 mg once daily, and abiraterone was administered at 1000 mg once daily. To be eligible for enrollment, patients had progressed on prior abiraterone acetate and/or enzalutamide, had ongoing therapy with an LHRH analog or bilateral orchiectomy, had radiographic progression at study entry while on androgen deprivation therapy, and a qualifying HRR mutation in tumor tissue.

Those who had received prior treatment with a PARP inhibitor, received prior DNA-damaging cytotoxic chemotherapy, had another malignancy within the last 5 years, and known brain metastases were excluded from enrollment.

The primary endpoint was rPFS in patients with BRCA1/2 or ATM mutations by blinded independent central review using RECIST 1.1 and PCWG3 criteria or death; secondary endpoints included objective response rate (ORR), time to pain progression, overall survival (OS), rPFS, and adverse events (AEs)/serious AEs and collection of clinical chemistry and hematology parameters.

In 2016, the FDA previously granted olaparib a breakthrough therapy designation as a treatment for patients with BRCA1/2- or ATM-mutant mCRPC in patients who received prior taxane-based chemotherapy and at least either enzalutamide or abiraterone.

The designation was based on findings from the open-label, single-group, two-stage, multicenter, phase II TOPARP-A study, in which the PARP inhibitor elicited a nearly 90% ORR in a subgroup of patients with DNA-repair defects.²

In this trial, olaparib was examined in 50 patients with mCRPC whose disease had progressed following 1 or 2 chemotherapy regimens. Patients had an ECOG performance status of 0 to 2 and all had received prior docetaxel. Most patients (98%) received prior abiraterone or enzalutamide, and 58% had received cabazitaxel (Jevtana).

In the 49 evaluable patients who received ≥1 dose of olaparib, the ORR was 33% (n = 16). At a median follow-up of 14.4 months, the median OS was 10.1 months, and the median duration of treatment was 40 weeks, with 12 patients receiving olaparib for >6 months and 4 patients receiving the agent for >12 months. A total 22% of patients had ≥50% reductions in prostate-specific antigen.

Moreover, 16 of the 49 (33%) patients had homozygous deletions, deleterious mutations, or both in DNA-repair genes. Fourteen of these 16 (88%) patients responded to olaparib treatment. Seven patients harbored BRCA2 mutations, 5 had ATM aberrations, and 2 had ATM mutations with no germline events.

Results showed that the median rPFS was 9.8 months in the biomarker-positive group treated with olaparib compared with 2.7 months in the biomarker-negative group (P <.001). Also in the biomarker-positive patients, the median OS was 13.8 months compared with 7.5 months in the biomarker-negative group (P = .05).

Regarding safety, grade 3/4 treatment-related AEs included anemia (20%), fatigue (12%), leukopenia (6%), thrombocytopenia (4%), and neutropenia (4%). Additionally, 26% of patients required a dose reduction to 300 mg twice daily. Of these 13 patients, 3 required a second dose reduction to 200 mg twice daily. Treatment was permanently discontinued in 6% of patients due to AEs.

Olaparib is currently FDA approved as a maintenance treatment of patients with platinum-sensitive, relapsed ovarian cancer regardless of BRCA status; as a first-line maintenance treatment of BRCA-mutant advanced ovarian cancer following response to platinum-based chemotherapy; and for the treatment of patients with germline BRCA-mutant, HER2-negative metastatic breast cancer previously treated with chemotherapy.

Ongoing research is exploring olaparib in additional prostate cancer studies, such as the phase III PROpel trial (NCT03732820), which is evaluating the PARP inhibitor in combination with abiraterone as a first-line therapy in mCRPC.

References

1. Lynparza Phase III PROfound trial in HRR* mutation-selected metastatic castration-resistant prostate cancer met primary endpoint. AstraZeneca. Published August 7, 2019. https://bit.ly/2Ysn95a. Accessed August 7, 2019.
2. Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Eng J Med. 2015;373:1697-1708.