Olaparib Combo Improves PFS/Responses in Metastatic CRPC

“2023, as you are all aware, was a really dynamic year for the PARP pathway,” according to Maha Mussain, MD, FACP, FASCO.

Patients with BRCA1/2– or ATM–altered metastatic castration-resistant prostate cancer (mCRPC) who were treated with first-line olaparib (Lynparza) plus abiraterone (Zytiga)/prednisone experienced an improvement in progression-free survival (PFS) and responses over olaparib or abiraterone/prednisone alone, according to data from a phase 2 study (NCT03012321) presented at the 2024 Genitourinary Cancers Symposium.¹

The study included several arms: patients in arm 1 received abiraterone and prednisone, arm 2 received 300 mg of olaparib, and arm 3 received 300 mg of olaparib plus abiraterone and prednisone.

The median PFS was 39 months (95% CI, 22-not reached [NR]) in arm 3 compared with 8.4 months (95% CI, 2.9-17.0) in arm 1 and 14 months (95% CI, 8.4-20.0) in arm 2. Additionally, the objective response rate (ORR) in each respective arm was 33.0% (95% CI, 15.0%-57.0%), 22.0% (95% CI, 6.4%-48.0%), and 14.0% (95% CI, 3.0%-36.0%). Moreover, the prostate-specific antigen (PSA) response rate in arms 3, 1, and 2, respectively, was 95% (95% CI, 76.0%-100.0%), 61% (95% CI, 36.0%-83.0%), and 67% (95% CI, 43.0%-85.0%). The rate of undetectable PSA was 33.0% (95% CI, 15.0%-57.0%), 17.0% (95% CI, 3.6%-41.0%), and 14.0% (95% CI, 3.0%-36.0%).

A total of 8 patients crossed over from abiraterone/prednisone to olaparib, and 8 crossed over from olaparib to abiraterone. The median PFS from crossover was 8.3 months (95% CI, 5.5-15.0) with crossover to olaparib and 7.2 months (95% CI, 2.8-NR) with crossover to abiraterone. Additionally, the median PFS from randomization was 16.0 months (95% CI, 7.8-25.0) and 16.0 months (95% CI, 11-NR). The ORR to and PSA response rate to crossover treatment was 38% and 25%, as well as 50% and 63%, respectively.

“2023, as you are all aware, was a really dynamic year for the PARP pathway,” lead author Maha Hussain, MD, FACP, FASCO, the Genevieve E. Teuton Professor of Medicine at Northwestern University’s Feinberg School of Medicine, said in a presentation on the data. “The FDA approved the combination of olaparib and abiraterone/prednisone² for frontline patients with castration-resistant disease and BRCA1/2 alterations. “

To be included in the study, patients needed to have an mCRPC diagnosis and no previous exposure to PARP or androgen receptor inhibitors or chemotherapy, washout of antiandrogen for metastatic hormone-sensitive prostate cancer, radiation, and other investigational agents. Those who enrolled received next-generation sequencing and germline testing. Those with inactivating BRCA1/2 and/or ATM alterations were randomly assigned 1:1:1 to one of the 3 arms. Those in arms 1 and 2 were able to cross over to olaparib and abiraterone/prednisone, respectively, upon progressive disease.

The study’s primary end point was radiographic PFS, with key secondary end points including ORR, PSA response rate, and toxicity.

A total of 165 patients were included in the study and received somatic/germline testing. Of these patients, 61 were randomly assigned to arms 1 to 3, including 19 in arm 1, 21 in arm 2, and 21 in arm 3. The median age in each respective cohort was 63 years, 68 years, and 69 years. Additionally, the baseline PSA in each respective group was 14 ng/mL, 14 ng/mL, and 15 ng/mL. Patients in each respective cohort had bone metastases (84% vs 57% vs 76%), lymph node metastases (47% vs 57% vs 48%), and visceral metastases (11% vs 14% vs 33%). In total, 47% of those in arm 1, 62% in arm 2, and 52% in arm 3 had germline alterations, and 53% vs 38% vs 48%, respectively, had somatic mutations. The most common genetic mutation was BRCA2 (68% vs 90% vs 71%, respectively).

“[In terms of] declines from baseline [PSA] to the lowest PSA, the combination arm does better than the single-agent arm,” Hussain noted.

Grade 3 adverse effects impacted 21% of patients in arm 1, 14% in arm 2, and 19% in arm 3. Common grade 3 AEs in each arm, respectively, included anemia (0.0% vs 4.8% vs 4.8%) and fatigue (5.3% vs 4.8% vs 4.8%).

Among those who crossed over to receive olaparib and abiraterone/prednisone, respectively, 1 patient in the latter arm experienced grade 3 hyperglycemia.

References

1. Hussain M, Kocherginsky M, Agarwal N, et al. BRCAAway: A randomized phase 2 trial of abiraterone, olaparib, or abiraterone + olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) bearing homologous recombination-repair mutations (HRRm). J Clin Oncol. 2024;42(suppl):19. doi:10.1200/JCO.2024.42.4_suppl.19
2. FDA approves olaparib with abiraterone and prednisone (prednisolone) for BRCA-mutated metastatic castration-resistant prostate cancer. News release. FDA. May 31, 2023. Accessed January 25, 2024. https://bit.ly/3C2UVzg