Post-Hoc Analysis Confirms Consistent Clinical Benefit With Olaparib Plus Abiraterone in HRR-Mutated mCRPC

Neal Shore, MD, FACS

Treatment with frontline olaparib (Lynparza) plus abiraterone acetate (Zytiga) produced a statistically significant and clinically meaningful improvement in radiographic progression-free survival (rPFS) and overall survival (OS) vs placebo plus abiraterone acetate in patients with metastatic castration-resistant prostate cancer (mCRPC) harboring common homologous recombination repair (HRR) mutations, according to a post-hoc analysis of the phase 3 PROpel trial (NCT03732820) presented at the 2024 Genitourinary Cancers Symposium.¹

Clinical benefit with olaparib plus abiraterone was observed in patients with BRCA2, ATM, and CDK12mutations, which were the most prevalent single-gene HRR mutations across all patients treated. The rPFS rate with the olaparib combination for patients with BRCA2, ATM, and CDK12 mutations were 27% (HR, 0.20; 95% CI, 0.08-0.44), 29% (HR, 0.55; 95% CI, 0.20-1.38) and 42% (HR, 0.51, 95% CI, 0.20-1.18), respectively. Corresponding OS rates were 20% (HR, 020; 95% CI, 0.07-0.48), 43% (HR, 0.79; 95% CI, 0.33-1.77), and 47% (HR, 0.57; 95% CI, 0.24-1.27).

In the placebo arm, the rPFS for patients with BRCA2, ATM, and CDK12 mutations were 71%, 50%, and 67%, respectively. Corresponding OS rates were 64%, 54%, and 71%. Notably, the analysis of treatment with the olaparib combination was limited in patients expressing other single-gene mutations due to their decreased incidence.

Overall, results were generally consistent with primary findings from the PROpel trial.

“The results from PROpel collectively support olaparib plus abiraterone as an important new first-line treatment option for consideration in patients with mCRPC [and] provide additional information on clinical outcomes in patients with various HRR mutations,” lead study author Neal Shore, MD, FACS, US chief medical officer of Surgery and Oncology at GenesisCare USA, and the medical director of the Carolina Urologic Research Center, wrote in a poster presentation of the data.

The PROpel trial previously met its primary end point of improved rPFS with the olaparib regimen compared with abiraterone and placebo in the intention-to-treat population. Previous data showed that the median rPFS with olaparib plus abiraterone was 24.8 months vs 16.6 months with abiraterone alone (HR, 0.66; 95% CI, 0.54-0.81; P < .0001). At the time of the final prespecified analysis, the median OS was 42.1 months with the olaparib combination vs 34.7 months with the placebo regimen. This difference was numerically, but not statistically, significant.

A post-hoc exploratory analysis examining aggregate subgroups of HRR-mutated, non-HRR-mutated, BRCA-mutated, and non-BRCA-mutated disease further demonstrated favorable rPFS outcomes with olaparib plus abiraterone vs abiraterone alone. The median HR for rPFS was 0.50 (95% CI, 0.34-0.73) in patients with HRR mutations, and 0.76 (95% CI, 0.60-0.97) for those without. Similarly, individuals with BRCA-positive disease demonstrated an HR for rPFS of 0.23 (95% CI, 0.12-0.43), whereas those without BRCA mutations had an HR of 0.76 (95% CI, 0.61-0.94).

Findings from PROpel supported the FDA approval of olaparib plus abiraterone and prednisone or prednisolone for the treatment of patients with deleterious or suspected deleterious BRCA-mutated mCRPC in May, 2023.²

Investigators conducted the current post-hoc analysis to build upon prior data and determine the efficacy of olaparib plus abiraterone according to the presence of single-gene mutations within the PROpel trial.¹

The double-blind, placebo-controlled trial enrolled patients at least 18 years of age with histologically or cytologically confirmed mCRPC and at least 1 documented metastatic lesion. Patients had an ECOG performance status of 0 or 1, ranged from asymptomatic to symptomatic, and had not previously received abiraterone. Other next-generation hormonal agents were permitted if patients had ceased treatment with the agent at least 1 year prior to study enrollment. Notably, patients were enrolled onto the study irrespective of HRR gene mutations, which were tested for following randomization.

HRR mutations were defined as mutations in one of the following genes: ATM, BRCA1/2, BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, RAD51B/C/D, and RAD54L. In the current analysis, HRs and confidence intervals were not reported for gene subgroups with less than 5 rPFS or OS events in either arm.

Patients were randomly assigned in a 1:1 ratio to receive a twice-daily dose of olaparib at 300 mg alongside a daily dose of abiraterone at 1000 mg (n = 399) or placebo plus abiraterone alone at the same dose schedule (n = 397). All patients received a twice-daily dose of prednisone or prednisolone at 5 mg per label requirements. Treatment continued until progressive disease, intolerable toxicity, or withdrawal of consent. Selection of subsequent treatment after progression was at the investigator’s discretion.

Patients were stratified based on their site of distant metastasis (bone only vs visceral vs other) and whether they had previously received a taxane for metastatic hormone-sensitive prostate cancer (mHSPC).

The study’s primary end point was rPFS by investigator assessment. OS was a key secondary end point and confirmed 50% reduction of prostate specific antigen (PSA50) from baseline was an exploratory end point.

Baseline characteristics were generally balanced between arms. The median age was 69 years in the olaparib arm (range, 43-91) and 70 in the placebo arm (46-88). The majority of patients had an ECOG performance status of 0 (71.7% in experimental arm vs 68.5% in control arm), and distant metastasis in the bone (87.5% vs 85.4%). A total of 22.6% and 22.4% of patients in the olaparib and placebo arms, respectively, received docetaxel at the mHSPC stage. Symptomatic presentation was observed in 25.8% and 20.2% of patients, respectively. The median PSA in each respective arm was 17.90 (6.09-67.00) and 16.81 (6.26-53.30).

Of the 796 patients included in the study, 226 expressed an HRR mutation. Moreover, the proportion of patients with an HRR mutation and the distribution of single-gene mutations was comparable between arms despite not stratifying patients with HRR status. In the olaparib arm, 27.8% of patients had HRR mutations, 69.9% did not, and 2.3% had unknown status; corresponding rates in the placebo arm were 29.0%, 68.8%, and 2.3%, respectively. Single-gene mutations in BRCA2, ATM, and CDK12 were observed in 7%, 6%, and 40 patients, respectively. Other low-prevalence genes made up 6% of the HRR-mutated population.

In the olaparib combination arm, 5 patients with CHECK2 mutations (n = 7), 0 patients with a BRCA1 mutation (n = 6), 1 patient with a PALB2 mutation (n = 3), 2 patients with a RAD54L mutation (n = 3), 3 patients with a FANCL mutation (n = 3), and 0 patients with a BARD1 mutation (n = 0) experienced an OS event; the corresponding incidence of OS events in the placebo arm were 8, 3, 3, 1, 0, and 1, respectively.

In the olaparib combination arm, 4 patients with CHECK2 mutations, 1 patient with a BRCA1 mutation, 2 patients with a PALB2 mutation, 2 patients with a RAD54L, 2 patients with a FANCL mutation, and 0 patients with a BARD1 mutation experienced an OS event; the corresponding incidence of OS events in the placebo arm were 6, 3, 3, 0, 0, and 1, respectively.

Assessment of PSA50 according to single-gene mutation showed that 93%, 76%, and 83% of patients with BRCA2, ATM, and CDK12 mutations who had a PSA measurement at baseline achieved a confirmed PSA50response on olaparib and abiraterone. Conversely, 41%, 75% and 62% of patients achieved a confirmed PSA50 response with abiraterone plus placebo.

“In patients with HRR gene mutations, results suggest that olaparib plus abiraterone delays progression of disease and helps patients live longer,” Shore concluded in the poster presentation.

Dr Shore reports the following disclosures: employment with GenesisCare; a leadership role with Alessa Therapeutics, Photocure; a consulting or advisory role with Abbvie, AIkido Pharma, Amgen, Arquer Diagnostics, Asieris Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, Boston Scientific, Bristol-Myers Squibb/Sanofi, CG Oncology, CG Oncology, Clarity Pharmaceuticals, Clovis Oncology, Dendreon, Exact Imaging, Exact Sciences, FerGene, Ferring, Fize Medical, Foundation Medicine, Genesis Cancer Care, Genzyme, Guardant Health, ImmunityBio, Incyte, InVitae, Janssen Scientific Affairs, Lantheus Medical Imaging, Lilly, MDxHealth, Medivation/Astellas, Merck, Minomic, Myovant Sciences, Myriad Genetics, NGM Biopharmaceuticals, Nonagen Bioscience, Novartis, Nymox, Pacific Edge Biotechnology, Peerview, Pfizer, Phosphorus, Photocure, PlatformQ Health, Profound Medical, Promaxo, Propella Therapeutics, Protara Therapeutics, Sanofi, Sesen Bio, Speciality Networks, Telix Pharmaceuticals, Tempus, Tolmar, Urogen pharma, Vaxiion, Vessi Medical; served on a speakers’ Bureau for Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Dendreon, Foundation Medicine, Guardant Health, Janssen, Merck, Pfizer; was granted research funding from Abbvie, Advantagene, Amgen, Aragon Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, Boston Scientific, Bristol-Myers Squibb/Pfizer, CG Oncology, Clovis Oncology, Dendreon, DisperSol, Endocyte, Exact Imaging, Exelixis, Ferring, FKD Therapies, FORMA Therapeutics, Foundation Medicine, Genentech, Guardant Health, InVitae, Istari Oncology, Janssen, Jiangsu Yahong Meditech, MDxHealth, Medivation, Merck, MT Group, Myovant Sciences, Myriad Genetics, Novartis, Nymox, OncoCellMDx, ORIC Pharmaceuticals, pacific edge, Palette Life Sciences, Pfizer, Plexxikon, POINT Biopharma, Propella Therapeutics, Propella Therapeutics, RhoVac, Sanofi, SeaGen, Sesen Bio, Steba Biotech, Theralase, Tolmar, Urogen pharma, Urotronic, US Biotest, Vaxiion, Veru, Zenflow; povided expert testimony for Ferring; received grants from Roche, received consulting fees from Immatics, Tacalyx, Boehringer, received support for meeting attendance/travel from Pfizer, Bristol-Myers-Squibb, Astra-Zeneca, Amgen, Gemoab, Sanofi, Immatics, Merck Serono, Janssen, Iovance, served on advisory boards for Bristol-Myers Squibb, Novartis, Lilly, Boehringer, ISA, Amgen, Immatics, Bayer, ImCheck, received honoraria from Lilly, Boehringer, SYNLAB, Janssen, Merck Serono, GWT, Amgen, Novartis.

References

1. Shore N, Clarke N, Armstrong A, et al. Efficacy of olaparib (O) plus abiraterone (A) versus placebo (P) plus A in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with single homologous recombination repair gene mutations (HRRm) in the PROpel trial.. J Clin Oncol. 2024; 42(4): 165. Doi: 10.1200/JCO.2024.42.4_suppl.165
2. FDA approves olaparib with abiraterone and prednisone (or prednisolone) for BRCA-mutated metastatic castration-resistant prostate cancer. FDA. May 31, 2023. Accessed January 25, 2024. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-abiraterone-and-prednisone-or-prednisolone-brca-mutated-metastatic-castration