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SAN FRANCISCO -- Combining a PARP inhibitor with an androgen receptor pathway inhibitor as first-line therapy for biomarker-selected patients with metastatic castration-resistant prostate cancer (mCRPC) significantly improved progression-free survival (PFS) versus either agent alone, findings from a small randomized phase II trial showed.

In 61 patients with homologous recombination repair (HRR) gene-mutated disease, median PFS reached 39 months with the combination strategy of olaparib (Lynparza) plus abiraterone (Zytiga) and predisone, as compared with 14 months with olaparib alone (HR 0.32, 95% CI 0.14-0.75) and 8.4 months with abiraterone and predisone (HR 0.28, 95% CI 0.13-0.65).

"This is a small study, but it was really the separation of the curves that was impressive," said presenter Maha Hussain, MD, of Northwestern University's Feinberg School of Medicine in Chicago, at the Genitourinary Cancers Symposium here.

The combination of olaparib plus abiraterone is approved for patients with BRCA-mutated mCRPC, based on findings from the phase III PROpel trial, which showed an improvement in radiographic PFS versus abiraterone plus placebo. Following recommendations from an advisory committee, however, the FDA stopped short of a broader approval that would have included all patients with HRR gene-mutated disease.

Discussant Kim N. Chi, MD, of the British Columbia Cancer Agency in Vancouver, pointed out that most of the patients in the current study -- BRCAAway -- had BRCA2 mutations, and noted an imbalance between arms.

"In such a small trial that is driven by relatively few events, these kinds of differences can have substantial effects on the results," he said.

Despite the limitations, Chi said the findings support an upfront strategy of PARP inhibition plus androgen receptor pathway inhibition as first-line therapy for HRR gene-mutated mCRPC. He added that the data suggest synergy with the approach and, most importantly, no loss of opportunity by providing abiraterone and olaparib together.

"In clinical practice it is important to select the best treatment upfront first, rather than relying on some sort of sequential approach," he said.

PFS data from the 16 patients who crossed over from single-agent abiraterone to olaparib (or vice versa) suggested a greater benefit with the front-line combination than with sequential therapy (16 months total PFS from the time of randomization in each crossover group).

Crossover, or the sequential strategy, appeared to be "only additive," Chi observed.

"However, I think we need to be very cautious about these kinds of comparisons," he added. "The trial was not designed to compare this sequential versus combination strategy, and the patients that crossed over are a biased selection."

Hussain presented data from the open-label trial, a multicenter phase II study of patients with biomarker-selected mCRPC that began in 2017. Eligibility criteria required no prior exposure to PARP inhibitors, androgen receptor pathway inhibitors, or chemotherapy for mCRPC, as well as washout of antiandrogens, radiation, and other investigational agents.

Participants underwent tumor next-generation/germline testing, and patients with inactivating BRCA1/2 and/or ATM alterations were randomized 1:1:1 to either olaparib plus abiraterone and prednisone; olaparib alone; or abiraterone plus prednisone.

The 61 patients included in the data analysis had a median age of 67 years, with 90% white and 10% Black. Three-fourths had BRCA2 mutations, 18% had ATM mutations, three patients (5%) had BRCA1 mutations, and one patient (2%) had multiple gene mutations.

Objective response rates were higher with the combination, at 33%, than with either single-agent olaparib (14%) or abiraterone (22%).

The prostate-specific antigen (PSA) response rate (a 50% decline or greater) was 95% with the combination, 67% with olaparib, and 61% with abiraterone, while the undetectable PSA response rates were 33%, 14%, and 17%, respectively.

Regarding safety, Hussain said the treatments were well tolerated, with no grade 4 or 5 adverse events (AEs) observed. "When you look at the adverse events, they are pretty much consistent with what you expect to see with these particular agents."

AEs of any grade were reported in 95% of patients in the combination arm, 90% of those in the olaparib arm, and 58% of patients in the abiraterone arm. Grade 3 AEs were seen in 19%, 21%, and 14% of the groups, respectively. The most common grade 3 AEs were fatigue, anemia, and increased alanine aminotransferase.

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