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Adding PARP inhibition to first-line abiraterone (Zytiga) reduced the risk of radiographic progression or death in metastatic castration-resistant prostate cancer (mCRPC), a pair of phase III studies showed.

In PROpel, patients who received olaparib (Lynparza) along with abiraterone plus prednisone had a roughly 8-month improvement in median radiographic progression-free survival (rPFS) versus those assigned placebo (24.8 vs 16.6 months, respectively; HR 0.66, 95% CI 0.54-0.81, P<0.0001). And the benefit was observed in men with and without homologous recombination repair (HRR) gene alterations, reported Fred Saad, MD, of the University of Montreal Hospital Center.

The study "is the first combination approach to deliver consistent clinical benefit for patients in the first-line setting of mCRPC, irrespective of HRR mutational status," Saad said at the Genitourinary Cancers Symposium.

In the MAGNITUDE trial, also presented at the meeting, a cohort of patients with prospectively identified HRR gene alterations saw a 3- to 5-month rPFS improvement (as assessed by central review or investigators) when they received niraparib along with abiraterone-prednisone (HR 0.73, 95% CI 0.56-0.96, P=0.022), according to Kim Chi, MD, of BC Cancer and the University of British Columbia in Vancouver.

Here, a futility analysis showed no benefit with niraparib in a cohort of patients without HRR gene alterations.

"I want to caution you -- do not interpret this to mean that olaparib is better than niraparib," said discussant Celestia Higano, MD, also of the University of British Columbia. She pointed out that the difference in patient populations between the two trials did not lend itself to a comparison of the two agents.

As for whether the combination of olaparib and abiraterone should be used as a first-line therapy for all patients with mCRPC, Higano said overall survival (OS) data would be needed before making that decision.

"However, the rPFS appears to be quite outstanding," she observed. "I would like to have a better understanding of which patients benefit the most, and then, perhaps, the combination will be considered."

PROpel

In this study, 796 patients with mCRPC were randomized 1:1 to receive abiraterone with either olaparib or placebo. HRR gene mutations were present in 28% of patients in the olaparib arm and 29% of those in the placebo arm. The primary endpoint was rPFS by investigator assessment.

The 24.8-month rPFS in the olaparib group "I think is the longest rPFS we have seen to date in metastatic CRPC," Saad said. Median rPFS was similar by blinded independent central review (27.8 months with olaparib and 16.4 months with placebo). OS results were immature but showed a trend favoring the olaparib combination (HR 0.86, 95% CI 0.66-1.12).

Predefined subgroup analyses showed that the rPFS benefit extended across all subgroups, including patients with (HR 0.54, 95% CI 0.36-0.79) and without (HR 0.76, 95% CI 0.59-0.97) HRR gene alterations.

Secondary endpoints were also supportive of long-term benefits with olaparib, Saad said:

• Time to first subsequent treatment (HR 0.74, 95% CI 0.61-0.90)
• Time to second progression or death (HR 0.69, 95% CI 0.51-0.94)

Regarding safety, Saad said the adverse event profile was consistent with the known toxicity profiles of the individual drugs.

MAGNITUDE

The HRR biomarker-positive cohort analysis included 423 men who were randomized 1:1 to receive abiraterone plus prednisone and either niraparib or placebo. HRR gene alterations included those in ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, and PALB2. More than half of the men (53%) had BRCA1/2 mutations.

For the biomarker-positive cohort, median rPFS was 16.5 months for the niraparib group versus 13.7 months in the placebo group, as assessed by blinded independent central review. And 19.0 months versus 13.9 months, respectively, as assessed by investigators.

The rPFS improvement with niraparib was most evident in patients with BRCA1/2 gene mutations, at a median 16.6 months versus 10.9 months with placebo, as assessed by central review (HR 0.53, P=0.001). As assessed by investigators, the rPFS was 19.3 months versus 12.4 months.

Chi reported that clinically relevant improvements in outcomes were also seen for secondary endpoints with niraparib, including time to cytotoxic chemotherapy, time to symptomatic progression, time to biochemical progression, and overall response rate.

The treatment regimen had a manageable safety profile, with no new safety signals identified, he said.

"MAGNITUDE highlights the importance of testing for HRR gene alterations in patients with mCRPC to identify those individuals who will optimally benefit from the combination of niraparib plus abiraterone," Chi concluded. "These study results support niraparib plus abiraterone as a new first-line treatment option for patients with metastatic CRPC and alterations in genes associated with HRR."

Higano said that OS data, as well as results from a planned BRCA versus non-BRCA analysis, would be needed to clarify the benefit of the regimen before being considered as a first-line option for all patients with HRR gene mutations.

She did note, however, the substantial benefit in the BRCA1/2 population with niraparib.

"This is a very poor prognosis subset," she pointed out. "And it appears to have significant [benefit] in terms of rPFS, so it might be reasonable to treat such patients even before OS is available, given the poor outcomes with abiraterone alone."