PARP Inhibitors: Improving Outcomes in Metastatic Prostate Cancer

Roxanne Nelson, RN, BSN

February 22, 2022

SAN FRANCISCO — New data from two large clinical trials show that adding a PARP inhibitor to first-line treatment with abiraterone improves radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (mCRPC).

However, the results from the two trials were slightly different. The PROpel study with olaparib (Lynparza) showed a benefit in all patients, irrespective of mutation status, whereas the MAGNITIDE trial with niraparib (Zejula) showed benefit only in patients with homologous recombination repair (HRR) gene alterations.

The new results, which were presented here at the Genitourinary Cancers Symposium (GUCS) 2022, led to two different conclusions.

Olaparib is already approved for use in patients with mCRPC who have HRR gene alterations. The approval was based on results from the PROfound trial.

But new results from the PROpel trial suggest that the benefit is not limited to patients with gene alterations. There was a 34% reduction in the risk of progression or death with olaparib in the overall patient population.

"The phase 3 PROpel study is the first combination approach to deliver consistent clinical benefits for patients in the first-line mCRPC setting, irrespective of HRR mutation status," said lead author Fred Saad, MD, of the University of Montreal Hospital Center in Quebec, Canada.

The benefit led to a median rPFS beyond 2 years, which "I think is the longest rPFS we have seen to date in metastatic CRPC," he commented.

Secondary and exploratory endpoints also support the treatment benefit of olaparib plus abiraterone in the overall patient population, he added.

However, the other large study presented at the meeting showed benefit only in patients with gene alterations.

Adding nilaparib to abiraterone resulted in a 27% reduction in the risk of progression or death in men with HRR gene alterations and a 47% reduction in a subgroup of men who had BRCA1/2 mutations. However, no benefit was seen in men without HRR gene alterations.

"MAGNITUDE highlights the importance of testing for HHR gene alterations in patients with mCRPC, to identify who will optimally benefit from the combination of niraparib plus abiraterone," said lead author Kim N. Chi, MD, senior research scientist, Vancouver Prostate Center, and professor, Department of Medicine, the University of British Columbia, Vancouver, Canada, "The study results support niraparib plus abiraterone as a new first-line treatment option for patients with mCRPC and alterations in genes associated with HRR."

Approximately 20% of cases of mCRPC harbor HRR mutations, he added.

The invited discussant for both abstracts, Celestia S. Higano, MD, adjunct professor in the Department of Urologic Sciences at the University of British Columbia, emphasized that in both studies, rPFS was used as a surrogate for clinical benefit in mCRPC.

"Clinical benefit can be defined as prolonged overall survival and/or improved quality of life," Higano noted. "The overall survival in these trials is not mature, and quality of life appears stable compared to baseline."

For a take-home message, Higano said that clinicians should wait for the overall survival data, as there is a risk of associated drug and financial toxicity from adding a PARP inhibitor.

Details of the PROpel Trial

The PROpel trial added olapraib to abiraterone in the frontline treatment in mCRPC. Participants were randomly assigned to receive olaparib 300 mg twice daily or placebo, and abiraterone 1000 mg once daily plus prednisone or prednisolone (5 mg twice daily).

HRR mutation status was similar between groups: 27.8% of patients who received olaparib and 29.0% of patients who received placebo had HRR mutations. Rates of non-HRR mutations were 69.9% and 68.8%, respectively. Rates for unknown HRR mutation status were 2.3% each.

The primary endpoint was investigator-assessed rPFS.

The median rPFS was 24.8 months with olaparib and 16.6 months with placebo (hazard ratio [HR], 0.66; P < .0001).

The rPFS benefit for combination therapy was observed across all prespecified subgroups, including site of distant metastases (bone-only: HR, 0.73; visceral: HR, 0.62; other: HR, 0.62;) and HRR mutation status (HRR mutant: HR, 0.50; non–HRR mutant: HR, 0.76).

Data for overall survival trended toward olaparib plus abiraterone, but Saad cautioned that it was only at 28.6% maturity (HR, 0.86; P = .29).

For other secondary measures, the median time to first subsequent therapy or death was 25.0 months vs 19.9 months favoring the olaparib arm (HR, 0.74; P = .004), as did the overall response rate (58.4% vs 48.1%).

The most common grade ≥3 adverse event reported was anemia, which was higher in the olaparib plus abiraterone group (15.1 vs 3.3%); 13.8% vs 7.8% of patients discontinued therapy because of adverse events.

The safety and tolerability profile was consistent with the known safety profiles of the individual drugs, Saad commented.

"These results demonstrate the benefit of olaparib and abiraterone without the need for HRR stratification in the first-line treatment of mCRPC," he concluded.

In her discussion, Higano commented that the rPFS is outstanding but urged clinicians to wait for overall survival data. "We need better understanding of which patients benefit the most, and then the combination should be considered an option for first-line therapy," she said.

Details of the MAGNITUDE Trial

The MAGNITUDE study was conducted in patients with mCRPC who had previously received no more than 4 months of abiraterone and prednisone. Patients were tested for HRR gene alterations, including ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2 genes, but were included in the trial whether they did or did not have mutations.

Patients were randomized to receive niraparib 200 mg once daily or placebo, plus abiraterone.

The primary endpoint was rPFS assessed by blinded independent central review in the BRCA1/2 subgroup and in all patients who were HRR positive.

There were 233 biomarker-negative patients, but enrollment was halted in this arm on the recommendation of the independent data monitoring committee after treatment failed to show any benefit, explained Chi. "No benefit was observed with niraparib plus abiraterone in patients who were HRR biomarker negative."

The remaining 423 HRR biomarker-positive patients were followed for a median of 18.6 months.

Among patients with BRCA1/2 mutations, the median rPFS was 16.6 months with niraparib plus abiraterone vs 10.9 months for placebo (HR, 0.53; P = .0014).

For the whole HRR-positive population, the median rPFS was 16.5 vs 13.7 months (HR, 0.73; P = .0217), although the investigator-assessed rPFS was higher for combination therapy, at 19.0 months vs 13.9 months (HR, 0.64; P = .0022).

Secondary endpoints also favored the niraparib arm: prolonged time to initiation of cytotoxic chemotherapy (HR, 0.59; P = .0108), time to symptomatic progression (HR, 0.69; P = .0444), time to PSA progression (HR, 0.57; P = .0001), and overall response rate (60% vs 28%; P < .001).

Adverse events were higher in the niraparib group: 67% vs 46.4% had grade 3/4 events, and 9% and 3.8% discontinued treatment, respectively. "Niraparib plus abiraterone had a manageable safety profile with no new safety signals identified, and quality of life was maintained," said Chi.

Overall survival data are immature but favor combination therapy at this time (HR, 0.94; P = .733), Chi commented. He emphasized that these data are needed before this combination should be used for all patients with HRR mutations.

In her discussion, Higano agreed but added that niraparib plus abiraterone as first-line treatment for patients who are BRCA1/2 positive in the absence of overall survival data is a "maybe."

"We know these patients have a poor prognosis, and it appears to have significant benefit in terms of rPFS," she said. "It might be resasonable to treat such patients even before the overall survival data is available, given the poor outcomes with abiraterone alone."

Genitourinary Cancers Symposium (GUCS) 2022: Abstract 11 (PROpel) and abstract 12 (MAGNITUDE). Presented February 18, 2022.

Saad and Chi reported relationships with numerous pharmaceutical companies, as listed in the abstracts. Higano reported relationships with CTI BioPharma Corp, Astellas, AstraZeneca, Bayer, Clovis, eFFECTOR, Ferring, Genentech, Menarini, Merck Sharp & Dohme, Myovant Sciences, Pfizer, Roche, Tolmar, and Vaccitech Research Funding.

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