NEW YORK – Updated results from a three-arm Phase II clinical trial are giving genitourinary oncologists more to think about when it comes to prescribing PARP inhibitor combination therapy upfront to advanced biomarker-selected prostate cancer patients.
The Phase II BRCAaway trial randomized metastatic castration-resistant prostate cancer (mCRPC) patients harboring BRCA1, BRCA2, or ATM alterations to receive one of three first-line regimens: a triplet therapy comprising Merck and AstraZeneca's PARP inhibitor Lynparza (olaparib), Janssen's androgen receptor pathway inhibitor Zytiga (abiraterone), and a steroid; a combination of Zytiga and a steroid; or Lynparza alone.
Maha Hussain, a genitourinary oncologist at Northwestern Medicine, presented the results from BRCAaway during the American Society of Clinical Oncology's Genitourinary Cancers Symposium on Thursday. She reported that among patients who got the three-drug combination, the median progression-free survival was 39 months. In comparison, median progression-free survival was 8.4 months for patients who received Zytiga with a steroid, and 14 months for those on Lynparza.
The objective response rate in the triplet therapy arm was 33 percent, versus 22 percent for those on Zytiga and a steroid, and 14 percent for Lynparza-treated patients. The study also considered patients' decline in prostate specific antigen (PSA) as an efficacy endpoint. Here, Hussain shared that the triplet again won out over the other two arms. Ninety-five percent of patients on Lynparza-Zytiga and a steroid saw their PSA decline by at least 50 percent, whereas the same was true for 61 percent and 67 percent of patients on Zytiga and a steroid and on Lynparza monotherapy, respectively.
"The BRCAaway trial supports an upfront PARP inhibitor, androgen receptor pathway inhibitor combination as first-line therapy for homologous recombination repair gene-mutated metastatic CRPC," Kim Chi, a medical oncologist at the British Columbia Cancer Agency, said during a discussion following presentation of the data at the meeting. In his view, the findings suggest synergistic activity between the PARP inhibitor and Zytiga-steroid treatments.
Crossover inclusion sheds light on benefit
The combination of Lynparza, Zytiga, and a steroid is already commercially available for mCRPC patients harboring BRCA1/2 germline or somatic mutations. The US Food and Drug Administration approved this combination based on data from the Phase III PROpel trial last June. That trial included all comers, but the agency approved the drug combination for a biomarker-selected patient population based on a subgroup analysis suggesting patients with mutations in genes involved in homologous recombination repair were driving most of the benefit seen in that study.
Importantly, though, that trial didn't include a Lynparza monotherapy arm, which left a gap in oncologists' understanding of whether the three-drug combination upfront was more efficacious than sequentially treating patients with Zytiga and a steroid and switching to Lynparza once they progress, or vice versa, treating patients with Lynparza monotherapy first and giving Zytiga and a steroid upon progression.
"A lingering question currently is: 'Is the combination upfront better than a sequential strategy?'" Chi said during his discussion. "Combination therapy has been shown to improve overall survival in subgroup analyses [from other upfront PARP inhibitor trials], but there's been limited crossover for [patients] randomized to single-agent therapy."
In the BRCAaway study, eight out of 19 patients on the Zytiga-steroid arm crossed over to Lynparza and eight out of 21 patients on the Lynparza arm crossed over to the Zytiga-steroid arm. The median progression-free survival for those that received Zytiga-steroid first and Lynparza after was 8.3 months, and 7.2 months for those who received Lynparza first and then Zytiga-steroid.
"While the number of patients who crossed over was small, the frontline combination had better progression-free survival compared to the sequential treatment," Hussain noted.
Efficacy isn't the only consideration when deciding whether to give the combination regimen upfront or take a sequential treatment approach, Chi said, pointing to potential added costs associated with treating a patient with three drugs right off the bat, as opposed to trying one first then the other. That additional cost could be both physical and financial, he said.
Even though the three-drug combination was considered well tolerated in the BRCAaway trial and Hussain thought the adverse event profile was similar to what oncologists would expect to see with a PARP inhibitor, Chi worried that over the long term Lynparza could add toxicity. As far as financial considerations, at a list price of $2,881.38 for a 56-pack of 150 mg tablets, adding Lynparza to the combination would certainly add cost.
Limitations, other options
During a discussion of the BRCAaway trial's limitations, Chi highlighted its small size — the trial randomized just 61 patients — and an imbalance of biomarker-positive patients in the three arms. The majority of patients harbored BRCA2 mutations: 68 percent in the Zytiga-steroid arm; 90 percent in the Lynparza arm; and 71 percent in the three-drug combo arm. "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.
Additionally, Chi noted that the trial wasn't actually designed to compare the three-drug combination to the sequential strategy. It was designed to compare the activity of Lynparza-Zytiga-steroid treatment to Zytiga-steroid or Lynparza.
The fact that fewer than half of the patients in both comparator arms crossed over to triplet therapy suggested to Chi that perhaps the population of patients who crossed over might be a biased group. But then again, he offered that this is what happens in the real world much of the time.
"This is consistent with real-world data showing that many patients do not get more than one line of therapy for mCRPC," he said. "Many patients have aggressive disease and will not have the opportunity to get sequential therapy." This is especially the case for mCRPC patients with BRCA2 mutations, who often have a poorer prognosis and may develop primary resistance to an androgen receptor pathway inhibitor like Zytiga.
Added to this is the fact that many of these patients, outside of a clinical trial setting, don't get the chance to advance to an additional line of therapy after the first one fails, Chi underscored. As such, "it is important to select the best treatment upfront first, rather than relying on some sort of sequential approach," he said.
In designing future trials, he suggested that oncologists and drugmakers ensure that the control arm represents best practice in standard therapy. In the context of the BRCAaway trial, this would have meant powering the study to compare the three-drug combo to the sequential approach.
"We need to collect more complete data on subsequent therapy as well as [better understand the] reasons why patients don't go onto that subsequent therapy," he said. In Chi's view, the BRCAaway trial is informative for oncologists making treatment decisions for their mCRPC patients, but it won't single-handedly answer the question of upfront combination therapy versus sequential therapy.
"The limitations of this trial will not end this debate today," Chi said.
Meanwhile, as oncologists try to fine-tune the best regimens for Lynparza and Zytiga, other therapies, especially other PARP inhibitors, are entering the market. In 2023,the FDA approved Janssen's Akeesa, a combination of the PARP inhibitor Zejula (niraparib) and Zytiga, plus and a steroid for BRCA1/2-mutated mCRPC.
Also in 2023, regulators approved Pfizer's PARP inhibitor Talzenna (talazoparib) combined with its androgen receptor pathway inhibitor Xtandi (enzalutamide) for mCRPC patients harboring homologous recombination repair deficiencies.
"Last year was really a dynamic year for the PARP pathway," Hussain noted.
All of these PARP inhibitor discussions are taking place as newer classes of therapies continue to make their way into earlier treatment lines in mCRPC. Novartis, for instance, is trying to show that its radiopharmaceutical therapy Pluvicto (lutetium vipivotide tetraxetan) — approved for third-line mCRPC — can benefit patients in earlier lines.