The combination of the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib plus abiraterone acetate and prednisone as first-line therapy significantly improved radiographic progression-free survival vs abiraterone and placebo alone in men with metastatic castration-resistant prostate cancer characterized by specific alterations in homologous recombination repair (HRR) genes, according to a final analysis of the primary endpoint of the phase III MAGNITUDE trial reported at the 2022 ASCO Genitourinary Cancers Symposium (Abstract 12). The most robust effects of the triplet regimen on radiographic progression-free survival were observed in men with BRCA1/2 gene alterations. In a prespecified futility analysis based on prostate-specific antigen (PSA) and radiographic disease progression, the PARP inhibitor plus abiraterone and prednisone combination failed to improve progression-free survival in men without these specific HRR gene alterations.
“When choosing a treatment plan for patients, physicians must consider individual needs, particularly for patients with metastatic castration-resistant prostate cancer who have HRR gene alterations and face a poor prognosis. The MAGNITUDE data provide important context about the subgroup of patients who may benefit from treatment with niraparib in combination with abiraterone plus placebo in the first-line setting, as well as those patients who may be better served by other treatment options,” stated Kim Nguyen Chi, MD. Dr. Chi, Chief Medical Officer of BC Cancer, Vancouver, is principal investigator of the trial and presenting author.
Kim Nguyen Chi, MD
Eleni Efstathiou, MD
“The study included men with metastatic castration-resistant prostate cancer irrespective of whether they had bone or soft-tissue metastasis. We are targeting men with germline or tumor HRR genetic alterations [with this combination] because they have a worse prognosis. Our goal is not just to achieve a statistically significant benefit, but a clinically meaningful one,” noted Eleni Efstathiou, MD, in a separate interview with The ASCO Post. Dr. Efstathiou is Chief of GU Oncology and Professor of Medicine at Houston Methodist Cancer.
At a median follow-up of 18.6 months, patients in the triplet arm with HRR-positive disease had a 27% reduction in risk of disease progression or death (ie, radiographic progression-free survival) compared with the doublet (P = .0217). The improvement was of a greater magnitude in men with BRCA1/2 gene alterations, who experienced a 47% reduction in risk of disease progression or death vs those treated with abiraterone plus prednisone (P = .0014). Investigator-assessed radiographic progression-free survival was even greater with the triplet, with a 36% reduction in risk in patients with HRR alterations and a 50% reduction in risk in those with BRCA1/2 alterations vs the doublet (P = .0022 and P = .0006, respectively).
The phase III, randomized, double-blind, placebo-controlled, multicenter MAGNITUDE trial had separate cohorts of men with metastatic castration-resistant prostate cancer: those with prospectively defined HRR alterations and those without randomly assigned to niraparib plus abiraterone and prednisone vs placebo plus abiraterone and prednisone, plus a third cohort that received open-label treatment with the triplet. The prespecified genetic alterations included ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, and PALB2 alterations. Patients with HRR alterations (n = 423) were randomly assigned to receive the triplet (n = 212) or the doublet with placebo (control arm, n = 211).
The cohort without HRR gene alterations (n = 233) met the predefined futility criteria in August 2020, with no additional benefit for the addition of niraparib. Enrollment in this cohort was stopped; investigators and patients were unblinded and given the option to continue their assigned treatment at the discretion of the study investigator.
For the primary endpoint, among all HRR-positive patients, median radiographic progression-free survival was 16.5 months vs 13.7 months, respectively (P = .0217). In the BRCA-positive subgroup, median radiographic progression-free survival was 16.6 months with niraparib vs 10.9 months without (P = .0014).
“The benefit of niraparib plus abiraterone and prednisone was consistent across all prespecified subgroups,” Dr. Chi said.
In patients with HRR gene alterations, the triplet was superior to the doublet with placebo for all secondary and other endpoints at the first interim analysis. They included time to initiation of cytotoxic chemotherapy, time to symptomatic disease progression, and time to PSA progression. Additionally, the objective response rate was higher with niraparib than without in the HRR-positive cohort.
“Niraparib plus abiraterone and prednisone nearly doubled the time to PSA progression as well as complete and partial response rates compared with abiraterone and placebo alone,” Dr. Chi noted.
Survival data were still immature at the time of the first interim analysis and will continue to be followed.
The observed safety profile for the niraparib combination was consistent with the known safety profile for each agent. Among those with HRR gene alterations, 67% had grade 3 or 4 adverse events on the niraparib arm, and 46.4% had grade 3 or 4 adverse events on the control arm. These adverse events were mostly fatigue and anemia. The rate of treatment discontinuation was 9% in the triplet arm and 3.8% in the control arm. According to the Functional Assessment of Cancer Therapy–Prostate instrument, quality of life was maintained with and without niraparib with no clinically meaningful difference between treatment arms or over time.
Accessibility of Treatment
Even though the combination of the PARP inhibitor plus abiraterone and prednisone was statistically and clinically superior to the placebo plus abiraterone and prednisone in men with metastatic castration-resistant prostate cancer who harbor HRR genetic alterations, this combination may not be accessible to all patients, Dr. Efstathiou explained.
“Widespread availability of genetic sequencing testing for the HRR genes requires resources that include the supportive staff necessary to coordinate the tests and retrieve results. Of course, it also requires access to a validated quality-controlled test as well as retrieval of results in a prompt fashion,” she continued.
“Currently, there is not a systemic approach to incorporate germline testing and somatic sequencing for these men with advanced prostate cancer. We need to figure out how to introduce a seamless approach to testing for patients with prostate cancer, as we do for diagnostic biopsy, staging imaging, and PSA testing,” she said.
Dr. Efstathiou continued: “There are several roadblocks to implementing this type of testing in community practice. The first is the administrative burden; it can be time-consuming to retrieve and access a sample [if tissue] and then perform the test and finally retrieve the results, and not all practices are equipped for this. Just consider the consequence of a sample being inadequate or not informative and the need to repeat the process. The mere step of retrieving test results from a separate electronic platform can be quite the headache in a busy clinic. Second, the reimbursement status of tests is another hurdle. We still need to catch up with the results of the trial.”
Dr. Efstathiou said that the findings from the MAGNITUDE trial represent an ideal real-life situation. “This testing should become part of everyday practice in a more simplified fashion. For instance, the current electronic formatting of clinics does not include information [modules] about which tests are done and what type of sample or assay was used and whether the quality was adequate or not. This should be formatted in a similar way as our lab tests. We are simply unable to maximize patient outcomes if we keep increasing administrative burden,” she stated.
The trial raises some questions, many of which are being addressed in other studies, although the results may be years away. “MAGNITUDE showcases that the combination of the generic drug abiraterone acetate plus niraparib adds a significant benefit for men with prostate cancer the moment the disease has progressed to castration resistance in men with specific HRR gene alterations” stated Dr. Efstathiou. “Under standard practice, hormone-naive patients may be offered abiraterone and prednisone. What do we do upon further disease progression? Do we just add on niraparib? And if the patient is on a different agent—enzalutamide or apalutamide—do we switch to niraparib plus abiraterone and prednisone?”
Disclosure: For full disclosures of the study authors, visit coi.asco.org.
MAGNITUDE is challenging from a statistical point of view,” said formal discussant Celestia S. Higano, MD, currently Adjunct Professor, Department of Urologic Sciences at the University of British Columbia, Vancouver, Canada, and formerly of Fred Hutchinson Cancer Research Center in Seattle.