Rashid Sayyid: Hello everyone. I'm Rashid Sayyid, urologic oncology fellow at the University of Toronto and along with Zach Klaassen, assistant professor and program director at Augusta University, we'll be presenting the report from MAGNITUDE which assessed niraparib and abiraterone acetate in the first-line setting for mCRPC patients. This study was recently published in the Journal of Clinical Oncology.

mCRPC patients have poor prognoses. We know based on results of studies assessing abiraterone and enzalutamide in the first-line setting that the median overall survival with these agents in the pre-docetaxel setting is about three years, and as such, newer agents and combinations are needed. So HRR gene alterations, HRR is homologous recombination repair, is present up to 30% of mCRPC patients, and these gene alterations are associated with poor prognosis and resistance to current systemic therapies. BRCA1/2 mutations, which are a subset of these HRR gene alterations, sensitize prostate cancer cells to PARP inhibition, and this sensitivity can be further augmented by androgen receptor signaling inhibition, which can downregulate DNA repair gene expression. As such, the authors and many others have hypothesized that the combination of a PARP inhibitor and an androgen receptor signaling inhibitor may actually have synergistic potential.

Niraparib is one of these PARP inhibitors, and it specifically inhibits PARP-1/2, and it's approved in the US, Canada, Europe, China, for ovarian, fallopian tube, and primary peritoneal cancers. In prostate cancer, specifically in the Phase II GALAHAD trial, niraparib monotherapy was assessed in the third-line or worse setting in mCRPC patients with measurable metastases and BRCA1/2 mutations, and was found to have an objective response rate of 34% with niraparib monotherapy.

We know that abiraterone acetate plus prednisone is approved in the first-line setting for mCRPC patients and based on results from the COU-AA-302 trial pre-docetaxel setting, it does prolong progression-free survival and overall survival.

So the authors combined these two medications and the daily combination dose was established at 200 milligrams for niraparib and 1,000 for abiraterone acetate. This was based on results of the Phase Ib BEDIVERE study, when full-dose niraparib, which is 300 milligrams was used. This led to drug limiting toxicities in three out of eight patients when combined with abiraterone. As such, the pharmacokinetic studies demonstrated that the 200/1,000 milligram combination is the one that achieves the maximum concentration area under the curve within the efficacious target combination range.

The study objective was to compare the efficacy and safety of combination niraparib and abiraterone versus placebo in the first-line mCRPC setting. The authors also sought to identify the cohort of mCRPC patients most likely to benefit from such a combination approach. This trial included patients who were ages 18 years or older with an ECOG performance status of zero to one who had no prior PARP inhibitor treatment. Also, patients were not allowed to have any prior mCRPC therapy, be it apalutamide, enzalutamide, darolutamide or docetaxel. Again, this is a first-line mCRPC treatment setting. However, systemic therapies for mHSPC or non-metastatic CRPC were permitted. Also, abiraterone, one of the two combination drugs, was allowed for four or less months prior to randomization while completing the HRR testing, which we'll get into very shortly.

If patients received more than two months of abiraterone, all the patients got PSA-tested to ascertain lack of PSA progression before randomization, to minimize the chances of selection bias for patients with worse prognosis. This is a very important point and differentiates MAGNITUDE from both PROpel and TALAPRO-2, whereby eligible patients were all pre-screened for HRR-positive biomarker status. For this purpose, they used tissue and/or blood samples and they assessed for either germline or somatic alterations, and they assessed for mono- or biallelic gene alteration. The genes are listed here, most notable of which are BRCA1 and BRCA2.

Now, the HRR-negative cohort had to have both tissue and plasma negative for these HRR mutations, where the HRR-positive at least one of either blood or plasma or potentially both were positive for these HRR mutations.

We see in the trial design here, after patients were pre-screened, they went into either the HRR-positive or -negative cohort and then randomized in one-to-one fashion, either niraparib or placebo in two separate cohorts. The HRR-negative cohort underwent a futility analysis, which was pre-planned when 200 patients were enrolled and 125 composite endpoint events had occurred defined as first of PSA progression, radiographic progression, and/or death.

In the HRR-positive cohort, which was the primary cohort, the authors used a graphical testing approach to control the type I or the false positive error rate at a two-sided alpha level of 0.05. First of all, rPFS was assessed in the BRCA1/2 subgroup and then in the entire HRR-positive cohort. So this was sequential. If the rPFS was statistically significant in the HRR-positive cohort, the primary outcome, then secondary endpoints at that point would be analyzed in the entire HRR-positive cohort. From a sample size calculation in the HRR-positive cohort, if 220 radiographic progression events had occurred, this would give an 87% power at a hazard ratio of 0.65, again with a type I error of 0.05, and in the BRCA1/2 subgroup 102 radiographic progression events would give 93% power at a hazard ratio of 0.5.

Another important point, for rPFS and OS multivariate analyses were preplanned, adjusting for selected baseline prognostic factors. So this was predefined in the protocol before the analyses were conducted. At this point I'll turn it over to Zach to discuss the results and the discussion.

Zach Klaassen: Thanks so much, Rashid. So this is the CONSORT diagram for MAGNITUDE and it's a little more involved than previous CONSORT diagrams we've discussed in our UroToday journal club. So we'll take a moment and just walk through this.

Essentially, 3,283 patients were pre-screened. Ultimately, 946 entered screening. I'll move to the far right here. This is the HRR-negative patients, and essentially, long story short, a futility analysis was conducted in August of 2020 and this arm of the trial was subsequently closed. So I'll focus on the HRR+ randomly assigned patients, of which there was 423. Ultimately, this included 225 in the BRCA1/2 group and 198 in the other HRR group. Ultimately, 212 patients were randomized in niraparib plus abiraterone and 211 patients were randomized to placebo plus abiraterone. At the time of the data cutoff, in the niraparib arm, 115 patients were still receiving therapy. At the time of data cutoff, 88 patients in the placebo plus abi group were still receiving therapy.

With regards to baseline characteristics, you can see here that there's the total cohort on the right, and this is in the HRR-positive patients. Placebo plus abi to the left and to the left of that is the niraparib plus abiraterone arm. With regards to age, the median age was 69, in each of these groups. The majority of these patients, nearly three quarters, were white. I will say that similar to other prostate cancer trials, there was a paucity of black or African-American men that were randomized in this trial.

With regards to median PSA at baseline, 21.4 plus for the niraparib plus abi arm, compared to 17.4 in the placebo plus abi arm. With regards to the gene mutations, most commonly was BRCA2 at over 40% in each arm. Second was ATM at roughly 20%, and third was CHEK2 at 8.5% in the niraparib arm and 9.5% in the placebo arm.

Moving down halfway through the table, ECOG performance status was excellent in these patients. Roughly two-thirds had an ECOG of zero. The most common site of metastatic disease was bone disease, 86.3% in the niraparib arm and 80% in the placebo arm. Visceral disease, 24.1% in the niraparib arm compared to 18.5% in the placebo arm.

With regards to metastatic disease at diagnosis, roughly 50% of these patients in the placebo arm were M1 compared to 59.9% in the niraparib arm, and the majority of these patients, over two-thirds had Gleason greater than 8 disease at the time of diagnosis.

So this is the Kaplan-Meier estimate of rPFS. This is the primary outcome. As Rashid mentioned, this was first tested in the BRCA1/2 group by central review, and we can see that there's a significant benefit to the niraparib arm for rPFS in the BRCA1/2 patients compared to placebo plus abiraterone, with a hazard ratio of 0.53 to 95% confidence interval of 0.36 to 0.79. When looking at the BRCA1/2 group with investigator assessment, again a statistically significant benefit favoring niraparib, hazard ratio of 0.50 and 95% confidence interval of 0.33 to 0.75.

Moving to the right of this figure, this is rPFS in the HRR-positive cohort by central review. Again, a statistically significant benefit both at central review and investigator assessment, favoring the niraparib plus abiraterone arm.

This is the forest plot for the rPFS subgroups in the HRR-positive cohort. I've highlighted in asterisks the statistically significant groups here. Again, all HRR patients, a three-month improvement in rPFS, statistically significant. We also see statistically significant benefit for niraparib in men that were 65 to 74 years of age, those with an ECOG of zero, those that did not have prior taxane-based chemotherapy, and those that did not have prior abiraterone therapy. With regards to visceral metastases, those that did not have visceral metastases had a benefit with niraparib as well as those with a baseline PSA above the median.

When we look at a mutation type, BRCA had a six-month rPFS benefit for niraparib, hazard ratio of 0.55, 95% confidence interval of 0.38 to 0.81. Notably, at the very bottom, other mutations did not have a benefit with niraparib with a hazard ratio of 0.99. The next several slides we'll look at some additional Kaplan-Meier estimates of the secondary endpoints. This is in the HRR-positive cohort on the left. As time to initiation of cytotoxic chemotherapy which was significantly benefited, niraparib plus abiraterone, hazard ratio of 0.59, 95% confidence interval of 0.39 to 0.89. There's also a benefit to niraparib in time to symptomatic progression, with a hazard ratio of 0.69, and a 95% confidence interval of 0.47 to 0.99.

Similar outcomes in the BRCA1/2 cohort. Time to initiation of cytotoxic chemotherapy and time to symptomatic progression, both had a hazard ratio that favored the niraparib plus abiraterone, but was not statistically significant in either of these two secondary endpoints.

This is the Kaplan-Meier estimate of overall survival both in the HRR-positive cohort on the left and the BRCA1/2 cohort on the right, and we can see that the median was not reached in either the HRR-positive cohort or the BRCA1 cohort, with a hazard ratio that was not statistically significant between these two groups.

This is the Kaplan-Meier estimate of time to PSA progression and objective response rate in the HRR-positive cohort. On the left, time to PSA progression was statistically significantly beneficial for niraparib plus abiraterone with a hazard ratio of 0.57 and a 95% confidence interval of 0.43 to 0.76. On the right, we can look at objective response rate. 60% for niraparib plus abiraterone compared to 28% for placebo plus abiraterone, which was statistically significant.

Similar-looking slide for the BRCA1/2 cohort. Again, we see a benefit in time to PSA progression from niraparib plus abiraterone, hazard ratio of 0.46, 95% confidence interval of 0.30 to 0.69. We also saw a benefit in objective response rate in the BRCA1/2 cohort, for niraparib plus abiraterone, 52% ORR compared to 31% for the placebo group.

With regards to treatment-emergent adverse events, this is in more than 10% of the patients, if we look at any treatment-related adverse event, grade 3, 56% for niraparib compared to 42.7% for placebo. With regards to grade 4 adverse events, 10.8% for niraparib, compared to 3.8% for the placebo group. And a couple of specific treatment-related adverse events of note: anemia was quite a bit higher for grade 3 adverse events in the niraparib group at 28.3%, compared to 7.6% in the placebo group.

By way of discussion, the MAGNITUDE trial found that radiographic progression-free survival was significantly longer for niraparib plus abiraterone versus placebo plus abiraterone in first-line treatment of HRR-positive mCRPC patients. And the greatest benefit in this cohort was in the BRCA1/2 patients. The benefit of an rPFS was also supported by clinically meaningful improvements in time to initiation of cytotoxic chemotherapy and time to symptomatic progression.

The results of MAGNITUDE should be taken into the context with the phase III PROpel trial, which was published last year, which looked at olaparib plus abiraterone versus placebo plus abiraterone in the first-line treatment of mCRPC. In the PROpel trial, patients were unselected for HRR alterations, and the primary endpoint of rPFS was met with a 24.8 versus 16.6 month benefit to the olaparib arm, with a hazard ratio of 0.66 and a 95% confidence interval of 0.54 to 0.81. Interestingly, the rPFS improvement of olaparib plus abiraterone was seen in both the HRR-positive and the HRR-negative populations; however, this was a lesser benefit in the HRR-negative population. However, differences in study design, gene-testing strategies, prior exposure to novel hormonal agents, and the patient population limit these cross-trial comparisons.

In conclusion, HRR-positive patients with mCRPC derive significant and clinically meaningful benefit from the combination of niraparib plus abiraterone and prednisone. The safety profile of this combination was manageable, with no new safety signals that affected the risk-benefit profile. Finally, these data, the need to test for HRR gene alterations for metastatic prostate cancer and support the use of niraparib plus abiraterone as first-line combination therapy for these patients with particularly poor prognoses. We thank you very much for your attention. We hope you enjoyed this UroToday Journal Club discussion of the MAGNITUDE trial recently published in the Journal of Clinical Oncology.