At 2023 ASCO Genitourinary Cancers Symposium, Eleni Efstathiou, MD, Houston Methodist Cancer Center, Houston, TX, shared data from the second interim analysis of MAGNITUDE, a phase 3 trial evaluating the addition of niraparib to abiraterone acetate and prednisone for patients with metastatic castration-resistant prostate cancer (CRPC). This analysis addressed the cohort of patients with homologous recombination repair (HRR) gene alteration, focusing on the BRCA subgroup.

Dr Efstathiou explained, “This second interim analysis supports clearly the first report that showcases adding niraparib to abiraterone plus prednisone in the first-line metastatic CRPC state for tumors that harbor HRR mutations, and specifically BRCA, is beneficial, improving outcomes and reducing, by 45%, the risk of progression or death.”

Transcript:

Hello, I'm Eleni Efstathiou. I'm a GU medical oncologist from Houston Methodist Cancer Center and we just presented the second interim analysis of the MAGNITUDE study. Let me tell you a little bit about the study and what we have presented in the past and where we are now. The MAGNITUDE study is a phase 3, double blinded, international, placebo-controlled study that asked the question of whether the combination of a PARP inhibitor with an androgen-signaling inhibitor of the novel generation is a better combination than using abiraterone plus placebo alone, in men who have tumors that are castration-resistant and metastatic and that harbor [homologous recombination repair] HRR mutations.

Backing up, the trial was originally designed to have 2 cohorts. One cohort was this HRR-positive cohort that we're going to speak more about and the other cohort was a cohort of patients who did not harbor HRR mutations. We designed the trial so that the patients, the moment they got enrolled, they would be pre-screenedfor presence or absence of these mutations. And this was clarified both by doing analysis on tissue and liquid biopsies, and you had to have both negative before enrolling in the trial in the HRR-negative cohort, we went on to randomize the patient on receiving the combination of niraparib plus abiraterone plus prednisone, vs placebo plus abiraterone plus prednisone. There were 2 parallel cohorts.

The HRR-negative cohort was designed in a way that we would not fully accrue until we knew that there was some signal. We initially accrued 200 patients and then we stopped accrual and waited to see if there was a signal that would favor continuing in the combinatorial arm. And at that point in time we did not see a difference in signal between the two arms. That was studied by looking at time to PSA progression and radiographic progression-free survival, and we didn't see a clear signal. We stopped accrual of that HRR-negative arm. Then we went on to complete the accrual in the cohort that had patients with metastatic castration-resistant prostate cancer that harbored HRR mutations. There was a panel of 9 genes included and the main mutation that we were looking for was of course the BRCA family, BRCA1/2. In fact, 53% of patients that were included on the trial harbored BRCA2 mutations, whether somatic or germline. That makes up for the biggest cohort of BRCA2-mutated tumors that has been studied in this field, 225.

The primary end point of the trial was radiographic progression-free survival by central independent blinded review. Secondary key end points included time to symptomatic progression, a paramount clinical endpoint, time to cytotoxic chemotherapy, overall survival, that always remains important, and other exploratory endpoints, such as time to pain interference and other quality of life measures. 

We just presented the second interim analysis results. These were focused on the BRCA subgroup and we  showcased that in this BRCA subgroup the addition of niraparib to abiraterone improves by 45% the outcomes. The hazard ratio was 0.55 to favor the introduction of niraparib to abiraterone in this first-line metastatic castration-resistant disease. Now there's an important key here: patients were allowed to have been previously exposed to enhanced androgen-signaling inhibition in the hormone-naive setting, or they may have initiated abiraterone up to four months before randomization. So this is a patient population is very, very close to real life practice.

When it comes to the baseline characteristics of the patients, they were well-balanced between the 2 groups and there was a slightly higher number of patients with compromised performance status and visceral metastases on the side of the combinatorial arm. And I will come back to that to actually address how we tried to correct the analysis for that matter. So going on to the secondary end points, they were all supportive of the primary endpoint. Time to symptomatic progression met the same criteria, a did time to cytotoxic chemotherapy. And why does that become important? It's so much the fact that we are going to give a subsequent treatment. It's actually measuring the time from when you initiate 1 treatment to the need of a second treatment that has great implications for the quality of life of the patient, the clinical correlates that make up how the patient performs.

Finally, when it comes to overall survival trends, it is still early. We do not have enough events, thankfully, to have a clear outcome. But there is a trend, and we saw this trend by doing what we called an inverse probability censored weight analysis. What does that do? It actually corrects for these baseline characteristics that may be a little bit different between the 2 groups, and it corrects for differences in subsequent treatments. And this analysis also showcased a clear trend for survival benefit in patients who are receiving the combinatorial treatment of niraparib plus abiraterone vs abiraterone alone.

To conclude, the second interim analysis supports clearly the first report that showcases adding niraparib to abiraterone plus prednisone in the first-line metastatic CRPC states for tumors that harbor HRR mutations and specifically BRCA, is beneficial, improving outcomes and reducing by 45% the risk of progression or death. Thank you very much.

Source:

Efstathiou E, Smith MR, Sandhu S, et al. Niraparib (NIRA) with abiraterone acetate and prednisone (AAP) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations: Second interim analysis (IA2) of MAGNITUDE. Presented at ASCO Genitourinary Cancers Symposium; February 16-18, 2023; San Francisco, CA. Abstract 170