NS - Dr Neal Shore – Carolina Urologic Research Center, Myrtle Beach, USA
KC - Prof Kim Chi – BC Cancer Research Centre, Vancouver, Canada
NS: Hi everyone, I’m Neal Shore, I’m the Medical Director of Carolina Urologic Research Center and the Chief Medical Officer of Urology and Surgical Oncology for GenesisCare US. What a great pleasure to have with me today my good friend and colleague, internationally renowned Professor of GU Medical Oncology at BC Cancer and the University of British Columbia, Kim Chi. Kim is the global PI and the lead author on the MAGNITUDE trial; we were very fortunate to be a site. Kim, congratulations – you gave a fantastic presentation at ASCO GU 2022 this year on the results of the MAGNITUDE trial. Can you begin by telling us why we see the efficacy for PARP inhibitors in prostate cancer, a top line, and how that led to the trial design for MAGNITUDE?
KC: Thanks for those kind words, Neal, and just to address your question, we know that PARP inhibitors do have activity in patients with metastatic castration resistant prostate cancer. This is because up to 30% of them can have alterations in genes associated with homologous recombination repair. We have olaparib as a single agent approved for patients that have these gene alterations after they’ve progressed on androgen receptor pathway inhibitors like enzalutamide or abiraterone and even chemotherapy. So, as a starting point, we know that PARP inhibitors do have activity and improve overall survival in these patients.
In terms of the MAGNITUDE study, what we’re doing here is trying to bring PARP inhibitors earlier in the disease process. MAGNITUDE was a phase III study that was looking at the combination of niraparib plus abiraterone and prednisone as first line treatment in patients with metastatic CRPC. We were doing it in patients that were so-called biomarker positive, that had alterations in homologous recombination repair genes but we also looked at patients that were homologous recombination repair intact, at least they didn’t have identified gene alterations. The rationale behind this is that androgen receptor signalling regulates DNA repair in prostate cancer and inhibition of AR signalling may result in a BRCA-like or BRCA-ness phenotype that may be amenable to PARP inhibition, so even in the absence of a gene alteration in homologous recombination repair. So the MAGNITUDE study really set out to identify both cohorts of patients and then see what the benefit of adding niraparib onto abiraterone and prednisone for these patients would be.
NS: Exactly, it’s so interesting that there’s a potential mechanism of action synergy by combining even in wildtype patients, as opposed to those who only have the HRR mutation, we might see a decrease in the development of resistance to AR therapy and an increase in sensitivity to PARP inhibition for the patients who are wildtype. So it made great sense to do that. So what were the top line results? It was a two arm trial that also had bifurcation within the two arms.
KC: Exactly, so the MAGNITUDE study prospectively identified these patients and that’s a key thing because when we’re testing whether a biomarker is predictive of the clinical utility you really have to identify the patients prospectively to the two cohorts – biomarker negative, biomarker positive – and then each of those cohorts subsequently gets randomised. Now, in the biomarker negative cohort, so the wildtype patients, in the futility analysis that was performed after a couple of hundred patients were randomised, we saw no benefit of adding niraparib onto abiraterone. The hazard ratio for the composite progression endpoint of PSA and radiographic progression was 1.09, so really no benefit. And we know niraparib and other PARP inhibitors have toxicity so at that point the Data and Safety Monitoring Committee recommended halting accrual onto that cohort.
However, in the biomarker positive cohort, in the patients that had identified homologous recombination repair gene alterations, this completed accrual. Again, there was a bit more analysis because we specifically powered a subgroup of patients with BRCA1/2 alterations. Now, these patients we know particularly respond well to PARP inhibitors and that’s why this was done – to look at this subgroup in particular. In those patients there was a very large benefit in radiographic progression free survival. The hazard ratio was 0.47, improving median radiographic progression free survival by about six months.
What’s also important to note is that these patients with BRCA1/2 alterations, with standard abiraterone alone their median time to radiographic progression free survival was just over 10 months. This is quite important because typically in unselected populations we would expect to see a radiographic progression free survival in about the 16.5 month range. So it points out, as we know all along, that patients with BRCA1/2 alterations, particularly BRCA2 alterations, do particularly poorly. Really, again, it emphasises the need to bring these treatments up earlier for these poor prognosis patients.
NS: You made that point in your presentation which I thought was outstanding. The discussant also amplified that point. These patients who are BRCA positive, they have a worse phenotype, they have a worse biology, as you point out, in the active control arm of abiraterone they didn’t do as well as they did, for example in the COUGAR-302 trial, pre-chemotherapy mCRPC patients. So I have two additional questions off of those findings, Kim, and thanks for boiling it down so clearly. One, maybe you get to where we may expect to see overall survival data but then, additionally, the importance of performing genomic profiling and testing.
KC: Yes, so in the first interim analysis for overall survival there was no difference. However, again, it was the first analysis. Only just over 20% of death events had occurred and so it’s very early on. The median follow-up is only about a year and a half. So we really need to follow-up these patients more to understand what the overall survival benefit is.
Nevertheless, a multivariate analysis that incorporated baseline prognostic features did show a trend towards an overall survival benefit in the niraparib plus abiraterone arm in patients in the overall biomarker positive cohort. The hazard ratio was in the 0.77 range, again p-value not statistically significant but there’s a little bit of a trend there.
So what is the importance of identifying? I think the importance of identifying is that this way we identify, number one, it’s a predictive marker. We understand who are the patients that are going to respond best to PARP inhibitors. Number two, it’s a prognostic factor, so understanding who are the patients that are going to have the worst outcomes. Now, regardless of the treatment, we may want to follow these patients more closely; we may want to change their treatments more earlier rather than waiting for further progression; we may want to change up their treatments earlier, understanding that they are more likely to have resistance and a poor prognosis. Thirdly, and very importantly, there are hereditary cancer considerations. Patients with BRCA2 alterations, about half of them are germline in origin meaning that they’ve inherited it from their parents and they could have passed this down to their children. So understanding that could help prevent or have early detection for the patient’s family. So there are a lot of good reasons that we should be really doing genomic, genetic testing in all our patients with advanced prostate cancer.
NS: I fully agree, excellent answer, very complete. So, two additional questions. In a word, there’s a lot to always cover, we could present a lot, but in a word were there any additive safety tolerability concerns outside of what we already know of concepts of adverse event tolerability for either abiraterone or PARP inhibitors such as niraparib?
KC: Essentially no, we didn’t see any new toxicities or synergistic toxicities. PARP inhibitors cause myelosuppression as well as nausea, those are common side effects, and that’s what we saw in this trial, that in addition to the typical abiraterone side effects we saw some myelosuppression. But it was easily managed; it was managed with dose reductions, interruptions and, furthermore, when we looked at quality of life based on FACT-P questionnaires there was no clinically meaningful difference between the treatment arms or over time. So overall it’s a well-tolerated treatment regimen.
NS: So if you have a patient who comes in now who is, for example, BRCA2 positive, first line mCRPC, no prior exposure of any significance to a novel hormonal agent, based upon this data, and with the caveat that cost is not an issue and there is accessibility, would you start that patient on combination therapy right now, assuming you had access to both abiraterone and niraparib?
KC: Yes. So, if I had a patient coming in with a homologous recombination repair gene alteration, I would definitely start them on a combination of a PARP inhibitor like niraparib with abiraterone, based on these data, given the improvements in radiographic progression free survival and, as well, the aggressiveness of the disease. Now, definitely for BRCA2 alterations that would be particularly so.
NS: This is great. This is an opportunity for us to further add proverbial tools into the toolbox and the importance of understanding the different mechanisms of action of PARP inhibitors and androgen biosynthesis inhibitors and AR blockers and doing what we can to optimise patient care and cutting down on resistance and, as you also mentioned, the importance of cascade testing. It’s good to know that the combination didn’t have any significant untoward toxicity. So thanks, Kim Chi, so much for your education and your leadership in this important trial.
KC: Thanks. Thanks Neal.