SOLO-1 Phase 3 [2022]: Newly Diagnosed Advanced Ovarian Cancer Research
Dr. Greg Rossi talks with OncologyTube about the SOLO-1 Phase III Trial
The history of Lynparza, Olaparib, and PARP inhibitors stretches back really a couple of decades in cancer research. We had an observation a number of researchers an observation that we could target the DNA damage responses, and pathway of tumor cells as a therapeutic target, and with Olaparib, we’ve been able to do that in not just ovarian cancer, but actually in breast cancer, prostate cancer, and in pancreatic cancer.
And it really harnesses the approach of how PARP works to repair single-strand breaks. And if it doesn’t repair that single strand break, then the double-strand break mechanisms pathways kick into gear. And there are a number of genetic backgrounds that prevent that from happening, such as BRCA mutation. And so this was the idea that we took into really a broad program Lynparza (Olaparib).
What is the Current Standard of Care for Lynparza (Olaparib)?
So the one actually started back in 2013, so nearly 10 years ago, which makes the data that we are presenting at this most recent European Society Medical Oncology this year really extraordinary in terms of the update, the duration of follow-up that we have from this study. But let me take you back to where we were in 2013.
So we understood that in platinum-sensitive relapsed ovarian cancer, we saw a significant potential benefit for Olaparib through the study 19 data. And so we initiated a number of studies back then, both in the relapsed setting, the PSR setting, as well as in the frontline setting, which is with the SOLO-1 clinical trial.
And at that time, the standard of care in most countries was double platinum-based chemotherapy with either primary upfront surgery or interval debulking surgery. And that was the basis that we developed the control arm and the standard for the SOLO-1 trial.
Please Tell Us About The SOLO-1 Trial Design.
Let me start with the design of the study. So as I said back in 2013, we designed this study as a randomized phase 3 trial, comparing placebo controlled (placebo group was randomly assigned) with a lab in patients that had received initial platinum-based double chemotherapy. The type of patients (with newly diagnosed advanced ovarian cancer) we had in the study were cyst ovarian cancer patients and fallopian tube cancer or primary peritoneal cancer.
Those patients (with newly diagnosed advanced ovarian cancer) had to be in clinical response to their chemotherapy. And they had to have good performance status. And most importantly, they had to have a BRCA mutation evidence of BRCA mutation. So that was really the design of the trial. The other design feature that I think is important to understand is that we designed in fixed treatment duration, 24 months fixed treatment duration for patients with BRCA mutation.
So the vast majority of patients stop therapy, either on (disease) progression or at 24 months, with a few patients (with newly diagnosed advanced ovarian cancer) having clinical cases evaluated to be able to prolong beyond that, but the vast majority, 24 months of treatment, and the second part to the question which is what were the results? What were the outcomes? The outcomes have been really reported in 3 time periods. So initially, we reported the data from SOLO-1 back in 2018, with Dr. Moore publishing it in the New England Journal. And this was the primary PFS outcome.
And the PFS (progression free-survival) outcome was designed to be at 3 years after the last patient was randomized and finished treatment in the study. So that was still a very prolonged period, and the reason that we did that is that the event-driven analysis was actually looking as though the events were coming in very slowly and the results of the primary PFS (progression free-survival) analysis at that time were extraordinary. We saw a 0.3 hazard ratio for Olaparib versus placebo (group) controlled in a adverse events. We didn’t have an estimate for the new median (duration) at the time. And we saw around 14 months of medium PFS in the control arm with a placebo group that was updated with PFS in 2020.
So Dr. Suzi Banerji presented those data and we, at that stage, got a PFS (progression free-survival) estimate. So we had 56 months, so nearly 5 years, versus that 14 months and you can see the extraordinary difference in terms of the PFS (progression free-survival) Delta that we were reporting, and this most recent analysis, the 7 years analysis that was reported at ESMO, was the first time we’d really had a mature survival.
Although it is still an interim analysis of survival, it’s around 38% mature on survival. And what we see there is we don’t see a median for Olaparib, and we see around about 75 months for the control arm. Most of those or many of those patients (with newly diagnosed advanced ovarian cancer) in the control room actually followed onto PARP inhibitor, mostly Olaparib, in their second or third line cancer therapy.
So that’s confounding a little bit of the estimate you see there. I think the most significant clinical piece of data from the updated analysis is the fact that 2/3 of patients (with newly diagnosed advanced ovarian cancer), 67% at 7 years, are still alive, and many of those are relapsed-free. So, in essence, treatment, free toxicity-free relapse-free at 7 years, is quite an extraordinary outcome, I think for these patients.
Highlighted Key Data Points Of the SOLO-1 Trial Of Lynparza (Olaparib group).
The SOLO-1 trial, which started in 2013, actually had patients finishing therapy after 2 years in these types of clinical trials. And so this was really in about 20, 2018, and we’ve just been monitoring patients (with newly diagnosed advanced ovarian cancer) in terms of their events since then. And so we really have a, I think, a very rich and rare data set in terms of long-term survival for these, for newly diagnosed disease in ovarian cancer patients.
What Stood Out The Most From This Data?
The most remarkable data, I think, from this 7 years update that was recently published in the JCO and presented at ESMO. Is the fact that 2/3 of patients are still alive at 7 years. That compares to about 46% on the control arm. But remember that almost half of the control arm patients (with newly diagnosed advanced ovarian cancer) actually have received a part in the second or third line.
And so their survival is affected by those data as well. The other, I think, piece of data that is important is the fact that many of those patients (with newly diagnosed advanced ovarian cancer) are actually still relapse-free, so they haven’t gone onto their second (disease) progression. So we monitored. Time to first subsequent therapy, and we see an extraordinary impact on time to first subsequent therapy as well.
What Was The Long-term Safety Data?
And the last thing I will say for your viewers is long-term safety data is also, I think, a really important aspect of this trial. So we know the treatment. Profile of Olaparib and PARP inhibitors in general, looking at the anemia and nausea you’re vomiting that is associated.
Most of that is mild to moderate, and you don’t need to discontinue therapy, but one of the open questions was really about whether there was an impact on secondary malignancies or MDs and AML.
And now we have a long-term observation on that, and in fact, since the original study, we only had seen a couple of patients (with newly diagnosed advanced ovarian cancer), one in both arms.
Getting MDs and AML from the previous analysis. So that gives us a lot of confidence about the long-term safety profile that we see for this compound in this patient population.
What Led to Olaparib’s FDA-approval?
Back in 2012, when we saw the results from a really, very significant what was designed actually as a phase 2, but it was a large phase 2, and it was really practiced changing in the platinum-sensitive relapsed ovarian cancer. We realized that we really had validated, at least in this setting, the idea of Olaparib as a treatment and par as a therapeutic target.
What Were the Phase III Studies That Were Initiated in the Olaparib Group?
And so what we did at that time is we actually initiated a range of phase 3 studies. So the SOLO-1 study that we’ve just been talking about, along with the SOLO-2 study in the platinum-sensitive relapsed setting, along with the POWER-1 trial in combination with bevacizumab in first-line ovarian cancer, but we also initiated studies in breast cancer, OlympiAD, and OlympiA.
So one in the metastatic setting, one in the early stage setting. We initiated studies in prostate cancer, and we initiated studies in pancreatic cancer. And in fact, we also initiated one in gastric cancer, which unfortunately failed to demonstrate the benefit.
So all of these went in parallel because we realized that if we were able to target this harmonics combination deficiency or this DNA damage response pathways, That was actually something that was in multiple different tumor types.
And so we initiated those studies in parallel, and so there wasn’t really a relationship between the OlympiA trial and the SOLO-1 trial, but absolutely the early observations allowed us to feel confident about bringing that forward. And of course, we are very happy to see the outcome.
The idea that targeting this particular therapeutic target in all of those indications that I just mentioned, barb gastric, has proven to be a way to really benefit patients (with newly diagnosed advanced ovarian cancer).
What Was The Primary Endpoint Of The SOLO-1 Trial Of Lynparza (Olaparib)?
So the primary endpoint of the SOLO-1 trial was progression-free survival that was conducted in 2000, and 18 showed highly significant benefits with a hazard ratio of 0.3.
And then subsequent to that, we’ve been able to follow that up with additional information to be able to start to characterize the longer impact, the 5 years data, and the 7 years data, which obviously is what has been most recently published.
Highlighted Points From The SOLO-1 Trial of Lynparza (Olaparib)?
I think the last 20 years validating PARP as a therapeutic target investigating this concept of synthetic vitality, and establishing Olaparib in multiple tumor types in ovarian cancer, (metastatic) breast cancer, prostate cancer, and pancreatic cancer as a therapeutic option for those patients (with newly diagnosed advanced ovarian cancer) have really been transformative.
And I think it’s very exciting to think about what we can do building upon. We now understand more about the biology of these tumors.
We understand more about the concept of targeting PARP, and we know now that if we can isolate even further, some of the therapeutic targets down to, for example, part one, rather than other parts that may be of additional benefit.
Greg Rossi, Ph.D. – About The Author, Credentials, and Affiliations
Dr. Greg Rossi is the Senior Vice President and Head of Oncology at AstraZeneca in both Europe and Canada.