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Advanced OC: Interpreting the Design and Results of SOLO-1

Insights From: Michael Birrer, MD, ONeal Comprehensive Cancer Center; Ursula A. Matulonis, MD, Dana-Farber Cancer Institute; Kathleen Moore, MD, Stephenson Cancer Center
Published: Friday, Jun 07, 2019



Transcript:

Kathleen Moore, MD: SOLO-1 is a randomized phase III study that enrolled women with BRCA mutations. They could be either germline or somatic, but the vast majority were germline. They had to have advanced ovarian cancer, so stage III or IV. They had to have excellent performance status. They had to have undergone an attempt at surgical cytoreduction. It could be primary, or it could have been interval. And at the end of their induction chemotherapy they had to either be in a complete or partial response to chemotherapy.

They were then randomized in a 2-to-1 fashion to receive olaparib tablets at 300 mg twice a day or placebo twice daily. And the stratification factor was interim study with a complete or partial response. So they did stratify there. Patients continued their assigned therapy until disease progression. Or, if no disease progression had occurred at the 2-year mark, they discontinued at 2 years unless they came onto the study with partial responses. And at the time that they reached 2 years, if there was still something on the CT [computed tomography] scan that the patient’s provider was perhaps worried about or maybe their CA-125 [cancer antigen 125] was a little elevated and there was just something that made them want to continue beyond 2 years, and with discussion with the medical team, they were allowed to do so. And so we had about 12% of patients do that.

So the primary endpoint was progression-free survival as measured by the physicians taking care of the patient. Secondary endpoints were progression-free survival [PFS] confirmed by what’s called the blinded independent central radiographic review, or the BICRR. Overall survival was included, of course. Progression-free survival 2, which is the time from randomization in SOLO-1 until the second progression. So of those patients who progressed and got something else, when did they progress again? So that’s PFS2. And then time-to-second subsequent therapies. And then the primary quality of life analysis was the FACT-O TOI [Functional Assessment of Cancer Therapy-Trial Outcome Index], although there are a number of other quality of life analyses that will be done as well. So that’s the design.

So 393 patients were accrued over 18 months, so it accrued very rapidly. And when we look at the demographics of who was accrued, it really represented ovarian cancer. You had about 30% of patients who came on with neoadjuvant chemotherapy. But of those patients who came on with primary cytoreduction, around 75% of them were cytoreduced to complete, no gross residual disease. The majority, around 80%, were stage III instead of stage IV. Most were BRCA1 versus BRCA2, which is the normal distribution of BRCA. And so otherwise they were very well-matched populations in the placebo group, the olaparib group.

But it was a very good prognostic group of patients as compared with studies ongoing now where they’re trying to identify very high-risk patients, where you get events. This was a really good prognostic group of patients. They’re younger patients with BRCA mutation. Most had primary surgery. Most were cytoreduced. Most were stage III. The best group of patients you could possibly ever enroll on a clinical trial.

And I say that because those patients are difficult to do clinical trials with because you expect them to do very well and the events are very slow to come, which is what happened in SOLO-1. It took us years to find the primary result, but we did. And so the primary endpoint was progression-free-survival. And at the time of data cutoff, we actually had not yet met the median progression-free-survival for the olaparib group. But the median progression-free-survival for the placebo group was only 13.8 months from the end of chemotherapy. So to compare it to other studies you’d have to add the chemotherapy time in, so add 5 or 6 months into that. It’s about 19 months. So longer than non-BRCA, but still not forever: 19 months, and you had patients who had recurred.

When you look at sensitivity analyses, the estimate for the median in the olaparib group is between 47 and 50 months. So that resulted in a hazard ratio of 0.3, which means we had a 70% reduction in the risk of progression with use of 2 years of olaparib as compared with placebo. And not most importantly but importantly, when you look at the survival curve for the olaparib group, at the 2-year mark you do not see this decrement of the curves coming down to the median, so you don’t see patients all of a sudden starting to come off when they stopped the olaparib. It’s very flat. So we’ll see if that’s maintained over time. We won’t look at the data again really until the overall survival is mature, which will be several years. But we are hopeful that that flattening of the curve that was maintained after completion of assigned therapy is an early signal that we do have some increased cures.

A key secondary endpoint that was also mature at the time of the presentation was progression-free survival 2, which was a hazard ratio of 0.5. Even more importantly with that is that a third of the patients in the placebo group had crossed over to PARP [poly ADP ribose polymerase] as their next line of therapy, appropriately. They should have gotten a PARP but were still maintaining that benefit even with a third of patients getting a PARP in the next line of therapy, either a PARP alone or a PARP as maintenance. We don’t have that granularity yet. So very promising PFS2. In the European Union, PFS2 is felt to be a surrogate of overall survival. We’ll see if that holds true here, but it is a nice signal that the benefit is maintained over time.

There were really no new safety signals noted with SOLO-1. It looks very similar to SOLO-2 and every other PARP inhibitor tested with low-grade GI [gastrointestinal], fatigue the source of toxicities. And really the only grade 3 toxicity of note is anemia in 21% of patients, which is a common PARP inhibitor adverse event. So that study very quickly led to the FDA approving olaparib as maintenance following induction chemotherapy in BRCA patients. And that was done in January, so we’re still on the upswing from that approval. But it was a very important approval for our patients, and hopefully we can do something similar for BRCA wild-type patients, but that was a big gain for our BRCA patients.

Transcript Edited for Clarity.
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Transcript:

Kathleen Moore, MD: SOLO-1 is a randomized phase III study that enrolled women with BRCA mutations. They could be either germline or somatic, but the vast majority were germline. They had to have advanced ovarian cancer, so stage III or IV. They had to have excellent performance status. They had to have undergone an attempt at surgical cytoreduction. It could be primary, or it could have been interval. And at the end of their induction chemotherapy they had to either be in a complete or partial response to chemotherapy.

They were then randomized in a 2-to-1 fashion to receive olaparib tablets at 300 mg twice a day or placebo twice daily. And the stratification factor was interim study with a complete or partial response. So they did stratify there. Patients continued their assigned therapy until disease progression. Or, if no disease progression had occurred at the 2-year mark, they discontinued at 2 years unless they came onto the study with partial responses. And at the time that they reached 2 years, if there was still something on the CT [computed tomography] scan that the patient’s provider was perhaps worried about or maybe their CA-125 [cancer antigen 125] was a little elevated and there was just something that made them want to continue beyond 2 years, and with discussion with the medical team, they were allowed to do so. And so we had about 12% of patients do that.

So the primary endpoint was progression-free survival as measured by the physicians taking care of the patient. Secondary endpoints were progression-free survival [PFS] confirmed by what’s called the blinded independent central radiographic review, or the BICRR. Overall survival was included, of course. Progression-free survival 2, which is the time from randomization in SOLO-1 until the second progression. So of those patients who progressed and got something else, when did they progress again? So that’s PFS2. And then time-to-second subsequent therapies. And then the primary quality of life analysis was the FACT-O TOI [Functional Assessment of Cancer Therapy-Trial Outcome Index], although there are a number of other quality of life analyses that will be done as well. So that’s the design.

So 393 patients were accrued over 18 months, so it accrued very rapidly. And when we look at the demographics of who was accrued, it really represented ovarian cancer. You had about 30% of patients who came on with neoadjuvant chemotherapy. But of those patients who came on with primary cytoreduction, around 75% of them were cytoreduced to complete, no gross residual disease. The majority, around 80%, were stage III instead of stage IV. Most were BRCA1 versus BRCA2, which is the normal distribution of BRCA. And so otherwise they were very well-matched populations in the placebo group, the olaparib group.

But it was a very good prognostic group of patients as compared with studies ongoing now where they’re trying to identify very high-risk patients, where you get events. This was a really good prognostic group of patients. They’re younger patients with BRCA mutation. Most had primary surgery. Most were cytoreduced. Most were stage III. The best group of patients you could possibly ever enroll on a clinical trial.

And I say that because those patients are difficult to do clinical trials with because you expect them to do very well and the events are very slow to come, which is what happened in SOLO-1. It took us years to find the primary result, but we did. And so the primary endpoint was progression-free-survival. And at the time of data cutoff, we actually had not yet met the median progression-free-survival for the olaparib group. But the median progression-free-survival for the placebo group was only 13.8 months from the end of chemotherapy. So to compare it to other studies you’d have to add the chemotherapy time in, so add 5 or 6 months into that. It’s about 19 months. So longer than non-BRCA, but still not forever: 19 months, and you had patients who had recurred.

When you look at sensitivity analyses, the estimate for the median in the olaparib group is between 47 and 50 months. So that resulted in a hazard ratio of 0.3, which means we had a 70% reduction in the risk of progression with use of 2 years of olaparib as compared with placebo. And not most importantly but importantly, when you look at the survival curve for the olaparib group, at the 2-year mark you do not see this decrement of the curves coming down to the median, so you don’t see patients all of a sudden starting to come off when they stopped the olaparib. It’s very flat. So we’ll see if that’s maintained over time. We won’t look at the data again really until the overall survival is mature, which will be several years. But we are hopeful that that flattening of the curve that was maintained after completion of assigned therapy is an early signal that we do have some increased cures.

A key secondary endpoint that was also mature at the time of the presentation was progression-free survival 2, which was a hazard ratio of 0.5. Even more importantly with that is that a third of the patients in the placebo group had crossed over to PARP [poly ADP ribose polymerase] as their next line of therapy, appropriately. They should have gotten a PARP but were still maintaining that benefit even with a third of patients getting a PARP in the next line of therapy, either a PARP alone or a PARP as maintenance. We don’t have that granularity yet. So very promising PFS2. In the European Union, PFS2 is felt to be a surrogate of overall survival. We’ll see if that holds true here, but it is a nice signal that the benefit is maintained over time.

There were really no new safety signals noted with SOLO-1. It looks very similar to SOLO-2 and every other PARP inhibitor tested with low-grade GI [gastrointestinal], fatigue the source of toxicities. And really the only grade 3 toxicity of note is anemia in 21% of patients, which is a common PARP inhibitor adverse event. So that study very quickly led to the FDA approving olaparib as maintenance following induction chemotherapy in BRCA patients. And that was done in January, so we’re still on the upswing from that approval. But it was a very important approval for our patients, and hopefully we can do something similar for BRCA wild-type patients, but that was a big gain for our BRCA patients.

Transcript Edited for Clarity.
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