Transcript

Hello, my name's Richard Penson. I'm a medical oncologist at Mass General Hospital and the clinical lead on gynecologic oncology. It's my privilege and pleasure to just touch on some of the highlights from the American Society of Clinical Oncology virtual meeting that happened recently.

ASCO 2020 was a big splash for 2 particular reasons - we continued the debate about the role of surgery for recurrent ovarian cancer, and the SOLO-2 study, for the first time, reported an overall survival advantage for the PARP inhibitor class for patients who carry a BRCA mutation... So exciting times!

There were also some interesting abstracts about sort of novel approaches, things like combination targeted therapy.

Stephanie Gaillard presented data on the combination of tremelimumab and olaparib. This was in a group of patients who had platinum-sensitive disease up to a year and platinum-resistant disease. There was a relatively high rate of colitis, 8% grade 3 colitis, and a relatively disappointing response rate and actually, in some ways, matches our experience with niraparib, pembrolizumab that is. The full study has been published.

Again, we only found an 18% response rate and quite a lot of immune complications. The question is, “How do we specifically target patients?” In her study and ours, there was really responses independent of HRD status in platinum-free intervals.

We don't know how to pick patients who are able to really significantly benefit from bio-immunotherapy, the combination of anti-angiogenics and PARP inhibitors or immunotherapy and PARP inhibitors.

There were also other really interesting approaches. Hydroxychloroquine was given in combination with itraconazole. Ainhoa Madariaga's study looked at that trying to stimulate autophagy, the intracellular dissolution of organelles. It's a really important target in maybe that it's like the statins that may work through autophagy or the RAS signaling pathway.

These sort of different approaches to try and attack what we're now calling HR-proficient, patients who don't have susceptibility to PARP inhibitors, are really coming to the fore. Sadly, that study did not work, but at AACR, the lipophilic statins looked really quite good for reducing mortality from ovarian cancer, even not just the prophylactic but the treatment cohort.

Interestingly, the TROPHIMMUN study, avelumab, Michael Seckl presented data that 53% of patients with elevated HCG could actually be prevented from getting polychemotherapy, which is quite exciting.

But the 2 big, important studies was the AGO study in which DESKTOP III demonstrated an overall survival advantage. There are now five randomized, controlled trials that look at this. You may well know that that US study was negative, GOG-0213, but the Chinese study, we're waiting for final data but more promising progression-free survival data.

In these very carefully selected patients in the German study, an overall survival advantage. It reopens the debate about the role for surgery in platinum-sensitive recurrent ovarian cancer. We are distilling to a place where it is possible to make clinical recommendations. The 67% who got an R0 resection were the ones who really benefited.

We are looking for a biomarker for patients where we know that their surgeon's not going to be able to completely remove all tumor, but in patients who have a long disease-free interval and who can get a complete cytoreduction, surgery is back on the table.

The other important thing is that in the German study, very different to the American study, we're really purely looking at a surgery question, whereas the use of bevacizumab in GOG-0213 really likely confounded the outcomes.

Surgery shouldn't negate the use of the new maintenance biotherapeutics, the anti-angiogenics, bevacizumab being the prime example, and the PARP inhibitors.

But I think my excitement was really about a milestone presentation in terms of SOLO-2, the randomized participants with platinum-sensitive recurrent ovarian cancer who'd had a response to platinum-based combination therapy, and 2:1 they got olaparib or placebo.

Andres Poveda presented the first overall survival advantage. I think it was important for 3 reasons. It really is that milestone presentation where overall survival is statistically and clinically significantly advanced, more than a year extra survival, extra life, the participants who got olaparib. That's with a 38% crossover in the placebo arm.

The fact that 12.9, nearly 13 months, more than a year, overall survival advantage is able to be demonstrated where there's clearly crossover and patients live for years after initiating switch maintenance PARP inhibitor therapy, really very exciting, a coming of age where we really can say to patients it's not just delaying recurrence but truly impacting overall survival.

And then, really, a little bit moderated by the fact that in the PARP inhibitor arm, 8% of patients actually did eventually develop either MDS or acute myelogenous leukemia, a catastrophic complication, but this is 5-year follow-up as opposed to the 2-year follow-up when the PFS was presented by Eric Pujade-Lauraine. It reminds us about the necessity for full disclosure and truly informed consent there.

Unequivocally, in patients who carry a BRCA mutation, who've had a lot of platinum prior exposure, PARP inhibitors are unequivocally associated with that catastrophic consequence of disrupting DNA, but that should not stop anybody getting switch maintenance PARP inhibitor when they carry a BRCA mutation, because the >1 year survival advantage really does change the timeline for patients.

For us, looking at the ASCO abstract, it really does change the timeline. We've moved into an age where treatment, chemotherapy and surgery, clearly gets patients into a state where biological therapies can really meaningfully impact survival for our patients.

Thank you.