Hello everyone, this is Dr Bishal Gyawali from Queen’s University, Kingston, Canada and today I want to summarise some of the major results from the breast cancer trials and the gynaecological ovarian cancer trials from the ESMO 2022 annual congress.
First, let’s just start with the gynaecological trials. We had the presentation of overall survival data from the SOLO1 trial. The seven year OS hazard ratio was 0.55, not significant. One of the reasons that was proposed was the crossover rate: 44% of the patients crossed over to a PARP inhibitor at the time of relapse. But actually what that tells me is that means you probably do not need to give a PARP inhibitor up front and you could give it in later line and achieve the same survival results. It was interesting that the median overall survival reported here was not reached for the olaparib arm versus 75 months for the control arm. These are quite long-term survivals that our patients with ovarian cancer are able to achieve, which is phenomenal.
Then there was the PAOLA-1 trial. Again the overall survival results here are what they call 50% mature but unfortunately there was no survival difference here again in the ITT population. 50% of the patients had received PARP inhibitor from the control arm and, again, that could be one of the reasons but, as I mentioned, if crossover is diluting the survival results then that probably means the drug can be given in a later line of therapy. This is for the ITT results, when they looked at the HRD positive population the hazard ratio was 0.62. But in the BRCA mutation positive patients the hazard ratio was impressive and the survival results looked significant, in the HRD not significant. So these are the subgroups. Clearly in the BRCA mutation positive population PARP inhibitors improve outcomes but for the HRD positive population and all-comers we need to be careful about not over-treating them unnecessarily.
Then there was the ARIEL4 trial. This ARIEL 4 trial, we need to talk about the role of PARP inhibitors here because this was a trial of rucaparib and here the hazard ratio was more than 1.0. This is in the late line of treatment, this is not first line. In the late line of treatment the PARP inhibitor rucaparib had a hazard ratio of more than 1.0 which signifies harm. In fact, I see that they have already withdrawn this approval from the FDA, I do not know whether they have withdrawn it from elsewhere, from other jurisdictions but from the FDA they have voluntarily withdrawn after knowing this data, which is a good thing. But we have to be careful why are we seeing signals of harm here. Is it relevant only for rucaparib or is it relevant for other PARP inhibitors as well? Are all PARP inhibitors the same? These are some important questions that need to be answered now. If it’s the disease setting, if PARP inhibitors are harmful when used at later lines of therapy, then that could mean that PARP inhibitors will have to be used in an earlier line of treatment, contrary to what I inferred from the overall survival results from the SOLO1 and PAOLA-1 trial. But this is an important question – a signal of harm is not something that we can dismiss easily. Withdrawal of rucaparib is fine but the broader questions that this trial asks are important to answer – why did we see such harm? Is it from toxicity? Is it from rapid progression of disease? What’s happening here? That is important to consider.
Then there were the avelumab trials and the atezolizumab trials in ovarian cancer that were all negative. At this year’s ESMO we have the ATALANTE trial. PFS did not improve in the ITT population; it did not improve in the PD-L1 population. The point that I’m trying to make here is when we already had the avelumab trials and the atezolizumab trials that were already negative in ovarian cancer, now this is the third trial of checkpoint inhibitor in ovarian cancer and this is also negative. Back in 2015 or 2016 I had written an editorial in Ecancer Journal called ‘Negative trials in ovarian cancer – is there such a thing as too much optimism?’ Some of my colleagues were unhappy with that paper but in ovarian cancer we see this theme that we sometimes do not know when to give up. That’s natural as an oncologist – we do not want to give up, never, but sometimes we are spending too many resources into pursuing the same treatment that has failed again and again. How many negative trials do we need in ovarian cancer to say that immunotherapy is not beneficial here? We tried the same thing in glioblastoma as well – we did more than three or four immunotherapy trials, all of them were negative. I see a similar thing happening in ovarian cancer – the same trial design, the same strategy just testing another PD-1 or PD-L1 molecule. I don’t think that’s going to give us the results that we need.
Moving on to breast cancer, again, we are needing to ask this question again and again – are all checkpoint inhibitors the same? Are there differences between nivolumab and pembrolizumab and avelumab and atezolizumab? Similarly in ovarian cancer we just discussed should we ask this question – are olaparib, niraparib, rucaparib the same or are there important differences? In breast cancer we have to ask are all CDK4/6 inhibitors the same? We have seen negative results for survival from palbociclib, that has been presented at ASCO. Here at ESMO the results of MONARCH3 were presented –abemaciclib interim analysis for overall survival and shows an overall survival of 67 months versus 54 months in the control arm but it’s not significant. This is the second interim analysis, we need to wait until the final mature analysis because it’s not significant yet. There will be questions about crossover and post-progression treatment; 1% of the patients got access to CDK4/6 inhibitors after progressing. But, as I mentioned, given the negative results of the palbociclib and the discrepant results even in the adjuvant setting, and we have recently published a paper about this in Ecancer Journal, about CDK4/6 inhibitors in early breast cancer, we need to start asking these questions – are there any specific important differences between agents in the same class.
One quick note: when presenting these results of CDK4/6 inhibitors or other so-called targeted drugs, sometimes people highlight about the chemo-free interval period or the chemo-free survival. I think that’s a little bit misleading because, yes, technically it’s not a chemo but it does have important side effects. It does have important detrimental effects on quality of life; it does have important quality of life issues. We even published a paper about quality of life effect by drug class so just because a treatment is not cytotoxic chemotherapy does not necessarily mean it will improve quality of life. We’ll have to measure it specifically and show it. Therefore this chemo-free interval or chemo-free survival is meaningless when we are giving another toxic drug. If we are not giving any drug then that is meaningful to say this is a chemo-free interval or chemo-free survival but just you are not giving chemo but you are giving something else which also has side effects does not necessarily mean anything in terms of quality of life.
Then there was the trial of another CDK4/6 inhibitor called dalpiciclib. This is a Chinese CDK4/6 inhibitor. We have seen this now with several tumour types. In lung cancer we have several EGFR TKIs and a couple of checkpoint inhibitors developed from China; similarly now we have a CDK4/6 inhibitor developed from China. I think this is a very encouraging development that China is producing these molecules locally because we all expect these molecules to cost substantially less than what their counterpart molecules cost in the developed world. These molecules coming out of China could be the answer to access to newer medications for patients in the lesser developed regions of the world so I’m always encouraged to see these trials. So this was the trial, the DAWNA trial, of dalpiciclib plus fulvestrant in pre/peri menopausal patients and not surprising results – a substantial improvement in median PFS with a hazard ratio of 0.42.
Then there were the overall survival results from the TROPiCS-02 trial of antibody-drug conjugate sacituzumab in the ER positive/HER2 negative patients in almost last line of therapy. The improvement in PFS was not impressive, it was just 1.5 months improvement from 4 to 5.5 months but the improvement in overall survival remains significant statistically with a difference of 3.2 in the overall survival and a hazard ratio of 0.79. There will be some questions about the place for this drug after the results of the DESTINY-04, specifically for the HER2 low population, but it’s good to see positive overall survival results in breast cancer because this is a field where the field has [inaudible] rapidly changes based on PFS results alone and sometimes those results have been quite disappointing. So it was good to see some difference in overall survival here.
Then there were the results from the DATA trial and compared to if we combine the results from all similar trials, comparing the duration of hormonal therapy for patients with early hormone receptor positive breast cancer, the DATA trial results fit nicely into the results with other trials although there was a non-statistically significant difference in the DATA trial for six years versus three years of anastrozole after 2-3 years of Tamoxifen. As I always say, this will be an important shared decision making with the patient because the risk of relapse stays for quite a while, up to decades after the treatment of initial early breast cancer. So after the patient has been on a treatment for three years, whether or not to continue it for another three years, another six years, the total duration of treatment up until ten years, this will be an important shared decision making with the patient. For some patients they tolerate it very well and it’s like taking any other medications for chronic disease but for some patients it can be quite a burden in the quality of life so that has to be decided individually. But at least now we have data to say that and, in fact, we already had some of this data in the past to say that if you are tolerating it well and if you are at a high risk, if you have 5-6 node-positive cancer and you are tolerating this well, then probably you should just continue with this medication even beyond the initial five years.
A final note in breast cancer to the GIM trial, the Italian group trial, confirming that dose density is meaningful. Dose-dense chemotherapy improves disease free survival, overall survival. So this is just practice affirming, nothing is going to change, but this was also an important result to see.
That concludes my summary for the ovarian and the breast cancer trials. Thank you.