Prática de Shadowing: PARP Inhibitors: 2023 Updates - Aprenda a falar inglês com vídeo
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Thank you for joining us for this session on PARP inhibitors.
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PARP inhibitors have been one of the most exciting advancements in the treatment of ovarian cancer in years,
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but recently have come under increasing scrutiny from the Food and Drug Administration.
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Dr. Ginny Fleming from the University of Chicago will update us on the latest.
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Dr. Fleming is Professor of Medicine and Director of the Medical Gynecologic Oncology program at the University of Chicago,
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and we're thrilled to have her join us for this session.
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Hello, it's a pleasure to be here with you to discuss
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some of the changing indications for PARP inhibitors in the treatment of ovarian cancer.
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Here are the topics I'm going to try to cover.
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First, what is HRD?
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Second, in brief, how do PARP inhibitors work?
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Third, which ones are currently FDA -approved and for what ovarian cancer indications?
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And finally, what has been a whirlwind of changes,
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what are the recent changes in the FDA -approved settings for PARP inhibitor use for women with ovarian cancer?
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And what has motivated these changes.
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First, homologous DNA repair, sometimes abbreviated HR for homologous repair.
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DNA is what carries the messages for all the proteins and enzymes in our body.
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It's the mat for everything.
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DNA is usually wound together in double strands, and there can occur from many various reasons,
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ultraviolet light, many other things, breaks in the DNA.
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And these are primarily repaired by what we call the homologous recombination repair pathway, the HR repair pathway.
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The BRCA gene is involved in homologous repair.
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A mutated BRCA gene does not do its job, So cells with BRCA deficiency lack HR repair,
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and they're referred to as HR deficient or HRD.
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Ovarian cancers may also harbor many other alterations which lead to deficiency in the HR pathway,
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and these tumors are also referred to as HRD.
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About half of ovarian cancers are HRD, including those with germline or tumor BRCA alterations.
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Homologous recombination deficiency leads to increased sensitivity of cancers to both platinum therapy and PARP inhibitor therapy.
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Tests for HRD are generally done on the tumor, and there's a variety of approved companies that do these tests
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and you are probably familiar with their use as physicians consider whether
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or not PARP inhibitor maintenance should be used in a particular situation.
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So PARP inhibitors, as you can see here, are also involved in the repair of DNA breaks.
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That's a double -strand DNA diagram there and the PARP inhibitors help repair a single -strand break.
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Single -strand breaks occur all the time, and PARP helps detect and repair them.
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However, during the replication process, they convert single -strand breaks into double -strand breaks.
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Normal cells then repair these by homologous recombination, but cells that are HRD do not have an effective repair pathway, and this leads to cell death.
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So these are the cells, the HR -deficient cells, that are particularly sensitive to PARP inhibitors.
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PARP inhibitors can clearly shrink ovarian cancer.
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What is not so clear is in what situations they are better than other options
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when they are used in trials of treatment.
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The very first, I'm going to give some examples here of use in what we're calling treatment,
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which is when it's used in the setting of measurable disease, usually not just as maintenance after chemotherapy.
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So Rocaprib, one of the three PARP inhibitors approved for ovarian cancer,
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was initially approved based on two actually quite small studies for
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the total of 106 patients with high -grade ovarian cancer whose disease had progressed after two or more prior therapies.
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All the women in this study had either a germline mutation or their tumor had a somatic mutation.
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So a germline mutation is when the mutation is inherited and can be passed on to your children.
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And it's found in all the cells of your body, blood cells, cells from a cheap swab.
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But ovarian cancers can also have what we call somatic mutations.
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And those are mutations that are only in the tumor and not passed on from, you know, parent to child.
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Either one of these confers sensitivity to platinum or PARP inhibitor therapy.
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The primary endpoint of the study, meaning how was the study designed, what was it designed to find, was response rates or rate of tumor shrinkage.
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And in these two studies, the rate of tumor shrinkage was over 50%,
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and these shrinkages lasted for a median or an average of 9 .2 months.
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So that's if it shrank, how long did it stay shrink?
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similarly another one of the PARP inhibitors used for ovarian cancer
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olaparib was in an early study tested again in women all of whom had a germline BRCA1
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or 2 mutation and who had more than three lines of prior chemotherapy
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and was found to have a response rate of 34 percent where these responses lasted an average of eight months.
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However, notice below
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that you can see on this table divides the tumors treated
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on this admittedly small group of patients into tumors in the situation that were expected to be platinum sensitive,
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generally more than six months from prior platinum therapy and shrank with the prior platinum therapy, platinum resistant, so recurrence less than six months,
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and platinum refractory progressed on platinum.
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And you can see that the rate of tumor shrinkage was clearly highest in tumors that were platinum -sensitive,
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and only two patients responded who had platinum refractory disease.
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So clearly there is, as we say, non -cross -resistance between platinum and a PARP inhibitor.
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Tumors that are resistant to platinum are much more likely to be resistant to PARP inhibitors as well.
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And this will become important when we discuss why there have been some changes in indications for PARP inhibitors.
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That is to say, they are no longer indicated.
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The FDA no longer approves them for use as so -called treatment.
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All the current approvals are only as maintenance.
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So one very early trial, again, many years ago, one of the first PARP inhibitor trials, they compared PARP to liposomal doxorubicin in women,
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all of whom had a germline BRCA mutation and had recurrence within 12 months of prior platinum therapy.
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These women were only about 100 in total,
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and they were randomized to one of two different doses of Olaprib versus liposomal doxorubicin,
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and patients were permitted to cross over at the time of progression.
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So a woman who was on doxyl could cross over at the time of progression to a PARP inhibitor and vice versa.
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And here you see the schema of the trial, low -dose olaparib, higher -dose olaparib, and liposomal doxorubicin.
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And here are the response rates and the progression -free survival.
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So the progression -free survival was slightly higher in the high -dose olaparib than it was in liposomal doxorubicin,
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but these results, all of them, were no different than what was expected to be with chance.
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So here was an early trial that began to raise questions about, although PARP inhibitors clearly have activity, are they better than something else?
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And a lot of the trials
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that were used to try to gain FDA approval were trying to show
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that PARP inhibitors were better than something else in some way.
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So again, the terminology I'm using, when I say we're using it as treatment,
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it's used to treat a cancer that would generally have progressed or recurred after some other therapy, although you could use it for first -line treatment.
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But none of the PARP inhibitors are approved as first -line treatment.
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Whereas maintenance, the drug is used to treat a cancer after chemotherapy has already decreased the size of the tumor
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or made it disappear entirely.
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And the idea is to maintain that response, hence maintenance therapy. So back in 2014,
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Olaparib was approved by the FDA for use as treatment in patients who had BRCA -mutated ovarian cancer
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and at least three or more rounds of prior treatment.
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However, and by 2018, Rucaparib and Naraparib were also approved, and in 2022, the FDA began issuing withdrawals.
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Currently, there are no more treatment approvals.
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The approvals are for olaparib for maintenance,
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niraparib as maintenance, and rucaparib as maintenance.
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And the exact indications, whether for BRCA or for any platinum -sensitive disease, have varied by drug.
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probably more due to details of trial design than because the different PARP inhibitors are so different.
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However, we are expecting a withdrawal, the first withdrawal of maintenance of Rucaparib,
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or may have already happened for platinum -sensitive disease.
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What has been withdrawn, which indications are no longer FDA approved?
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All the treatment indications.
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So all the uses of PARP inhibitors other than as maintenance have been withdrawn by the companies in response to FDA communications.
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And niraparib has been withdrawn for maintenance in platinum -sensitive recurrent disease for women and tumors that don't have BRCA mutations. So what happened?
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Why would they approve all these things and then change it?
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In general, of PARP inhibitors were initially approved based on information regarding progression -free survival,
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how long the treatment could continue before the cancer grows, or response rate,
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where response rate is generally in trials defined as percentage of subjects whose tumors shrink by 30 % or more.
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But later data began suggesting that overall survival was not as positively affected as progression -free survival.
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And in some trials, it appeared that the subjects getting PARP inhibitor therapy might even have decreased survival compared to controls.
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In many, it wasn't statistically significant, but it was alarming.
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There are a lot of arguments, as you can imagine, that have been flying about the validity of these different endpoints
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that are used to try to justify FDA approval.
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Again, the withdrawals are based on new overall survival information, which as you can imagine takes a lot longer to come by than tumor shrinkage.
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Tumor shrinkage is the first thing that you get out of a clinical trial.
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The time till the cancer grows takes longer and overall survival takes longer yet.
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So it's years before we have an adequate data set to really assess overall survival.
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Many of the trials were designed for progression -free survival, not overall survival.
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So their size and design may not have been adequate for an accurate assessment of overall survival.
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Crossover, as we discussed, is people who were, for example, randomized to placebo,
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but then after progression, maybe broke the blind and then took a PARP inhibitor.
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That's referred to as crossover.
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And that might affect overall survival.
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However, the hypothesis of people who are concerned about the decreased overall survival
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that is numerically shown in some studies is since tumors that are resistant to PARP inhibitors are more resistant to platinum,
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then taking PARP inhibitors may make subsequent treatment work less well.
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As we showed, people with tumors who's resistant to carboplatin will not have as good a response to PARP inhibitors.
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The converse is also true.
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And again, to review the terminology, progression -free survival in a clinical trial is the time from
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when drug therapy is started until the tumor grows or death of disease, if that happens first.
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Overall survival, obviously, is the time from when drug therapy is started on the study until death of the patient from any cause.
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I'm going to review for you one representative example.
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There are too many to go over, but what a specific example of concern that is caused for a withdrawal of indication.
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And I think that you'll find that if you look at all of them in detail, it's similar.
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So the representative example I'm going to use is the trial is called the NOVA trial.
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It was for niraparib, and it's in the setting of recurrent platinum -sensitive maintenance.
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So this is the design of the NOVA trial.
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Women who were on the trial had platinum -sensitive ovarian cancer.
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with at least two prior platinum treatments.
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So typically, they got platinum, maybe the cancer came back a year or two later, they got platinum again, and the tumor shrank.
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And then at that point, they were randomized to either noreparib or to placebo.
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So this was planned to be almost 500 patients participating,
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and all of them had to have high -grade serous tumors.
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And they had to be in complete or partial response to their most recent platinum therapy.
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And then they were randomized to one of these two regimens, placebo or noreparib, to try to maintain that response, hence the term maintenance therapy.
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So initial publication was in the New England Journal in 2016.
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And you can see that if we look at the group of women who had noreparib maintenance compared to those with placebo.
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they did better in all categories.
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Those that got the most benefit were those that had a germline BRCA mutation.
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And here you can see the time to progression was hugely improved, 21 months versus five months.
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In women who are not germline BRCA mutated, the progression was also improved, although it was shorter overall, nine months versus about four months,
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and so on and so forth for each of the subgroups.
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Again, benefits seen in all subgroups and most dramatic for the germline BRCA mutated.
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But when the later results then more recently came out, presented at 2023, again, overall survival takes years until we have the results,
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you can see that there was not any real difference, even in the patients with the germline BRCA mutation,
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that is 40 months, That's 40 .9 versus 38 .1, which, you know, is a little bit better.
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But when these confidence intervals, that's what we call the numbers in the brackets here, 0 .61 to 1 .2.
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When one is included in that, it's generally considered that it could have happened by chance.
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And then numerically, in the patients who did not have a germline BRC mutation,
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there was numerically worse survival in those who got niraparib, 31 months versus almost 35 in placebo.
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Again, you can see that one is included in the confidence interval.
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So none of these differences here are statistically significant.
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They're all could be the same, and the differences seen between the two groups could be chance.
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But again, there was concern that no survival benefit was seen.
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And even if patients did cross over and take olaparib subsequently, it's hard to understand how that would make them have a shorter survival.
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So the indication, again, for niraparib in the non -germline BRCA mutation was withdrawn as maintenance in the second -line setting.
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Now, in the frontline setting, we don't have overall survival in most of the trials yet.
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The one we do have is the SOLO1 frontline maintenance BRCA mutation carriers.
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And here, there still seems to be an overall survival benefit,
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although for technical reasons, it wasn't quite statistically significant in frontline.
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And I think at this point, the frontline indications are still in place.
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And this is probably where patients are going to get the most benefit.
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And there's also appears to be the lowest risk of secondary myelodysplastic syndrome or leukemia, which is a concern.
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So in conclusion, newer long -term trial results with overall survival continue to gradually come available.
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There is clear benefit for BRCA mutation cares when PARP inhibitors are used in frontline maintenance, and I think focusing on frontline use,
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where the benefit at this point still appears to be very strong is important.
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Thank you.
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Vocabulário e dicas de fala para esta lição
Esta aula de conversação usa o vídeo “PARP Inhibitors: 2023 Updates”. As palavras que mais se repetem: Parp, inhibitor, platinum, survival, tumor. Este vídeo tem 179 frases e 2557 palavras para praticar shadowing. A fala dura 18:18. O falante mantém um ritmo estável de cerca de 140 palavras por minuto, confortável para o shadowing. Apenas 78% das palavras estão entre as 3.000 mais comuns do inglês, por isso o vocabulário é exigente.
Vocabulário principal deste vídeo
15 palavras do vídeo que vale a pena aprender, com pronúncia e significado:
| Palavra | Pronúncia | Significado |
|---|---|---|
| survival substantivo | /sɚˈvaɪ.vəl/ | sobrevivência |
| platinum substantivo | /ˈplæt.ɪn.əm/ | platina |
| tumor substantivo | /tuː.məɹ/ | tumor |
| mutation substantivo | /mjuˈteɪʃən/ | mutação |
| repair verbo | /ˈɹiːpɛɚ/ | reparar |
| approve verbo | /əˈpɹuːv/ | aprovar, sancionar |
| progression substantivo | /pɹəˈɡɹɛʃən/ | progressão |
| indication substantivo | /ɪndɪˈkeɪʃən/ | símbolo |
| sensitive adjetivo | /ˈsɛn.sɪt.ɪv/ | sensitivo |
| resistant adjetivo | /ɹəˈzɪstənt/ | resistente |
| strand substantivo | /ˈstɹænd/ | cordel |
| versus | /ˈvɝsəs/ | contra, vérsus |
| withdrawal substantivo | /wɪðˈdɹɔ(ə)l/ | saque |
| dose substantivo | /ˈdəʊ̯s/ | dose |
| withdraw verbo | /wɪðˈdɹɔ/ | retirar |
Phrasal verbs que você vai ouvir
| Palavra | Pronúncia | Significado |
|---|---|---|
| come back verbo | voltar | |
| come out verbo | /ˌkʌm ˈaʊt/ | sair, partir |
Gramática neste vídeo
As estruturas que o falante mais usa, com as palavras exatas do vídeo:
| Estrutura | No vídeo |
|---|---|
| Present perfect have/has + particípio passado — uma ação passada que ainda importa agora | have been · have come · has been |
| Voz passiva be + particípio passado — o foco está no que acontece, não em quem faz | is usually wound · are primarily repaired · is involved |
| Orações relativas who / which + oração — informação extra sobre uma pessoa ou coisa | woman who was · people who were · people who are |
Pronúncia para ficar de olho
O falante usa 15 contrações e formas reduzidas, como I'm, we're, don't. Diga-as na forma curta, do jeito que você ouve.
- Os sons de “th”: withdrawal /wɪðˈdɹɔ(ə)l/, withdraw /wɪðˈdɹɔ/, pathway /ˈpæθˌweɪ/, chemotherapy /ˌkiːməʊˈθɛɹəpi/, hypothesis /haɪˈpɒθɪsɪs/
- Os sons de “sh” e “zh”: mutation /mjuˈteɪʃən/, progression /pɹəˈɡɹɛʃən/, indication /ɪndɪˈkeɪʃən/, deficiency /dɪˈfɪʃənsi/, publication /ˌpʌblɪˈkeɪʃ(ə)n/
- Palavras longas — acerte a sílaba tônica: indication /ɪndɪˈkeɪʃən/, statistically /stəˈtɪs.tɪ.kə.li/, deficiency /dɪˈfɪʃənsi/, chemotherapy /ˌkiːməʊˈθɛɹəpi/, sensitivity /ˌsɛn.səˈtɪv.ə.ti/
Sons difíceis para falantes de português:
- Consoante final — sem acrescentar um “i” depois: resistant /ɹəˈzɪstənt/, strand /ˈstɹænd/, adequate /ˈæd.ə.kwɪt/, topic /ˈtɑpɪk/, assessment /əˈsɛsmənt/
- /l/ final — a língua toca o céu da boca, não vira “u”: survival /sɚˈvaɪ.vəl/, withdrawal /wɪðˈdɹɔ(ə)l/, interval /ˈɪntɚvəl/, partial /ˈpɑɹʃəl/, thrill /θɹɪl/
- /h/ — um sopro suave, diferente do “r”: hence /ˈhɛns/, whereas /(h)wɛɹˈæz/, harbor /ˈhɑːbə/, hypothesis /haɪˈpɒθɪsɪs/, hugely /ˈhjuːd͡ʒli/
Como praticar com este vídeo
- Ouça o vídeo inteiro uma vez sem falar e anote as palavras que você não conhece.
- Faça shadowing frase por frase na velocidade normal, repetindo cada uma até o seu ritmo ficar igual ao do falante.
- Grave a sua voz e compare com o original, prestando atenção a palavras como survival, platinum, tumor.
O que é a Técnica de Shadowing?
Shadowing é uma técnica de aprendizado de idiomas com base científica, originalmente desenvolvida para o treinamento de intérpretes profissionais. O método é simples, mas poderoso: você ouve áudio em inglês nativo e repete imediatamente em voz alta — como uma sombra seguindo o falante com 1-2 segundos de atraso. Pesquisas mostram melhora significativa na precisão da pronúncia, entonação, ritmo, sons conectados, compreensão auditiva e fluência na fala.