Shadowing Practice: PARP Inhibitors: 2023 Updates - Learn English Speaking with Video
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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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אוצר מילים והערות הגייה לשיעור הזה
שיעור הדיבור הזה מבוסס על הסרטון “PARP Inhibitors: 2023 Updates”. המילים שחוזרות הכי הרבה: Parp, inhibitor, platinum, survival, tumor. בסרטון הזה יש 179 משפטים ו-2557 מילים לתרגול Shadowing. הדיבור נמשך 18:18. הדובר שומר על קצב יציב של כ-140 מילים בדקה, קצב נוח לתרגול Shadowing. רק 78% מהמילים נמצאות בין 3,000 המילים הנפוצות ביותר באנגלית, כך שאוצר המילים מאתגר.
אוצר מילים מרכזי בסרטון הזה
15 מילים מהסרטון שכדאי ללמוד, עם ההגייה והמשמעות שלהן:
| מילה | הגייה | משמעות |
|---|---|---|
| platinum שם עצם | /ˈplæt.ɪn.əm/ | פלטינה |
| mutation שם עצם | /mjuˈteɪʃən/ | מוּטַצְיָה |
| approve פועל | /əˈpɹuːv/ | אִשֵּׁר |
| indication שם עצם | /ɪndɪˈkeɪʃən/ | סימן, עות |
| sensitive שם תואר | /ˈsɛn.sɪt.ɪv/ | רגיש |
| strand שם עצם | /ˈstɹænd/ | גְּדִיל |
| versus | /ˈvɝsəs/ | נֶגֶד |
| withdrawal שם עצם | /wɪðˈdɹɔ(ə)l/ | מְשִׁיכָה |
| dose שם עצם | /ˈdəʊ̯s/ | מָנָה |
| decrease פועל | /dɪˈkɹiːs/ | פחת |
| hence תואר הפועל | /ˈhɛns/ | מכאן |
| gene שם עצם | /d͡ʒiːn/ | גֶּן |
| terminology שם עצם | /ˌtɝ.məˈnɑ.lə.d͡ʒi/ | טֶרְמִינוֹלוֹגְיָה |
| topic שם עצם | /ˈtɑpɪk/ | נוֹשֵׂא |
| assessment שם עצם | /əˈsɛsmənt/ | אֻמְדָּן |
Phrasal verbs שתשמעו
| מילה | הגייה | משמעות |
|---|---|---|
| come back פועל | שָׁב | |
| come out פועל | /ˌkʌm ˈaʊt/ | יָצָא |
דקדוק בסרטון הזה
המבנים שהדובר משתמש בהם הכי הרבה, עם המילים המדויקות מהסרטון:
| מבנה | בסרטון |
|---|---|
| הווה מושלם (Present perfect) have/has + past participle — פעולה שקרתה בעבר ועדיין יש לה חשיבות או השפעה עכשיו | have been · have come · has been |
| סביל (Passive voice) be + past participle — הדגש הוא על מה שקורה, לא על מי שעושה את הפעולה | is usually wound · are primarily repaired · is involved |
| משפטי זיקה (Relative clauses) who / which + clause — מידע נוסף על אדם או דבר | woman who was · people who were · people who are |
הגייה ששווה לשים לב אליה
הדובר משתמש ב-15 קיצורים וצורות מקוצרות, כמו I'm, we're, don't. אמרו אותם בצורה הקצרה, כפי שאתם שומעים אותם.
- הצלילים של “th”: withdrawal /wɪðˈdɹɔ(ə)l/, withdraw /wɪðˈdɹɔ/, pathway /ˈpæθˌweɪ/, chemotherapy /ˌkiːməʊˈθɛɹəpi/, hypothesis /haɪˈpɒθɪsɪs/
- הצלילים של “sh” ו-“zh”: mutation /mjuˈteɪʃən/, progression /pɹəˈɡɹɛʃən/, indication /ɪndɪˈkeɪʃən/, deficiency /dɪˈfɪʃənsi/, publication /ˌpʌblɪˈkeɪʃ(ə)n/
- מילים ארוכות — שימו לב להטעמה: indication /ɪndɪˈkeɪʃən/, statistically /stəˈtɪs.tɪ.kə.li/, deficiency /dɪˈfɪʃənsi/, chemotherapy /ˌkiːməʊˈθɛɹəpi/, sensitivity /ˌsɛn.səˈtɪv.ə.ti/
צלילים שדוברי עברית מתקשים בהם:
- /w/ — שפתיים מעוגלות, לא /v/: withdrawal /wɪðˈdɹɔ(ə)l/, withdraw /wɪðˈdɹɔ/, pathway /ˈpæθˌweɪ/, adequate /ˈæd.ə.kwɪt/, whereas /(h)wɛɹˈæz/
- /æ/ — פתוח יותר מה-“אֶ” העברית, לא כמו “a” ב-“cup”: platinum /ˈplæt.ɪn.əm/, strand /ˈstɹænd/, pathway /ˈpæθˌweɪ/, adequate /ˈæd.ə.kwɪt/, dramatic /dɹəˈmætɪk/
- /r/ — הלשון לא נוגעת בשום מקום, לא ה-“ר” הגרונית: tumor /tuː.məɹ/, repair /ˈɹiːpɛɚ/, approve /əˈpɹuːv/, progression /pɹəˈɡɹɛʃən/, resistant /ɹəˈzɪstənt/
איך לתרגל עם הסרטון הזה
- הקשיבו לכל הסרטון פעם אחת בלי לדבר, ורשמו את המילים שאתם לא מכירים.
- תרגלו Shadowing משפט אחר משפט במהירות רגילה, וחזרו על כל משפט עד שהקצב שלכם תואם את הדובר.
- הקליטו את עצמכם והשוו למקור, תוך תשומת לב למילים כמו platinum, mutation, approve.
מהי טכניקת השאדואינג?
שאדואינג היא טכניקת למידת שפה מבוססת מדע שפותחה במקור להכשרת מתורגמנים מקצועיים ופופולרית על ידי הפוליגלוט ד"ר אלכסנדר ארגואלס. השיטה פשוטה אך עוצמתית: אתה מקשיב לאודיו באנגלית ילידית וחוזר עליו בקול רם מיד — כמו צל העוקב אחרי הדובר עם עיכוב של 1–2 שניות בלבד. בניגוד להאזנה פסיבית או תרגילי דקדוק, שאדואינג מכריח את המוח והשרירים בפה לעבד ולשחזר דפוסי דיבור אמיתיים בו זמנית. מחקרים מראים שזה משפר משמעותית את דיוק ההגייה, האינטונציה, הקצב, הדיבור המחובר, הבנת השמיעה ושטף הדיבור — מה שהופך אותו לאחת השיטות היעילות ביותר להכנה לIELTS Speaking ולתקשורת באנגלית בעולם האמיתי.