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Elena Castro: PARP inhibitors are a fantastic type of drug, but we need to know how to manage the side effects. These are my disclosures. The safety profile of PARP inhibitors in prostate cancer is very similar to that in other tumor types. So the most frequent side effects are hematologic side effects, particularly anemia. And anemia has been reported in more than a third—in some studies, almost a half—of patients treated with PARP inhibitors. Fatigue and gastrointestinal toxicities are also frequent side effects.

And in the trials I have investigated, PARPis in combination with ARPis, the safety profile has also been very similar and aligned with this. And it's important to remember that no differences in toxicity have been seen between patients with and without HRR alterations, or with germline versus somatic alterations.

Importantly, the majority of these side effects usually occur early in treatment. So these are data from the PROFOUND study, and you can see that these frequent side effects usually occur between the second and fourth month of treatment. And these are data from the TALAPRO-2 study, where you see that the hemoglobin decline is more frequent in the first three months. After, with the use of dose reduction and supportive therapy, patients usually recover and don't present this as often.

So there are some differences in the frequency of this event between the different studies. Anemia was an important and a frequent side effect in the different studies. Perhaps it was more frequently seen in the TALAPRO-2 study. In this study, neutropenia—grade 3 neutropenia—was also more frequently reported than in the other two. Hypertension was more frequently reported with the use of niraparib, and as our cardiologist colleague reported earlier, this has been seen in different studies and seems to be related to the disruption of the dopamine and norepinephrine metabolism.

Gastrointestinal toxicity seems to be more frequent with olaparib. And in PROpel, we also saw more venous thromboembolisms than in both MAGNITUDE and TALAPRO. And so far, only a very small number of patients with myelodysplastic syndrome or acute myeloid leukemia have been reported with these combinations. I'll come back to this later.

So how can we manage these side effects in the clinic? Let's start with the anemia. Anemia is the most frequent side effect, and it's been the cause of more treatment discontinuations and dose reductions. So if a patient presents to us with anemia when we are using a PARP inhibitor, we need to consider other potential causes of anemia. We need to exclude folic acid or vitamin B12 deficiency, et cetera.

But if we are convinced that this is related to the PARP inhibitor, if it's a grade 1 anemia, we don't need to do anything except for monitoring that patient. We don't need to stop the treatment. We don't need to reduce the dose. If it's a grade 2 anemia, a dose interruption may be advisable at least until the hemoglobin is above 9. Blood transfusion may only be needed if the patient is symptomatic. We keep monitoring the blood count of these patients, but no dose reduction will be required. If it happens again, then we may consider a dose reduction.

If the patient presents with a grade 3 or grade 4 anemia, then we need to stop treatment. A blood transfusion is advised. We may restart, but at a reduced dose. And here you can see the different dose reductions from the different compounds. And always monitor—keep monitoring the blood counts of our patients. And if it happens again, we may need to further reduce the dose of the PARP inhibitor.

If we are confronted with a patient that doesn't recover after a month of interrupting the PARP inhibitor or becomes transfusion dependent, we may need to consider stopping the treatment but also referring the patient to a hematologist. What about other hematological side effects—neutropenia, thrombocytopenia? If it's grade 1 or grade 2, we can continue treatment. We just monitor. But if it's grade 3 or grade 4, we stop until the cytopenia is recovered to grade 1.

We keep monitoring every week the blood counts, and we may consider supportive treatment. Platelet transfusion is only recommended if the platelets are very low. It also may depend on your own— you may have different protocols in your institutions—but usually, unless bleeding is present or the levels are very low, it is not recommended.

G-CSF primary prophylaxis is not needed. It's not recommended, but we may need to use it if our patients present with neutropenia, and we will restart the PARP inhibitor at a reduced dose. Should this happen again, we will act the same way and will further reduce the dose. And again, if neutropenia or thrombocytopenia persist and even after interrupting the treatment it goes on for more than a month, we may consider stopping the treatment and referring the patient to a hematologist.

For other side effects—non-hematological side effects—grade 1, we don't need to stop treatment. But we may need to consider supportive treatment for nausea, for vomiting, the same way we do for chemotherapy. Nausea is quite frequent and could be very disturbing when using a PARP inhibitor, and could compromise compliance. So perhaps we can advise our patients to take a light meal with an antiemetic one hour before taking the PARP inhibitor.

And we should avoid aprepitant when using olaparib because it's a cytochrome inhibitor and can modify the olaparib plasma levels. For fatigue, diarrhea, constipation is the usual advice. The only comment, perhaps, is about renal toxicity, that an increase in creatinine may not reflect a true decline in the glomerular filtration rate. It could be an artifact, particularly with rucaparib.

If our patient presents with grade 2 toxicity, we, of course, implement supportive treatment. We may stop the PARP inhibitor until the patient recovers. And if it's grade 3 or grade 4, after recovery, we may need to reduce the dose or to stop it permanently. Depends on the severity of the side effects.

And I've been asked to discuss briefly the risk or the potential risk of myelodysplastic syndrome and acute myeloid leukemia, because these have been reported to be late toxicities from PARP inhibitors across different tumor types.

So just to remind you, myelodysplastic syndrome is a clonal hematopoietic neoplasm that is characterized by cytopenias and morphological dysplasias with the propensity to progress to bone marrow failure, and in some cases to acute leukemia. Acute myeloid leukemia, you know, is a clonal expansion of immature blood cells, both in the peripheral blood and the bone marrow, that results in ineffective erythropoiesis in the bone marrow, so it will present also with cytopenias.

Risk factors for both are an age over 60, as most of our patients are; genetic predisposition; chemotherapy; or exposure to different environmental compounds. When should we suspect it? If we are confronted with a patient with grade 3 or 4 neutropenia, or thrombocytopenia that persists after interrupting treatment for more than one month, or they present these recurrent cytopenias even when we have been reducing the PARP inhibitor doses, or in patients that become transfusion dependent because they have anemia. In those cases, we should refer patients to the hematologist.

I will very briefly—and I know the bell will sound for me—but allow me to discuss this study very briefly. Professor de Bono referred to it earlier. It is a meta-analysis of the 18 randomized clinical trials that were published until 2020, and the incidence of myelodysplastic syndrome or leukemia in these studies was less than 1%. The risk of developing these side effects was 2.63.

A closer look at these studies, and we will see that it includes a variety of different tumor types and only one prostate cancer study that had been published at the time. The median age of the patients included is significantly lower than the median age of our prostate cancer patients. Importantly, the studies that reported a case of myelodysplastic syndrome or leukemia were those in which patients were treated for more than 200 days, or the follow-up went on for more than two years. In all the other studies, no cases were seen.

In this study, the investigators also consulted the WHO database with the data available in 2020, and they identified 178 cases of myelodysplastic syndrome or leukemia. The median age at diagnosis was 64 years. The median treatment duration was around 10 months. The latency from starting a PARP inhibitor to the development of these side effects was 18 months for myelodysplastic syndrome, 20 months for acute leukemia, and 8% of the leukemias were related with myelodysplastic syndrome.

If we compare this with the latency periods for other chemotherapies, it is significantly shorter for PARP inhibitors. It’s over five years for platinum-based chemotherapy and for alkylating-based chemotherapy. This is my last slide. I don't have access to the WHO database, but I consulted the FDA database—with all the limitations of this analysis—but at the end of 2023, almost 900 MDS or leukemias have been reported in theory related to PARP inhibitors, 23 of them in prostate cancer.

So my conclusion is that for patients with BRCA or HRR alterations, PARP inhibitors’ benefit outweighs the risk associated with these side effects. Most toxicities are acute; we can manage them safely. We need to monitor these patients regularly. We need to take into consideration the risk of late side effects, which are infrequent but perhaps underestimated. And we need to suspect this in case of persistent or recurrent cytopenias.