Unique toxicities of PARP Inhibitors

  The class toxicities for PARPis include 

• fatigue and nausea, which are very common but usually low grade. 
• GI toxicity, such as diarrhea, constipation, or dysgeusia. 
• headaches. 
• Anemia is the most common of the hematologic AEs across PARPis, and approximately 20% to 25% of patients will have grade ≥3 anemia.

There are some differences and even unique toxicities among the PARPis. Niraparib is unique in that its metabolites exert dopaminergic and serotonergic effects leading to hypertension, palpitations, and insomnia. Hypertension is reported in 10% to 15% of patients. Although insomnia has been reported only with niraparib, we do see insomnia with all the PARPis, although it is more common with niraparib. Niraparib has a higher risk of thrombocytopenia than other PARPis.

Elevated liver enzymes are most common with rucaparib but can occur infrequently with niraparib. Elevated cholesterol is also unique to rucaparib. Elevated creatinine is, again, most common with rucaparib, although it can occur with olaparib. Regarding liver enzyme elevations with rucaparib, those occur in cycle 1. These ALT/AST elevations with rucaparib are simply a cycle 1 event and do not recur.

Regarding rash, a photosensitive rash can occur with rucaparib more often than with niraparib or olaparib. It can be bothersome and sometimes hard to differentiate from rashes caused by the ICI, because rashes related to PARPis do occur within the same timeframe as those related to ICIs. The median onset for rash is approximately 5-6 weeks with anti–PD-1/PD-L1 ICIs.

How to counsel patients as they start a PARP is and when to start it after chemo ( after 6-9 weeks)

When a patient is planned to start on a PARPi after first-line chemotherapy, you would ideally give them 6-9 weeks to recover from the chemotherapy before actually starting the PARPi. Avoid starting at cycle 7— approximately 3 weeks after their last chemotherapy—because the patient will still not feel good.

It is really important to set expectations about starting PARPi therapy. We counsel our patients that they are not going to feel well for the first 6 weeks of receiving a PARPi. In particular, the nausea starts within 3 days, peaks approximately 2 weeks in, and then starts to come down by 6 weeks. Patients usually have stabilized with a very low–grade nausea; they feel it, but they are able to eat and do their normal things.

Always send patients home with antiemetics.  use olanzapine because this drug does not cause constipation or interact with CYP3A4, like 5-HT3 inhibitors. start patients with olanzapine, and then wean them off the antiemetics as we get into cycles 2-3. Some HCPs prefer to send patients home with a prescription so they have a rescue.

In addition to setting expectations around nausea,  educate patients that when they start the PARPi, they should expect to be tired, things may taste funny, there is the potential for constipation or diarrhea, etc. Emphasize that their quality of life should start to get better after 6 weeks.

Reference: https://clinicaloptions.com/activity/ecase/2C94D1E2-2E46-4453-982C-7ADF3E0675C2/4