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

Monitoring on ICI/anti VEGF therapy

ICI VEGF combo- HCC, RCC, uterine ca MSI proficient

Lenvatinib induced HTN and ICI induced colitis were both markers of good outcomes.

1.  For diarrhea, prophylaxis includes patients keeping a stool diary to share with HCPs and altering their diet to one less likely to upset their digestion. Antidiarrheal agents can be offered as supportive care, as can hydration and moisture-barrier ointment.

2. Prophylaxis for fatigue includes establishing the patient’s fatigue history, encouraging healthy diet and fluid intake, and activity. Supportive care for fatigue includes referrals to a nutritionist and physical therapist, as well as psychosocial interventions.  If you have someone with grade ≥3 fatigue, you really should be thinking more about the ICI and the possibility of immune-mediated adrenal disorders or even myositis.

3. Stomatitis is an AE associated with cabozantinib. Regular dental examinations are recommended for patients, as is careful oral hygiene with frequent brushing and use of mouthwash. Supportive care includes sodium bicarbonate–containing oral rinses, swishing ice chips, and gum or candy to stimulate saliva production.

4. Avoiding hot water, friction, and pressure on the hands and feet may help patients avoid palmar–plantar erythrodysesthesia. If it develops, creams containing urea, salicylic acid, or ammonium lactate may be helpful. There are also topical numbing agents to help relieve symptoms, and oral analgesics can be considered if topical therapy is ineffective.

5.Evaluate blood pressure before starting treatment to check for preexisting hypertension. During treatment, patients should frequently monitor their blood pressure. Supportive care for hypertension includes antihypertensive agents and the avoidance of CYP3A4 inhibitors.

6. Monitor for proteinuria with lenvatinib

7. Monitor thyroid function routinely with all ICI. For grade 2 fatigue rule out pituitary and or thyroid dysfunction

8. Drop in EF could be due to VEGF TKI but also consider myocarditis due to ICI

9.AST ALT elevations with nivo cabozantinib. Grade 3  hepatitis, needs steroids. If steroid refractory--> MMF. Do NOT use infliximab or vedolizumab

Bladder and urothelial cancer

Spectrum of disease encountered by medical oncologist

1.  Non muscle invasive bladder cancer

2. Muscle invasive non metastatic

3. Locally advanced or Metastatic bladder cancer

Why is high grade T1 disease concerning?

Within 5 yrs, 9% could die of bladder cancer, 19% has progressed to MIBC and 51 % has recurred.

Restaging is the standard of care since upto 30% are underdiagnosed at the initial cystoscopy.

What are the 5 yr survival data?

NMIBC- 88%

MIBC- 50-60%

Locally advanced 40%

Stage 4-15%

Cystectomy is the best option for histologically variant T1 bladder ca ( squamous, sarcomatoid, NEC):  radical cystectomy compared to bladder preservation treatments (TURBT, intravesical therapies, radiation) for NMIBC with sarcomatoid, squamous, glandular, and neuroendocrine variants (Dursun et al., PMID 35351370). However, radical cystectomy was not associated with survival benefit compared to bladder preservation for NMIBC with micropapillary variant

Perioperative therapy MIBC

1. Upper tract urothelial ca: POUT trial- Gemcitabine–platinum combination chemotherapy initiated within 90 days after nephroureterectomy significantly improved disease-free survival in patients with locally advanced UTUC. Adjuvant platinum-based chemotherapy should be considered a new standard of care after nephroureterectomy for this patient population. ( T2 or higher, any N+) Lancet March 2020

2. Neoadjuvant GC for upper tract: path CR 14% phase II Wesley Yip ASCO GU 22

2 yr PFS and OS 78 and 93%. 5 yr OS was 79%

Those who attained path CR PFS 91% and OS 100% in 2 yr

Adjuvant nivolumab Checkmate 274 improves DFS to 20 months instead of 10 months in PDL1 > 1%

Neoadjuvant cisplatin based chemo in bladder ca: meta-analysis shows 5 yr OS and DFS benefit of 5% and 9% resepectively without compromising QOL.

median OS 77 months versus 46 months for MVAC versus placebo.

If giving NAC in bladder ca, how soon should you start? Less than 8 weeks to prevent upstaging

Choice of chemo for NAC: ddMVAC with better PFS and path CR rates compared to GC ( vesper trial). However a full 6 cycles was used in this trial rather than 3-4 cycles as before.

Metastatic bladder cancer

Predictors of worse outcome in MBC: non nodal mets and ECOG 2 or higher

Gemcitabine carboplatin or cisplatin first line followed by avelumab maintenance: Median OS 11 months ( same as gem cisplatin when compared head to head) without maintenance avelumab

With avelumab: Overall survival at 1 year was 71.3% in the avelumab group and 58.4% in the control group (median overall survival, 21.4 months vs. 14.3 months; hazard ratio for death, 0.69;

Pembro first line in platinum ineligible: Pembrolizumab, nivolumab, and avelumab are approved for the treatment of locally advanced or metastatic urothelial cell carcinoma that has progressed during or after platinum-based chemotherapy or that has progressed within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy, regardless of PD-L1 expression levels

Enfortumab pembrolizumab:KEYNOTE-869

 confirmed ORR in 121 patients was 68% (95% CI: 59, 76), including 12% with complete responses. The median DoR for the dose escalation cohort + Cohort A was 22 months (range: 1+ to 46+) and for Cohort K was not reached (range: 1 to 24+)

How to counsel patients about side effects of enfortumab?

The most common adverse reactions (>20%), including laboratory abnormalities, were increased glucose, increased aspartate aminotransferase, rash, decreased hemoglobin, increased creatinine, peripheral neuropathy, decreased lymphocytes, fatigue, increased alanine aminotransferase, decreased sodium, increased lipase, decreased albumin, alopecia, decreased phosphate, decreased weight, diarrhea, pruritus, decreased appetite, nausea, dysgeusia, decreased potassium, decreased neutrophils, urinary tract infection, constipation, potassium increased, calcium increased, peripheral edema, dry eye, dizziness, arthralgia, and dry skin

TDxd side effect management

 

Nausea

Moderately emetogenic. 5HT3 antagonist and dex front line, can add NK1 antagonist. Lorazepam for anticipatory nausea, olanzapine bedtime day 1-4

Hematological AE

1. Thrombocytopenia: if grade 3 or 4( less than 25K) wait until plt now 75  K or higher ( grade 1). If grade 4, reduce dose 1 level

2. Neutropenia: case by case use of growth factor. If grade 4 ( ANC < 500), dose reduce by 1 level. If grade 3, interrupt. Wait until ANC > 1000 ( grade 2)

Interstitial lung disease: ask at every visit for new or worsening resp symptoms. Can check PFT baseline and q 3 months or so, but unproven to detect grade 1. Walk test also useful but not perhaps for grade 1. Grade 1 is the only grade where you can interrupt and restart. Grade 2 : permanently discontinue, start steroids and antibiotics. Consider pulm consultation.

Cardiac dysfunction: not common, but assess baseline echo EF with strain. Repeat every 3-6 months depending on patients symptoms. If EF drops below 40% or > 20% from baseline, discontinue permanently.