PARPi

Question 1

Summarize the trial design and findings of the SOLO1 trial.

Answer 1

Phase 3 multicenter RCT to evaluate efficacy of olaparib as maintenance therapy in patients with newly diagnosed advanced (FIGO stage III/IV) high-grade serous or endometrioid ovarian cancer with g/sBRCA mutations who had a complete or partial clinical response after platinum-based chemotherapy in the frontline setting.

Primary Endpoint: PFS

Treatment groups: Olaparib (300 mg po BID) vs placebo (2:1)

Findings: The risk of disease progression or death was 70% lower with olaparib than with placebo maintenance.

• HR 0.30 (95% CI 0.23 - 0.41)
  https: //www.nejm.org/doi/full/10.1056/NEJMoa1810858

Question 2

Summarize the trial design and findings of the PRIMA TRIAL (PRIMA/ENGOT-OV26/GOG-3012)

Answer 2

Multicenter Phase III RCT where newly diagnosed advanced ovarian cancer were randomized in a 2:1 ratio to receive niraparib (300 mg daily then protocol amended for 200 mg daily if body weight <77kg, Plt <150, or both) or placebo once daily after a response to platinum-based chemotherapy.

Primary Endpoint: PFS in patients who had tumors with HRD [mychoice HRD score >= 42 or sBRCAm] and in those in the overall population, as determined on hierarchical testing.

Results:

• For patients with HRD (509%), mPFS was significantly longer in the niraparib group than in the placebo group (21.9 months vs. 10.4 months; HR 0.43; 95% CI 0.31 - 0.59).
• In the overall population, the corresponding PFS was 13.8 months vs 8.2 months (HR 0.62; 95% CI: 0.50 - 0.76)

Question 3

Summarize the trial design and findings of the VELIA TRIAL (VELIA/GOG-3005).

Answer 3

Multicenter phase III RCT to assess the effiacy of veliparib added to first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma (included those with or without response to chemotherapy)

• Patients were randomly assigned in a 1:1:1 ratio to receive

1. chemotherapy plus placebo followed by placebo maintenance (control),
2. chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or
3. chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout).

• Cytoreductive surgery could be performed before initiation or after 3 cycles of trial treatment. Combination chemotherapy was 6 cycles, and maintenance therapy was 30 additional cycles.
• Primary end point was investigator-assessed PFS in the veliparib-throughout group as compared with the control group
  
  • analyzed sequentially in the BRCAm cohort, the HRD cohort (which included the BRCAm cohort and HRD score >=33), and the intention-to-treat population.
• Results
  
  • BRCAm cohort: mPFS was 34.7 vs 22 months in the veliparib-throughout group vs control 22.0 months in the control group (HRD 0.44; 95% CI 0.28 - 0.68)
  • HRD cohort: mPFS 31.9 vs 20.5 months (HR 0.57; 95 CI, 0.43 - 0.76)
  • Intention-to-treat population: 23.5 vs 17.3 months (HR 0.68; 95% CI 0.56 - 0.83).
  • Veliparib: higher anemia and thrombocytopenia when combined with chemotherapy as well as of nausea and fatigue overall.

Question 4

Summarize the trial design and findings of the SOLO2 TRIAL (SOLO2/ENGOT-Ov21)

Answer 4

Multicentre phase 3 RCT evaluating olaparib maintenance treatment in platinum-sensitive, relapsed HGS/HGE ovarian cancer patients with a g/s BRCA1/2 mutation who had received at least two lines of previous chemotherapy

• PE: investigator-assessed PFS (ITT analysis)
  
  • SE: Time to first subsequent therapy or death (TFST), PFS2, TSST, OS, HRQoL
• Treatment: Olaparib maintenance vs placebo (2:1)
• mPFS 19.1 vs 5.5 months with olaparib vs placebo (HR 0·30 [95% CI 0·22–0·41])
  
  • based on SOLO2 data: FDA approval for Olaparib in August 2017 for maintenance therapy in platinum-sensitive OVCA
• Preliminary OS data (see figure)

Question 5

Summarize the trial design and findings of the NOVA TRIAL ENGOT-OV16/NOVA Investigators

Answer 5

Multicenter Phase 3 RCT to evaluate the efficacy of niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer. Patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the 3 types of non-gBRCA mutation (HRD >=42 +/- sBRCA or HR proficient) and were randomly assigned in a 2:1 ratio to receive niraparib (300 mg) or placebo once daily.

• PE: PFS
• Results
  
  • Patients in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group.
  • Among gBRCA cohort: 21.0 vs. 5.5 months (HR 0.27, 95% CI 0.17 - 0.41)
  • Among non-gBRCA with tumors with HRD: 12.9 vs. 3.8 months (HR 0.38; 95% CI, 0.24 - 0.59)
  • Among overall non-gBRCA 9.3 vs. 3.9 months (HR 0.45; 95% CI 0.34 - 0.61)

Question 6

Summarize the trial design and findings of the ARIEL3 TRIAL

Answer 6

Multicenter phase 3 trial evaluating rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with HGS/HGE, recurrent, platinum-sensitive ovarian carcinoma.

PE: PFS evaluated with use of an ordered step-down procedure for three nested cohorts:

• patients with g/s BRCAm
• patients with HRD (BRCAm or BRCA wild-type and high LOH)
• ITT population

Treatment: rucaparib 600 mg twice daily or placebo (2:1)

Results

• g/sBRCAm: mPFS 16.6 vs 5.4 months (HR 0.23, 95% CI 0.16 - 0.34)
• HRD: mPFS 13.6 vs 5.4 months (HR 0.32, 95% CI 0.24 - 0.42)
• ITT: mPFS 10.8 vs. 5.4 months (HR 0.36, 95% CI 0.30 - 0.45)

Question 7

Summarize the trial design and findings of QUADRA TRIAL

Answer 7

Single-arm, phase II study that evaluated the safety and activity of niraparib with relapsed, high-grade serous ovarian cancer (G2/G3) who had been treated with three or more previous chemotherapy regimens.

PE: investigator-assessed confirmed ORR in patients with Patient population:

• HRD tumours (including patients with BRCA and without BRCA mutations)
• Platinum-sensitive, resistant, and refractory patients
• 3-4 previous anticancer therapy regimens

Treatment: niraparib 300 mg once daily

Results: ORR 28% in plat. sensitive cohort (includes BRCA+/- patients)

Question 8

Summarize the trial design and findings of the PAOLA1 TRIAL (PAOLA1/ENGOT-ov25)

Answer 8

Multicenter Phase III RCT evaluating the efficacy of combining maintenance olaparib and bevacizumab in patients regardless of
BRCA mutation status in newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinum–taxane chemotherapy plus bevacizumab.

Treatment: Olaparib tablets (300 mg twice daily) vs placebo for up to 24 months (2:1 randomization)

• all the patients received bevacizumab at a dose of 15 mg per kilogram of body weight every 3 weeks for up to 15 months in total.

PE: investigator-assessed PFS

Results

• Overall, mPFS 22.1 vs 16.6 months (O+B vs P+B);
  
  • HR 0.59; 95% CI 0.49 - 0.72
• In HRD cohort,
  
  • Tumors including BRCAm
    
    • HR 0.33; 95% CI 0.25 - 0.45; mPFS 37.2 vs 17.7 months
  • Tumors without BRCAm
    
    • HR 0.43; 95% CI 0.28 - 0.66; mPFS 28.1 vs 16.6 months

Question 9

Define class effects vs non-class effects for TRAE in PARPi.

Answer 9

• Many adverse events of PARPi treatment are class effects, meaning that all the drugs of the PARPi family are associated with these specific adverse events.
• However, it is important to recognize specific drug-to-drug differences, including non-class effect adverse events as well as different incidence of the class effect adverse events.

Question 10

What’s the signficance of fatigue for PARPi TRAE? How is it managed?

Answer 10

• One of the most common TRAE (50 - 70%; mainly G1-2)
• Evidence that it improves over time
• Treatment:
  
  • Massage therapy
  • Psychosocial interventions
  • R/O other issues e.g. anemia, sleep dysfunction, nutritional imbalance.

Question 11

Significance of anemia as PARPi TRAE? Management?

Answer 11

• Hematologic toxicity related to mechanism of PARP1 trapping
• Anemia is a common PARPi associated adverse event
• Occurs in 40%–60% of patients
• Management
  
  • In general, <8 g/dL require dose interruptions with weekly monitoring until ≥9 g/dL. After this can be re-started at same level or lower dosage
  • R/O other causes of anemia e.g. iron-def, Vit B12, folate, hypoT4, etc
  • Transfuse as needed

Question 12

Significance of Thrombocytopenia TRAE? Management?

Answer 12

• More commonly associated with treatment with niraparib
• Management
  
  • platelet counts of <100 PARPi treatment should be withheld and counts monitored weekly until platelet counts are ≥100
  • Once recovered, PARPi can be resumed
    at the same or reduced dose level. However, if the platelet count remains <75 or at a second occurrence, a dose reduction should be considered
  • In the case of talazoparib, the recommended interruption threshold differs, and treatment may be continued if platelet counts are ≥50
  • Plt transfusion if <10 or higher if bleeding/invasive procedures; threshold may change to 20 given gyn tumors may bleed from necrotic tumor sites
  • Hold anticoag and other anti-plt drugs

Question 13

Significance of Neutropenia in PARPi TRAE? Management? What happens when there’s febrile neutropenia?

Answer 13

• Neutropenia reproted in 20% of patients on maintenance PARPi (up to 50% in patients on niraparib)
• Management
  
  • In general, if neutrophil levels are <1000/μL, PARPi treatment should be discontinued and monitored with weekly blood work; once the neutrophil level returns to >1500/μL treatment can be resumed, and reduction to a lower dose level can be considered.
  • Restarting the PARPi once neutropenia resolves to grade 2 (≥1000/μL) can also be considered.
  • In specific cases, short treatment interruptions may also be considered for asymptomatic grade 3 neutropenia, without dose reductions.
• Febrile neutropenia is rare (≤1%) when PARPi are administered as a single agent. Continuous GCSF not recommended during PARPi treatment. If continuous granulocyte growing factor is used in the event of a febrile neutropenia, growth factor support should be stopped at least 24 hours before restarting the study drug.

Question 14

Grade >=3 Hematologic TRAE are more common with which PARPi?

How do you monitor for heme toxicity?

Answer 14

Grade >=3 hematologic adverse events, especially thrombocytopenia, are more frequent with niraparib, in comparison with rucaparib, olaparib, and veliparib.

• NOVA study authors recommend a starting dose of 200 mg daily in those patients weighing <77 kg or with a platelet count <150

Monitoring

• In general, complete blood counts should be monitored weekly for the first month, monthly during the first year of treatment, and periodically after this time.
• Weekly blood work should also be considered following a grade 3 or 4 hematologic event until recovery.
• If hematologic toxicity does not recover within 4 weeks,
  clinicians should consider a referral to an hematologist for a bone marrow biopsy/aspirate, and blood sample for cytogenetics to rule out myelodysplastic syndrome/acute myeloid leukemia.

Question 15

Significance of GI issues with PARPi TRAE? Management per issue?

Answer 15

1. Nausea/vomiting:

• considered common class effect
  adverse events of PARPi
• moderate emetic risk (>30%)
• Nausea is an early event and improves over time
• Management
  
  • The use of metoclopramide, prochlorperazine, or promethazine 30 min prior to the PARPi is a good treatment option for its
    management, especially at the beginning of the treatment.
  • The administration of food 30–60 min before the PARPi may also help to prevent emesis.
  • In patients that experience anticipatory nausea
    and vomiting, benzodiazepines may be considered
  • Use of 5-HT3 receptor antagonist is not generally recommended given its PARPi continual admin and risk for constipation
  • Other options for nausea and vomiting management include steroids, domperidone, olanzapine, dronabinol, haloperidol, or scopolamine transdermal patch
  • A neurokinine-1 receptor antagonist,
    such as aprepitant, should be avoided while on treatment with olaparib due to drug interactions

2. Dyspepsia

• ~10%–20% of patients on maintenance PARPi
• Clinicians may advise patients to have small meals and assess potential dietary triggers (eg, fatty food, spices, alcohol).
• In cases where dyspepsia remains uncontrolled, proton pump inhibitor therapy may be indicated and if these are ineffective, tricyclic antidepressants or prokinetics may be recommended
• In certain cases, non-invasive test Helicobacter pylori or upper endoscopy may be considered to rule out other causes of dyspepsia.
• Treatment with rucaparib may increase the effect of omeprazole.

3. Dysgeusia

• ~10%–40% of patients, more commonly with rucaparib.
• Ensuring that patients maintain adequate oral hygiene care may also be helpful for dysgeusia management.

4. Diarrhea and/or constipation
   * ~1/3 of patients treated with PARPi maintenance and generally G1-2
5. Abdo pain
   * similar in placebo arms of trials
6. Decreased appetite
   * ~20% of patients and considered severe in <1%

Question 16

Significance of Hepatic and Renal abnormalities? Management?

Answer 16

Hepatic abnormalities

• Transient transaminase elevation is an adverse event commonly seen with rucaparib during the initial cycles of treatment.
• Maintenance rucaparib in platinum-sensitive patients was associated with ALT and/or AST increase in 34% of cases (grade ≥3 in 10%); in general self-limiting, not associated with other signs of liver toxicity, and recovery to normal limits was generally achieved within 3 - 4 cycles of treatment.
• In the event of a grade 4 ALT/AST elevation, rucaparib should be held until values return to grade ≤2, and treatment can be resumed with a dose reduction and weekly monitoring for at least 3 weeks.
• In the event of a grade 3 ALT/AST elevation, treatment should be individualized, and continuation of treatment under careful monitoring can be considered if bilirubin is normal and alkaline phosphatase < 3 of institutional normal limit. If levels do not decline within 2 weeks, treatment should be interrupted until resolution to grade ≤2, and treatment can be resumed at the same dose or lower dose level. Rucaparib treatment discontinuations due to ALT/AST elevation occurred in 0.5% of the patients in the ARIEL3 trial.
• Transaminase elevation has also been described in ~5% olaparib and ~10% niraparib treatment regimens.
• In the event of hepatic toxicity, other etiologies for liver enzyme elevation may be ruled out.

Renal abnormalities

• Elevations in creatinine have been described in approximately 10%–12% of patients across different PARPi.
• In fact, PARPi have in-target effects in renal transporters (such as MATE-1, MATE-2, OCT-1, OCT-2) that secrete creatinine into the urine, but are not usually not associated with a true renal injury (study showed that serum creatinine elevation in patients on PARPi may not be associated with a decrease in glomerular filtration rate as measured by renal scan.)
• In the event of a significant creatinine elevation, other causes should be ruled out and a renal scan may be considered. If the glomerular filtration rate remains maintained, dose modifications or treatment interruptions can be avoided.

Question 17

Significance of resp AEs associated with PARPi? Management?

Answer 17

General

• Dyspnea and/or cough occur in approximately 10%–20% of patients on PARPi treatment, generally grade 1–2.
• Comprehensive symptom assessment is required, as well as treatment of other potential reversible co-morbid
  conditions
• If new or worsening pulmonary symptoms are found treatment should be withheld, and a diagnostic workup including a high-resolution CT scan should be performed, to exclude pneumonitis

Pneumonitis

• Pneumonitis has been described in <1% of patients treated with olaparib.
• Symptomatic patients with radiographic findings
  of pneumonitis should hold the treatment, undergo investigations including pulmonary function tests and bronchoscopy, and initiate treatment with corticosteroids and antibiotics as appropriate. More data are required regarding low-grade pneumonitis and potential
  discontinuation of PARPi.

Nasopharyngitis

• ~ 10% of patients on maintenance PARPi
• Generally, decongestants may be used (eg, diphenhydramine, loratadine) for management; if very symptomatic, fluticasone nasal spray may also be considered.

Question 18

What is the significance of CNS or psych AEs in PARPis? Management?

Answer 18

CNS

Insomnia or headache

• Insomnia or headache have been reported during maintenance PARPi treatment in ~10%–25% of patients, and are usually grade 1–2.
  
  • Preclinical studies have shown that PARP1 is involved in the regulation of circadian gene transcription.
  • Sleep hygiene education, cognitive behavioral treatment, and/or pharmacologic approaches can be considered for its management in refractory cases.

Dizziness

• ~15% of patients across the different maintenance PARPi treatments
• In the event of neurologic adverse events other causes, such as central nervous system involvement, endocrine, or other laboratory abnormalities, may also be ruled out.

Neuropathy

• Uncertain effects; preclinical show decreased neuroinflammation but clinical studies have not demonstrated similar results.

Question 19

Significance of dermatologic AEs with PARPi? Management?

Answer 19

• Dermatologic adverse events have been mainly described with rucaparib and niraparib treatment.
• In the ARIEL3 clinical trial, 17% of the patients receiving rucaparib reported photosensitivity, 12% rash, and 13% pruritus, which were mainly grade 1-2
• SOLO2 trial assessing olaparib maintenance, 1% of the patients receiving olaparib experienced a rash
• Patients on PARPi treatment should be instructed to use sun protection, and a dermatology referral may be requested as needed.

Question 20

Significance of CVS AEs with PARPi? Management?

Answer 20

• Cardiovascular effects, including HTN, HTN crisis, tachycardia, and palpitations, have been reported as adverse events mainly related to niraparib
• niraparib has an off-target pharmacologic inhibition
  of dopamine transporter, norepinephrine transporter, and serotonine transporter, which may explain the distinct CVS side effect profile of the drug
• In the NOVA trial, 19% of the patients on treatment with niraparib experienced HTN of any grade and there was grade ≥3 HTN in 8% of cases; and 10% of the patients experienced palpitations, all grade 1 - 2.
• Blood pressure should be regularly monitored in
  patients on treatment with niraparib, especially in those patients with prior history of cardiovascular disease. If hypertension is diagnosed, non-pharmacologic and pharmacologic therapy should be considered as per the guidelines.

Question 21

What is a rare but serious long-term AE that can occur with PARPi?

Answer 21

• Myelodysplastic syndrome/acute myeloid leukemia is a serious rare adverse event related to PARPi treatment, found in approximately 1% of patients.
• Prior platinum therapy and other DNA damaging agents are added risk factors for the development of MDS/AML, as well as the presence of germline BRCAm.
• If unexplained or prolonged pancytopenia is found, patients should be referred to a hematologist for consideration for bone marrow aspiration. If MDS/AML is diagnosed, treatment with PARPi should be permanently discontinued.

Question 22

What PARPi are FDA-approved for maintenance therapy in the upfront setting and what are the indications?

Answer 22

Question 23

What PARPi are FDA-approved in the recurrence setting for maintenance therapy? What are their indications?

Answer 23

Question 24

What PARPi are approved in the recurrence setting for treatment? What are their indications?

Answer 24

Question 25

What are the dose levels and adjustments for olaparib, niraparib, and rucaparib?

Answer 25