Describes platinum sensitivity and Evidence based treatment options for Recurrent Epithelial Ovarian Cancers

1. Recurrent Ovarian
Cancer
Dr Pradeep Dhanasekaran
Postgraduate in Surgical Oncology
Prof M.P. Viswanathan and Prof. D. Sureshkumar Unit
TN Govt Multi Superspecialty Hospital, Chennai-02.
June 2021

2. Outline
• Platinum Sensitivity
• Platinum Sensitive Recurrence
• Secondary Surgical Cytoreduction
• Platinum Resistant/Refractory

3. Relapsed Ovarian Cancer
• 75% to 90% of Advanced EOC relapse and 5 year survival was less than 15%
• Likelihood of achieving response to subsequent chemotherapy depends on
platinum free interval
• Platinum Free Interval – interval between date of last platinum dose and date of
relapse detection (Ovarian Cancer Consensus Conference Vancouver 2010)
• Criticisms! Varying frequency and investigations for detecting relapse (clinical or
biochemical) and whether it is pertinent in current era of targeted therapies

4. Categories of Platinum sensitivity
• Refractory – Progression or within 1
month of last cycle
• Resistant – Recurrence within 1 to 6
months of chemo
• Partially sensitive – Between 6 to 12
months
• Fully sensitive - >12 months
• Response rate to subsequent
chemo in partially sensitive is 30%
and fully sensitive is 60% to 70%

5. Relapse?
• Biochemical or Clinical or
Radiologic evidence of disease
• Biochemical Relapse alone?
• Introduces Leadtime Bias

6. Platinum Sensitive Recurrence
Treatment Options:
• Platinum based Chemotherapy (Standard) f/b maintenance therapy
• Secondary surgical Cytoreduction (In selected group) followed by Chemotherapy

7. Platinum Sensitive Recurrence

8. How to choose?
• Persistent neuropathy - avoid paclitaxel containing regime
• Alopecia – avoid taxane containing regime
• Prior hematologic toxicity – avoid Gemcitabine
• HFMS – PLD
• Platinum hypersensitivity – m/c with carboplatin, after 7 or more doses
• Performance status and residual toxicity
• If not suitable for doublet, single agent carboplatin used

9. Addition of Bevacizumab?
• Response rate 16% to 21%
• Decrease tumor burden and ascites
• Overall good tolerability and non overlapping adverse effect profile
• Only significant PFS Benefit and modest OS benefit
• Bowel perforation in 11%, hypertension, Proteinuria, hemorrhage and thrombosis
are considerations

10. Bevacizumab Combinations

11. Treatment considerations
• Prior Bevacizumab in first line with PSROC – retreatment with bevacizumab has
definite value ( MITO – 16B-MANGO ENGOT OV 27 Trial in 2018) demonstrating
3 month significant PFS benefit (11.8 vs 8.8 months)
• In case of contraindications to Avastin (Recent MI/Stroke/uncontrolled
hypertension/ thromboembolism/ bowel obstruction) – Combination platinum
doublets alone followed by maintenance with PARPi to be used.

12. Maintenance?
Bevacizumab :
• From OCEANS, GOG 213 and AGO OVAR 2.2 – impossible to determine the
relative value of bevacizumab as a maintenance strategy (but 4 month PFS
benefit noted)
PARP Inhibitors:
• Concept of Synthetic Lethality
• Brought into use in BRCA mutations and HRD
• Initially used as single agent in both PSROC as
Well PRROC

13. Evidence for PARPi Maintenance

14. Results
• Till date no statistical significant survival advantage noted. Needs longer follow
up

15. What Maintenance?

16. Future directions in Rx of PSROC
• Role of PARP inhibitors in combination with antiangiogenic agents or immune
checkpoint inhibition without the use of platinum-based chemotherapy is
undergoing active investigation.
• Olaparib with Cediranib
• Niraparib with Bevacizumab (AVANOVA Trial)
• Niraparib with Atezolizumab (ANITA Trial)
• how prior exposure to PARP inhibitors in the first-line maintenance setting will
affect their utility in the setting of subsequent relapse is unknown
• MOLTO Trial and OREO Trial (Olaparib maintenance Retreatment)

17. Secondary Cytoreduction
• Theoretically, medically and nutritionally optimized patients with long DFI and
solitary, isolated abdominal or pelvic recurrences – most likely to enjoy survival
benefit from surgery
• Theoretically, maximal surgical effort may
• help overcome intrinsic drug resistance,
• increase drug perfusion,
• enhance host immunologic response,
• increase the growth fraction of tumor cells, and
• circumvent acquired drug resistance after adjuvant platinum-based and
taxane-based systemic therapy.

18. DESKTOP Study (2000 – 03)
• The Descriptive Evaluation of preoperative Selection KriTeria for OPerability in
recurrent OVARian cancer (DESKTOP OVAR) trial was undertaken to form a
hypothesis for a panel of criteria for selecting patients who might benefit from
surgery in relapsed ovarian cancer. (n=267)
• The above parameters could predict complete resection in 79% of patients
• Median OS for complete resection is 45.2 months vs 19.7 months in incompletely
resected.

19. DESKTOP II study (2006-08)
• Prospective validation of predictive AGO score of
DESKTOP I
• The trial was only powered to investigate the
prediction of operability in at least 2 of 3 patients, ie, at
least 67% complete resection rate with presumed 75%
resection rate and a sample size of 110 was intended
• The score predicted achievement of complete
resection in 76% of the cases, and the lower limit of
the 95% CI was 69%, thus fulfilling the requirement
that the score should predict successful cytoreduction
in at least 2 of 3 patients.
• Overall, the positive predictive value of the score in
patients with first relapse was 0.76 and the negative
predictive value was only 0.38 and specificity was low
(0.53).

20. Level I Evidences for Secondary
Cytoreduction

21. Concept of Extending PFI?
• Concept of prolonging PFI by using single agent Non platinum based chemo
might increase outcome
• Tested in MITO 8 Trial – PFI 6 to 12 months relapsed Ovarian cancer randomized
to non platinum based chemo f/b PBC vs PBC
• Concluded PBC not be delayed in favor of an NPBC in patients with partially
platinum-sensitive OC.

22. Platinum Resistance
• Treatment remains challenge
• Platinum Refractory (PFI <1month) and Platinum Resistant (PFI >1 but <6
months)
• PFI – predictor for PARPi but not for VEGFRi
• PFI validated only for first and second relapses but not beyond
• Ovarian cancer is a complex malignancy and comprises multiple histologic
subtypes; it is also a dynamic disease process in which genetic and epigenetic
alterations occur and evolve both with time and at different metastatic sites of
disease.

23. Mechanism of Resistance
Complex phenomenon influenced by intracellular alterations and by the omentum
and tumor microenvironment
• Decreased intracellular accumulation
• Increased ability to repair cisplatin induced DNA adducts
• Problems with cell death execution machinery and signal transduction pathways
• Chemotherapy resistant cancer stem cells subpopulation

24. Molecular Analysis of Resistance
• Independent reversions of gBRCA1 and 2 mutations
• Loss of BRCA1 promoter methylation
• Overexpression of MDR1 efflux pump ABCB1
• Proteomic analysis show STAT5B and RELA associated with carboplatin
resistance and SYK associated with Paclitaxel resistance

25. Treatment Objectives
• Platinum refractory and resistant cancers have low response rates (<20%) to
subsequent chemo
• Median PFS 3 to 4 months and m OS 12 to 15 months
• Give symptomatic relief and good QoL

26. Sequential Single agent Chemotherapy
• Sequential use of single agent nonplatinum compound is standard (Pegylated
Liposomal doxorubicin, Paclitaxel, Gemcitabine and Topotecan)
• Response rates 10% to 15%; mPFS 4 months and mOS 12 months
• Choice? Prior treatment, residual toxicity
• Weekly regimens are used
• Other options: Nab-paclitaxel, Pemetrexed, Docetaxel and Etoposide

27. Antiangiogenic therapy
• Bevacizumab – single agent activity in 16% to 21%
• AURELIA Trial (chemo + Bevaci vs chemo) – addition of bevacizumab doubled
PFS (6.7 vs 3.4 months significant) but no significant OS benefit
• RR was 55.3% vs 30.2%; mPFS 10.4 vs 3.9 m; mOS 22.4 vs 13.2 months
• Pazopanib and Cediranib
• Used according to cardiovascular, bowel history, prior avastin use and drug
availability

28. Immunotherapy
• Results disappointing
• Response rate with Avelumab was 9.6% and with Pembrolizumab was 9%
• Javelin Ovarian 200 Trial: Avelumab plus PLD vs PLD alone vs Avelumab alone.
Not meet endpoint, ie, PFS

29. Role of PARPi
• Not approved for platinum resistant or refractory EOC
• Little evidence available to tell Olaparib has objective response rate in patients
with platinum resistant but BRCAmutated disease (Olaparib vs PLD)
• Rucaparib was approved after prior 2 or more lines of chemo but platinum
sensitive
• Olaparib was approved after prior 3 or more lines, BRCAmut both PSR and PRR;
overall response rate is 34%
• Niraparib (QUADRA Trial) after prior 3 or more lines, BRCA mut had ORR of 33%
for Plat resistant and 19% for Plat refractory.
• Veliparib has ORR of 20% with plat resistant (GOG 280)
• Ongoing: ARIEL-4 (Rucaparib in plat resistant) and Olaparib with cediranib.

30. Summary of Rx of PRROC
• Sequential use of single nonplatinum chemotherapy drugs remains the standard
of care.
• The addition of bevacizumab to single-agent chemotherapy provides an
improvement in response rate and PFS.
• Symptom relief and best QOL are the main goals for these patients

31. Thank You