Surgical and management options. Trials in sippets

1. Management Of
Recurrent Ovarian Ca (ROC)
Presenter: Dr Shruthi Shivdas
Moderator: Prof Dr PallaviVR
Dept of Gyn Oncology, KMIO
Bangalore

2. Incidence
Patterns
Defining Sensitivity
2L Chemotherapies
SCRS
Mgt of PRROC
TargettedTherapies
Sequencing therapies

3. Incidence
According to the Ovarian Cancer Research Alliance (OCRA), the risk of EOC
recurrence is:
• ~10 % in stage 1
• Stage1c3 – up to 33% risk
• ~30 % in stage 2
• ~70 to 90 % in stage 3
• ~90 to 95 % in stage 4
• In total, about 70 % of patients with EOC experience a recurrence
• In stage III disease-For patients with low residual disease (all lesions < 1 cm in size following
surgical debulking), the risk for recurrence after completion of primary therapy is 60% to
70%; for women with large-volume residual disease, the risk is estimated at 80% to 85%.
• 25% of ROC occur within 6 months after end of primary chemotherapy and 75 – 80 % after
6 months
• The mean 5-year survival rate following the diagnosis of recurrent EOC is < 10%.
Dr Shruthi Shivdas

4. Patterns of Recurrence
Among advanced EOC, 75% of clinically complete
responders and 50% of pathologically complete
responders recur after a median time of 18 to 24
months
70% of first relapse was found at pelvis or abdomen
No difference in first recurrent sites between early and
advanced stage cancer
Overall survival was related to FIGO stage, residual
disease after initial surgery , time to recurrence, site of
relapse (abdominal vs other, median = 66 vs 44
months, P = 0.04;), and treatment at recurrence
(surgery plus chemotherapy vs others – Sx alone/ CT
alone / HT/RT).
A.Gadducci et al., “Are surveillance procedures of clinical benefit for patients treated for ovarian cancer?A retrospective Italian
multicentric study,” InternationalJournal of GynecologicalCancer, vol. 19, no. 3, pp. 367–374, 2009
Dr Shruthi Shivdas

5. Imaging
USG
• Appear as hypoechoic single solid lesions with irregular margins, a moderate to rich vascularization at
Color Doppler (CD). Retroperitoneal lesions often missed.
CT scan:
• Sensitivity- 40–93% ; FNR ~45%
• Specificity- 50–98% for recurrent disease
MRI
• Sensitivity- 62 to 91% & specificity- 40 to 100%, which is comparable to CT scans
• whole-body MRI with DRI has higher accuracy than CT scans for determining potential operability in
women with recurrent ovarian cancer
PET/CT
• Sensitivity- 88.2–98.3%, specificity- 71.4–100% for detecting recurrent ovarian cancer
• Sensitivity of combined PET and serum CA-125 testing was 97.8% to detect recurrent disease
• PET detected 87.5% of tumor recurrences in patients with an asymptomatic rise of serum CA-125 levels
and inconclusive findings on conventional imaging
Dr Shruthi Shivdas

6. Biochemical Recurrence
• The GCIG definition of progression was initially meant for use in first-line therapy.
• In the GCIG guidelines, the upper limit of normal for the CA 125 value was defined as 30
U/ml.
Dr Shruthi Shivdas
For patients with an elevated CA 125 level pretreatment that never normalized,
progression was defined as CA 125 2x the nadir value on two occasions .
In those patients with either a normal CA 125 or an elevated CA 125 level pre-treatment
that normalized, progression was to be defined as a CA 125 level 2x the upper limit of
normal documented on two occasions (CA 125 levels performed at least 1 week apart for
confirmatory value).
 The predictive value of CA125 > 35U/dL is 100%; disease always detectable if second look
done.
 The predictive value of a negative test is only 56%; disease missed in 44% patients.
Berek & Hacker’s, 7th Ed, 2021

7. Biochemical Recurrence :ToWait orTreat?
Rustin et al/ EORTC 55955
The LANCET, 2010
1. Prospective RCT of 1400+ pts post 1st line
2. Randomised on biochemical recurrence – GCIG criteria
(590+ with 2xBLN), to early treatment & delayed on
clinical / radio rec.
3. No OS advantage in early treatment on BC rec
4. Early starting of third line treatment also in early arm
5. Significant deterioration of QoL in early arm
Conclusion
To avoid starting 2L CT in asymptomatic patients whose
only evidence of disease recurrence is a CA-125 rise, in the
absence of radiographic findings
• Reserve platinum-based therapy for the development of
radiographic or clinical signs of relapsed disease
Wang et al.
Journal of Ovarian Research, 2013
 Prospective OBSERVATIONAL study at MDACC of 410
pts with Complete Clinical Response after 1st line
 Pts with CA 125- 1.68xbaseline--Biochem Rec
 Median lead-time to clinical / radiological relapse was 31
days (range: 1 to 391 days)
 OS of patients with asymptomatic relapse who
underwent a SCRS and an optimal sx was sig longer than
that of patients with no SCRS 0r suboptimal sx.
 Asymptomatic patients with biochemical rec had a higher
optimal SCRS rate (92.2% vs 43.5%) and longer OS & PFS
than the symptomatic patients (p = 0.02; 0.004)
. Conclusions:.
 Using CA-125 levels in guiding the treatment of patients
with asymptomatic ROC, who have shown CCR to
primary therapy, can facilitate optimal secondary CRS
and extend the survival duration of the patients
No comment on comparison with clinical / radio recurrence
Dr Shruthi Shivdas
In the absence of radiographic or clinical findings, labelling
biochemical “recurrence” can result in artificially shortening
the PFI and causing some patients to be inappropriately
labelled as platinum resistant.
Rustin et al, 2010

8. Time to challenge “theWAIT”
• “Perhaps it is time to challenge a management paradigm that was based on a trial that opened to
recruitment >20 years ago in 1997, when ovarian cancer was considered to be a single disease entity,
the importance of BRCA mutations and HRD as well as histological subtype was not appreciated,
and treatment options for patients with ROC were very limited.”
• “ It would be impossible to repeat the MRC OV05/EORTC55955 trial and it is likely this question will
remain contentious and continue to be debated.”
• “Treatment should be considered before patients develop large-volume disease, particularly those
with HGSC, those with BRCAm / HRD, andTFI ≥6 months given that we have many more treatment
options currently available compared with 20 years ago and better supportive care during
treatment.These patients also may benefit from maintenance therapy with a PARP inhibitor, which
could further delay the time to subsequent chemotherapy”.
Friedlander, M.L. (2019), Do all patients with recurrent ovarian cancer need systemic therapy?. Cancer, 125: 4602-4608.
Dr Shruthi Shivdas

9. Biochemical Recurrence - Options
ESMO ESGO 2019
 At present, CA125 remains the most important of the various biomarkers available for the detection of ROC.
 CA125 is the simplest tool to trigger imaging and is a better approach than regular routine imaging for diagnosis of
ROC. Imaging, such as ultrasound, chest-abdomen-pelvis CT, whole-body MRI or PET-CT, should only be carried out if
clinically indicated, based on symptoms, clinical examination or a rising CA125 level.
“It should be noted that the EORTC 55955 trial was not carried out in an era where surgery could be
considered for selected cases, or where targeted therapies were used as a maintenance strategy for
treatment of recurrent disease to lengthen disease control or survival.”
 Currently, evidence is lacking to demonstrate that routine follow-up of patients treated for ovarian cancer improves
outcome. However, monitoring for recurrence might become more important as SCRS for recurrent ovarian cancer
has shown to improve survival (DESKTOP III).
Dr Shruthi Shivda
NCCN
After an increase in CA-125, median time to clinical relapse is 2-6 months
Immediate treatment (Early treatment) NCCN,Category 2b
Tamoxifen or other hormonal agents can be used NCCN,Category 2b

10. Goals ofTreatment
Relapsed disease is generally incurable, and the goals of therapy are t0:
Prolong survival
Delay progression
Control disease related symptoms
Minimize treatment related symptoms
Improve Quality of life
Dr Shruthi Shivdas

11. Issues ImpactingTherapy for ROC
• Tumour Biology & Histology
• Treatment free interval
• Number of previous regimens
• Toxicity from prior therapy
o Prior use of growth factors
o Blood transfusions
o Neuropathy
• Volume and site of disease
• Symptomatic urgency
• Performance status
• Quality of Life
• Patient Preference
Credits : Dr Neha Dr Shruthi Shivdas

12. TFIp is a continuous variable, and the 6-month definition is somewhat arbitrary.
A patient withTFIp of 6 months might respond in a similar manner to a patient whose tumor is
platinum resistant.
ESMO ESGO 2019
Credits : Dr Neha J Dr Shruthi Shivdas
TFI from last
platinum dose (PFI)
TFI from last
non-platinum therapy
TFI from last
biological agent
TFIp TFInp TFIb
From the 5th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG)
in 2015 ,Wilson MK, et al. Ann Oncol. 2017;28(4):727-32
GOG,1992
Markman et al
4th OvarianCancer
ConsensusConference
of the GCIG, 2010

13. Dr Shruthi Shivdas
Approximately 30% of patients with a PFI of 5 to 12 months will respond to platinum
retreatment, and 60% to 70% of patients with a PFI of more than 24 months will respond.
mOS is 24 – 36 mo in PS; 15 – 20 mo in PPS & 10 – 12 mo in PRROC.
Traditional Approach toTreatment of ROC

14. Management of
Platinum Sensitive ROC
(PSROC)
Second line chemotherapy (2L)
Secondary Cytoreductive Surgery (SCRS)
Dr Shruthi Shivdas

15. Dr Shruthi Shivdas
Regime Freque
ncy
Trial Arms Results Comments
Carboplatin (AUC-
5) + paclitaxel (175
mg/m2)
Q3w ICON4 +
AGO OVAR 2.2
2003
Pacli plat
vs PBC*
(CDDP / Carbo /
CAP/AP)
Sig OS benefit (5 mo)
PFS ben (3 mo)
More alopecia , neuropathy,
neutropenia
Less thrombocytopenia
Carboplatin (AUC
4) + gemcitabine
(1g/m2 on days 1
and 8) IV
Q3w IntergroupTrial
AGO-NCIC-EORTC
Pfisterer et a
2006
Gem – carbo
vs SAC
Sig PFS benefit (3mo) & better
RR
OS similar
Increased rates of grade 3-4
hematologic toxicity &
mucositis with GC
Carboplatin (AUC 5)
+ PLD, 30 mg/m2 IV
Q4w
CALYPSO trial
2009
PLD-C vs
T+C
Non inferior in PFS/ OS
(better trend)
More mucositis and HFS
Less haem toxicity, HS &
neuropathy
Markman et al,
SWOG S0200
2010
PLD –C vs
SAC
Sig better PFS with CD
Trend for better OS
If bevacizumab is used for
either of the above
regimens, it should be
continued without
chemotherapy as
maintenance treatment
Pujade-Laureine
et al, 2010
PLD+C vsTC Sig better PFS with CD
Better Ther Index of CD
Subgroup Analysis
of CALYPSO
Gladeiff et al
2012
PLD-C vsT+C
PPSROC
Significantly better PFS with
CD over CP
2L CT in PSROC (TFIp>=6mo)
* - Platinum Based Chemotherapy

16. CT in PSROC (ctd..)
Regime Dose Trial Arms Result
Topotecan
plus
Carboplatin IV
0.75 g/m2 oral
d1-3
AUC 5 day 3
Q3w
HECTOR
2016
Topo+ C vsTC
/Gem-C/PLD-C
No diff in OS/PFS
Better haem
toxicity profile
Dr Shruthi Shivdas
HOWTO CHOSE ?
 Mainly based on toxicity profile, residual toxicities, patient preferences and PS.
 For women with residual neuropathy or those who express a strong preference not to lose their hair, gemcitabine or PLD may be the
preferred partner with carboplatin, rather than taxane.
 PLD C
 Less neutropenia, neurotoxicty, alopecia; allergy; More HFS, mucositis, NV, thyrombocytopenia
 Better PFS & RR thanTC ; better general tolerability thanTC / GC
 For women who travel from a far distance, PLD may be the preferred option since it is administered on a-four-week schedule in
combination with carboplatin
 Gem –C
 potential to cause considerable hematologic toxicity, especially in a pretreated patient population.
 70% of patients of Gem-carb in the AGO-OVAR study had G3/4neutropenia, and 35% had G3/4 thrombocytopenia.
 Carbo vs CDDP
as many as 44% of patients may develop hypersensitivity to carboplatin by their third course of treatment. The incidence of
hypersensitivity increases with each subsequent cycle, particularly with seven or more doses.

17. Dr Shruthi Shivdas

18. • In platinum-sensitive relapse-
o PLD/carbo is more effective than PAC/carbo and is better tolerated
o Should therefore be considered as first-line treatment
o PLD/carbo - more anaemia and thrombocytopenia than PAC/carbo
o PAC/carbo -with significantly more alopecia, neuropathies, hypersensitivity reactions and
arthralgias/myalgias.
o Women receiving PLD – C were significantly less likely to discontinue treatment than those
receiving PAC/carbo
• Platinum resistant relapse-
o PLD alone is a useful agent
o It remains unclear how it compares with other single agents for this subgroup and in what
order these agents should be used
o There is insufficient evidence to support the use of PLD in combination with other agents
in platinum-resistant relapsed EOC
2016
Credits : Dr Neha J Dr Shruthi Shivdas
2013

19. The Partially Platinum Sensitive ROC
Dr Shruthi Shivdas

20. ANNALS oF OMCOLOGY, 2012
Dr Shruthi Shivdas
Annals of Oncology, 2012

21. The patients were stratified by the length of their PFI. OVA-301 included 216 PS and 214 PPS patients.
• The primary endpoint of the trial was PFS, with OS as a secondary endpoint.
• Results showed a significant improvement in OS in patients treated with the combination, with a difference in
median survival of 3.2 months (18% risk reduction, P = .0285).
• Although there was a consistent improvement in OS across all PFI groups of 21%–28% reduction (PS, PPS, and PR),
the most pronounced difference was seen in the PPS subgroup. (36% , 17%, and 6% for the PPS, PR, and PS
subgroups, respectively.)
• This study had one of the longest overall survival data among clinical trials, taking 4 years to complete.
• PPS patients in the study were further followed for survival until their death and analyzed based on their subsequent
therapies after the OVA-301 trial regimens.
Dr Shruthi Shivdas

22. 2010/ ANNALS OF ONCOLOGY
• In patients with partially platinum-sensitive disease- 35%– reduction of DP or 41%
reduction of death
• Trabectedin/PLD combination grp experienced significantly longer survival counted
from the initiation of subsequent platinum based therapy- 13.3 months versus 9.8
months in the PLD arm (P=0.0357) OS
Conclusion:
Superior benefits with trabectedin / PLD in terms of PFS & OS in the overall
population of ROC appear enhanced in patients with PPSROC (PFI 6-12 months).
Trabectedin + PLD may be administered to ROC pts while they recover from
prior platinum-related toxic effects; helps in prolongation of PFI and to
improve response & survival after–subsequent platinum-based therapy
This
hypothesis is
under
evaluation in
the
prospective
phase III trial
comparing
TBD/PLD,
followed by
platinum
versus
platinum-
based
chemotherapy
(INOVATYON
trial)

23. 2017
• Prospective RCT open –labelled.Terminated prematurely as slow recruitment.
• 215 patients with PPSROC patients, (TFIp:6 to 12 months) after ≤2 previous chemo, randomly
assigned to nonplatinum-based chemotherapy followed by PBC at subsequent relapse or the
standard PBC
• Nonplatinum-based therapy PLD, topotecan, or gemcitabine, and the platinum-based
therapy was carboplatin +paclitaxel / gemcitabine
• No OS benefit (primary obj) in the experimental arm (21.8 v 24.5 months; P = .06).
• PFS2 was significantly shorter in the experimental arm (12.8 v 16.4 months; HR 1.41; P = .025).
• Global QoL change worse in the experimental arm
• Objective RR (51.6% versus 19.4%, P = 0.0001) significantly lower with NPBC.
MITO-8 Conclusion:
PBC should NOT be delayed in favor of an NPBC in patients with partially PSROC
Introducing a NPBC even worsens efficacy outcomes in patients with partially platinum
sensitive recurrent OC
2016
Dr Rajatharangini T
2016

24. Dr Shruthi Shivdas
Sub groupAnalysis 2012
2010
Good option for PPS
pts who are NOT
candidates for
platinum

25. Single Agent therapy in PSROC
• A subset of women may not be candidates for retreatment with platinum agents (eg,
carboplatin, cisplatin) either due to a history of a hypersensitivity reaction or persistent
toxicities from first-line therapy.
• Such patients may be candidates for single-agent therapy with other drugs
• Paclitaxel weekly 80mg /m2 ORR- 65%
• Nanoparticle albumin-bound paclitaxel (nabpaclitaxel): 260 mg/m2 on day 1 every three weeks or 100
mg/m2 on days 1, 8, and 15 every 4 weeks, ORR- 64%
• Etoposide: 50 mg/m2 orally x 21 days ORR:34%, toxicity: mainly hematological
• PLD : 50mg/m2 every 4 weeks, ORR: 28%
• Topotecan: 1.5 mg/m2/day for five days every 21 day ORR:29%, main toxicity: hematological
• Trabectidin : 1300 mcg/m2 over three hours every three weeks or 580 mcg/m2 over three hours weekly
for three weeks followed by one week off, ORR- 29 percent with a median PFS of five months
• Gemcitabine 1g/m2 D1/8 or 1500 – 2500 mg /m2 D1 ever 3 weeks; ORR: 28%, main toxicity: neutropenia
ORRs mentioned are for PSROC from various phase 3 and 2 trials
Robert Coleman, Paul Sabbatini. Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-
sensitive disease, 2021
Dr Shruthi Shivdas

26. Secondary Cytoreductive Surgery
Dr Shruthi Shivdas

27. Trials on SCRS
DESKTOP
III
GOG213 SOC-1
SOCcer LOROCSON
• SOCcerSurgery for Ovarian Cancer recurrence
• LOROCSON Late Onset Recurrent Ovarian Cancer: Surgery or Not
• Multicenter RCTs In Netherlands..Prematurely stopped due to low recruitment.
• “CA125 monitoring (abandoned after EORTC55955 ) which led to delay in diagnosing recurrence and which could be the
cause of inoperability in many cases of recurrence…”
• Also quoted was the trend towards interval SCRS after NACT, such pts were excluded from these trials
RaffiVan de Laar. Correspondence: Premature Stop of the SOCceRTrial, a Multicenter Randomized ControlledTrial on Secondary Cytoreductive Surgery, IJGO,Jan 2017

28. AGO-DESKTOPOVAR studies
Arbeitsgemeinschaft Gynakologische Onkologie –
DESKTOP I, 2006
Retrospective multicentre series
 Identify an appropriate
endpoint / goal of surgery
 To create a predictive score to
select patients who could
achieve the endpoint
DESKTOP II, 2011
Prospective study
Validation of the DESKTOP I
model (AGO score)
Description of ROC surgery–
associated morbidity
DESKTOP III, 2020
Prospective Ph3 RCT
SCRS vs 2L CT in PSROC with +
AGO score
impact of ROC surgery on OS
Acute and delayed morbidity
 Only R0 is beneficial with an OS of 45.2 months
(vs vs. 19.7 mo)
 No differences between RD of 1–10 or >10 mm (19.7
versus 19.6 months).
 ECOG PS- 0, R0 at first surgery (alternatively,
FIGO I/II in patients with unknown residual
disease after primary surgery), and absence of
ascites(/<=500mL) identified as predictive Fs
 Complete resection was feasible in 79% of pts
with all these conditions (AGO-score positive).
• In 122 of 516 screened patients of ROC
with a positive score, a complete resection
could be achieved in 76%, resulting in a
positive validation of the AGO score.
• mean morbidity rate was 19.2% and 30d
mortality was reported to be 0.8%
• 44% of patients had to receive PRBCs, and
33% of patients had at least one
perioperative complication
 OS & PFS benefit
significantly high &
exclusively seen in
PSROC (TFIp>6 mo)
WITH AGO score +
WITH R0 resection in
SCRS.
 G3/G4 AEs comparable
Credit : Dr Rajatharangini Dr Shruthi Shivdas
Descriptive Evaluation of preoperative Selection KriTeria for OPerability in recurrent OVARian cancer

29. GOG 213
USA , 2017
Surgical Cohort
• No OS / PFS benefit of Sx
over 2L CT
• PFS benefit Only when CGR
vs No Sx
• QoL decreased in Sx Arm
postoperatively with no diff
btw 2 arms after recovery
Chemo Cohort
• Addition of Bevacizumab to
CT gave 5 mo OS benefit.
 Patients in the surgery
group rather than in the no
surgery group benefited
from bevacizumab.
DESKTOP III
Germany , 2020
• OS & PFS benefit +
• OS benefit exceeding 12 mos for pts
with complete resection (CR) compared
to pts without surgery (median 60.7 vs.
46.2 mos);
• pts with surgery and incomplete
resection did worse than non-surgical
pts (median 28.8 mos).
• 60 d mortality rates were 0 and 0.5% in
the surgery and no-surgery arm.
• Re-laparotomies were performed in
3.7% of operated pts (DESKTOP 2 -11%)
• G 3/4 adverse events did not differ
significantly between arms.
Dr Shruthi Shivdas
Trials on SCRS
Sx Beneficial Exclusively if
R0 feasible in AGO + pts
Sx feasible with acceptable
morbidity.
But NOT beneficial
SOC-1
China , 2021
 Significant PFS
benefit with
SCRS over 2L CT
 OS data yet to
mature
 No OS benefit
on interim
analysis
All pts of PSROC
should be
counselled for
SCRS in specialized
centres

30. Dr Shruthi Shivdas
• Because of their exceptional OS rate with a median of 64.7 months for the chemotherapy +
bevacizumab arm, no significant difference in OS between the two arms could be reported.
GERMANY
US CHINA

31. ESMO ESGO - SCRS
• Complete cytoreductive surgery followed by systemic treatment improves PFS and
extends benefit to the next line of treatment in selected patients with first recurrence of
ovarian cancer; (OS data were not yet mature). Patients eligible for cytoreductive surgery
should be informed about this option.
• Level of evidence: I
• Strength of recommendation: A
• Complete cytoreductive surgery in second or later recurrence may provide benefit in
selected patients and specialised centres.
• Level of evidence:V
• Strength of recommendation: A
Dr Shruthi Shivdas
Generally the max PFS ranges given in 2L CT trials are 11-14 mo, while in Sx arms in SCRS
trials are 18-20 months .

32. SOC -1
CONCLUSION
SCRS followed by chemotherapy improved PFS with acceptable morbidity compared with
chemotherapy alone for patients with PSROC selected using iMODEL scores and PET-CT imaging.
All patients should be counselled about the options of secondary cytoreduction in specialized centres
with high volumes of ovarian cancer surgery.
Long-term survival outcomes will be assessed using mature data on overall survival and
accumulating treatment-free survival.
The major limitation of the current trial was the 37% of cross-over from the no surgery group to surgery
at subsequent relapses, which was decided on by either surgeons or the patients. Such cross-overs
might extend the median OS in the no surgery group and lead to reduced statistical power to detect a
significant benefit in OS.
Dr Shruthi Shivdas

33. Role of HIPEC in ROC
• The results of multiple RCTs on HIPEC in recurrent ovarian cancer are awaited.
• Until these results are available, HIPEC remains an experimental therapy with
potential harm and should only be offered in the context of well-designed,
prospective RCTs.
ESMO ESGO 2019
In recurrent ovarian cancer, HIPEC added to cytoreductive surgery has not
been proven to be beneficial in appropriately designed prospective studies.
Level of evidence: IV Strength of recommendation: A
Dr Shruthi Shivdas

34. • 120 women with PSROC & PRROC
• Randomized into two groups.
• Group A (N= 60)-S CRS + HIPEC f/b CT
• Group B (N=60) -SCRS only f/b CT
• Mean OS - HIPEC group 26.7 versus 13.4 months in
non-HIPEC group, statistically significant p = 0.006
• 3-yr OS-75 % -grpA vs 18 % grp B (p < 0.01)
• In CC-0 cytoreduction, survival was significantly
higher in the HIPEC group (30.9 months vs. 16.9
months in the non-HIPEC group, p = 0.038) Conclusion:
• CRS and HIPEC offer a significant
survival benefit in ROC in PSROC &
PRROC.
• Maximum efficacy with CC0 SCRS.
• PCI of <=15 appeared also to have longer
survival.
SPILIOTIS
STUDY
IP Regimens were as follows:
• PSROC : 100 mg/m2 cisplatin & 175 mg/m2
paxcitaxel
• PRROC : 35 mg/m2 doxorubicin and 175 mg/m2
paxcitaxel or 15 mg/m2 mitomycin
• 60 min at 42.5 ℃ in both groups.

35. Dr Shruthi Shivdas

36. Platinum Resistant Recurrence
(PRROC)
Dr Shruthi Shivdas

37. NO BENEFIT
WITH
COMBINATION
IN PROC
Dr Shruthi Shivdas
PhIII : Gem vs PLD
MUTCH ET AL, 2007
Similar efficacy & therapeutic index with different toxicity profile.
The PLD group- significantly more HFS and mucositis; the gemcitabine group - significantly more
constipation, nausea/vomiting, fatigue, and neutropenia ( but not febrile neutropenia).
PROC

38. ESMO 2019
• Enrollment on available clinical trials or treatment with non-platinum chemotherapy
• The reported response rates are low, about 10% to 15%
• Median time to progression is 3–4 months
• Median survival is 9–12 months
• Goal of CT is to palliate symptoms / improve QoL.
• SEQUENTIAL SINGLE AGENT
• Chemotherapy options-
o Pegylated liposomal doxorubicin (PLD)
o Weekly Paclitaxel (80 mg/m2)
o Gemcitabine
o Topotecan
o Etoposide
Dr Shruthi Shivdas
NCCN
• PLD – 26%
• Docetaxel – 22%
• Weekly Paclitaxel– 21%
• Gemcitabine – 19%
• Oral etoposide – 27%
• Topotecan - 20%

39. Can platinum be re-challenged in PRROC?
• The definition of the PFI is subject to variability in the literature depending on whether relapse is
defined by CA-125 or radiographic or clinical progression.
The use of maintenance therapies after first-line treatment may change the meaning of the PFI.
• Bouberhan et al. Advances in the Management of Platinum-Sensitive Relapsed OvarianCancer.JCO, 2019
• BRCA-mutated patients in particular, but also BRCAWT patients, may respond to rechallenge with
platinum-based chemotherapy, even with aTFIp of <6months
• Even in “platinum resistant”, tumour response rates to platinum are at least as good as to non-
platinum drugs in this setting.
• Patients for whom platinum-based chemotherapy might not be the best option are those patients
with early symptomatic relapse or progression during prior platinum-based chemotherapy and
patients with platinum intolerability.
• Nonplatinum drugs should be selected based on the toxicity profile and patient preference;
bevacizumab may be added to aid a reduction in ascites and improve gastrointestinal symptoms .
ESMO ESGO 2019
Dr Shruthi Shivdas

40. Dr Shruthi Shivdas
Alsop K, , et al. BRCA mutation frequency and
patterns of treatment response in BRCA mutation-
positive women with ovarian cancer: a report from
the Australian Ovarian Cancer Study Group
[published correction appears in J Clin Oncol. 2012
Nov 20;30(33):4180]. J Clin Oncol. 2012;30(21):2654-
2663. doi:10.1200/JCO.2011.39.8545
SHOULD the new terminology be
“POTENTIALLY PLATINUM
RESPONSIVE”?

41. Dr Shruthi Shivdas

42. TargetedTherapy in ROC
MAINTENANCETherapies
1. Antiangiogenic agents (CONTINUATION Maintenance)
2. PARP Inhibitors (SWITCH Maintenance)
Dr Shruthi Shivdas

43. MaintenanceTherapy in ROC
• Maintenance treatment for ROC is the extended pharmacologic treatment of a
patient who has had a CR or PR to their most recent therapy.
• The main goals of maintenance treatment are to extend clinically meaningful
survival and prolong the period between chemotherapy treatment lines,
allowing patients to avoid the toxicities associated with chemotherapy that can
affect their QoL.
• real-world evidence suggests that ≈51% of eligible patients do not receive
targeted maintenance treatment in the second-line maintenance setting
Dr Shruthi Shivdas I. Ray-Coquard, et al. CancerTreatment Reviews 90 (2020) 102107
Bevac PARPi

44. The addition of bevacizumab in combination with chemotherapy for PS/PR-ROC followed
by single-agent maintenance bevacizumab has led to an approximately 4-month
prolongation in PFS
2012
2017
2020
2014
2018
Longest PFS with Q3wT+C+Bev
PFS benefit with rechallenge too
OS benefit only in
addition of Bev to CT
AFTER SCRS
• PFS & OS benefit with PLD +C+Bevac
irrespective of prior Bev use
• PLD less G3 AEs
OS benefit only in
Q1wT + Bev arm
52% reduction in
recurrence risk
37% reduction in
recurrence risk
12% grade 3 HTN,
and 2% GI Perforation
17% grade 3 HTN,
and NO GI Perforation
MUST
Allowed

45. PARP inhibitors in ROC
NIRAPARIB
NOVA/ENGOT OV16 -
maintenance
QUADRA – ph2
monotherapy
OLAPARIB
Maintenance
STUDY19 – ph2
SOLO2/ENGOTOV21
MONOTHERAPY
STUDY42- ph2
SOLO3 – ph3
RUCAPARIB
Maintenance
ARIEL 3 – Ph3
Study 10 – ph2
monotherapy
ARIEL2 – Ph 2
Credit : Dr Rajatharangini Dr Shruthi Shivdas

46. Dr Shruthi Shivdas

47. PFS in bevacizumab and PARPi pivotal maintenance studies in PSROC
Dr Shruthi Shivdas
52% reduction in recurrence / death risk
37% reduction in recurrence / death risk
70 % reduction in recurrence / death risk
12 months OS benefit with Olparaib
• 65 % reduction in recurrence / death
risk in ITT
• 82% BRCAm ; 46% in BRCAwt
• 30% OS benefit in all
• 73% risk reduction in BRCAm
• 55% in BRCAwt
• 62% HRd, BRCA wt
• 42% in BRCA wt/ HRp
• 64% risk reduction in ITT
• 80% risk reduction in BRCAm
• 66 % HRd, BRCA wt
• 42% in BRCA wt/ HRp
gBRCAm
Absolute PFS benefit
ranging from
 3-4 mo in BRAwt/HRp
 9-10 mo in HRd
 14 – 25 mo in BRCA m

48. FDA-Approval for Bev & PARPi in ROC
Slide credit: clinicaloptions.com
Dr Shruthi Shivdas
PARPi - MAINTENANCE IN RECURRENT SETING (Switch Maintenance) >=2L
OLAPARIB NIRAPARIB RUCAPARIB
 Maintenance therapy for ROC in
CR/PR to platinum-based CT
regardless of BRCA mutation status
 Maintenance therapy for ROC in
CR/PR to platinum-based CT
regardless of BRCA mutation
status
 Maintenance therapy for
ROC in CR/PR to platinum-
based CT regardless of
BRCA mutation status
PARPi- MONOTHERAPY IN RECURRENCE
 >=3 LINES with gBRCA mutations
 PS/PR
 >=3 LINES with HRD / BRCAm
 PS/PR if BRCAm; PS if HRd
 >=2 LINES WITH s/gBRCA
mutations
 PS/PR
Approval
year
Indication for Bevacizumab
(Continuation Maintenance)
2014
Platinum-resistant recurrent, and received no more
than 2 prior chemotherapy regimens
AURELIA
Platinum-sensitive recurrent OCEANS;GOG 213
2016
• At 5 years F/U of SOLO1, 50% of olaparib gr had not experienced disease
progression vs 20% placebo arm. (mDFS : 56 mo vs 13.8 mo). NO OS DATA.
• SOLO2 : first time documentation of OS (secondary end-point) after Study19
and its improvement with PARPi maintenance (unprecedented 12.9 months).
At 5 years, 42% of olaparib arm alive vs 33% placebo. 28% were progression
free on olaparib vs 12% placebo. (ASCO, May 2020)
THE ABSOLUTE BENEFIT IN PFSWITHTHE ADDITION OF OLPARIB in gBRCA
mWAS INTHE RANGE OF 42 MO IN SOLO1VS 14 MO IN SOLO2 !!
“Considering the fact that the best chance of cure is always in the
first line setting, it would seem reasonable to regard maintenance
PARPi following response to 1L therapy as the current std of care in
HGSOC or HGEOC , rather than deferring use until recurrence.”
Berek & Hacker, 7th Ed, 2021

49. PARP Inhibitors in PROC
Olaparib: In a small, randomized, phase II trial comparing two doses of olaparib (200 and 400 mg twice
daily) and PLD in patients with resistant disease, olaparib compared favorably to PLD in terms of efficacy
(overall response rate[ORR] and PFS) and QOL (by FACT-O). [N=97]
Kaye SB et al: Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a PARP inhibitor, and PLD in patients with BRCA1 or
BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 30:372-379 2012
Olaparib (200mg) Olaparib (400mg ) PLD (50mg/m2) P value
mPFS(mo) 6.5 8.8 7.1 0.66
ORR 25% 31% 18% >0.05
Dr Shruthi Shivdas
• QUADRA ( niraparib monotherapy in late-line rOC) had patients with platinum-resistant or -refractory disease
• ORR of patients with BRCA mutations (g/s)who had previously received three or more lines of therapy was
• 33% for platinum resistant disease (n = 21) and
• 19% for platinum refractory disease (n = 16)
• Rucaparib: ARIEL4 trial is an ongoing, randomized, phase II trial evaluating single-agent rucaparib
compared with standard chemotherapy in BRCA-mutated ovarian cancer and includes patients with
platinum resistant disease.

50. Single agent bevcizumab in PROC
GOG170
Phase II trial: 62 patients with recurrent
ovarian cancer with 1 or 2 prior regimens,
measurable disease, PS=<2 received
bevacizumab 15 mg/kg q 3 weeks
• 66% received 2 prior regimens
• 58% platinum-resistant
• Grade 3 HTN: 6/61
• ORR: 21% (2 CR, 11 PR)
• MMedian PFS: 4.7 months
• Median OS: 17 months
Conclusion:
→ Bevacizumab well tolerated and active in
second- and third-line treatment
CANNISTRA
Phase II trial: 44 pts with PRROCwho
progressed during or within 3 months of
discontinuing topotecan or liposomal
doxorubicin, and 3 prior regimens received
bevacizumab 15 mg/kg q 3 weeks
• Grade 3–4 HTN: 9.1%
• Proteinuria: 15.9%
• Wound-healing complications: 2.3%
• GI perforations: 11.4% (23.8% with 3 prior
lines, 0% with 2 prior lines, p < 0.01)
• Arterial thromboembolic events: 6.8%
• Median PFS: 4.4 months
• Median OS: 10.7 months
Conclusion:
→ BEV with single-agent activity in PRROC
- higher than expected incidence of GI
perforation noted in these heavily
pretreated patients
Credit : Dr Rajatharangini Dr Shruthi Shivdas

51. HOWTO SEQUENCE therapies in Roc?
• Classes of biological therapy currently indicated to treat recurrent ovarian cancer
for patients with potentially platinum-responsive disease, are bevacizumab and
PARPi (olaparib, niraparib and rucaparib)
• In selecting next therapy for recurrent disease, four clinical scenarios can be
defined based on patients’ previous exposure to biological therapy:
• Scenario 1:Previous chemotherapy only; no previous bevacizumab, no previous PARPi;
• Scenario 2: Previously chemotherapy plus PARPi, no previous bevacizumab;
• Scenario 3: Previously chemotherapy plus bevacizumab, no previous PARPi;
• Scenario 4: Previously chemotherapy plus bevacizumab plus PARPi.
Dr Shruthi Shivdas

52. SCENARIO 1-Targetted therapy-
naïve patient with ROC
High disease burden
Dr Shruthi Shivdas
ESMO ESGO 2019
NO ROLE
FOR PARPi
NO ROLE
FOR PARPi
+ BEVAC

53. • Scenario2: Previously chemotherapy plus PARPi, no previous bevacizumab
• In potentially platinum-responsive patients with previous exposure to a PARPi, ESMO-
ESGO guidelines recommend platinum-based rechallenge plus bevacizumab
Dr Shruthi Shivdas
Scenario3 :Prior chemotherapy plus bevacizumab, no previous PARPi;
In potentially platinum-responsive patients previously exposed to bevacizumab, platinum-based rechallenge
followed by PARPi maintenance therapy is effective irrespective of BRCA mutation and HRD status .
Olaparib , niraparib or rucaparib can also be considered for use as monotherapy in patients with recurrent
disease who have received several previous lines of treatment
Scenario 4: Prior chemotherapy plus bevacizumab plus PARPi. (PAOLA-1 regimen)
Evidence is currently insufficient to recommend a general approach.
 Second-line options are likely to be limited to platinum- or nonplatinum-based regimens without additional maintenance
therapy.
 Bevacizumab MAY be reintroduced (MANGO 16B / ENGOT –OVAR 20; NOT endorsed by ESMO)
 Olaparib retreatment (maintenance) may be considered , but clinical benefit doubtful (OReO)
 A prospective real-world study of trabectedin and PLD in heavily pretreated patients (n = 158) with PSROC ≥3 previous
lines: 40%) found that the safety profile of the combination was consistent with that previously observed in less
pretreated patients
Pignata S, Scambia G, MazzeiT, Arruti Barbia M, Naglieri E, de Sande LM.Trabectedin plus pegylated liposomal doxorubicin (PLD) in patients with platinum-sensitive
recurrent ovarian cancer (PSROC) regardless of prior use of antiangiogenics: first results of an observational, prospective study. Ann. Oncol. 29(Suppl. 8), viii352 (2018

54. Bevac vs PARPi maintenance in PSROC –
Biologically Naïve pt
• Various meta-analysis and real world studies have shown thatTST and DFS are prolonged
significantly more with PARPi vs Bevacizumab.
• But conclusions cannot be drawn due to important differences in their use.
• To qualify for maintenance therapy with PARPi, patients must be in response to platinum.
• Conversely, bevacizumab is combined with chemotherapy from the start of treatment for
recurrent disease without patient preselection according to platinum response.These
methodological differences imply different and better prognoses among PARPi-treated
patients and preclude making comparisons.
Lorusso et al. Managing recurrent ovarian cancer in daily clinical practice: case studies and evidence review with a focus
on the use of trabectedin. Futute Oncology, Vol 70 S3 , Dec 2020
Dr Shruthi Shivdas

55. Bevac vs PARPi maintenance in PSROC
1. A PARPi is treatment of choice if there is no priority for a symptomatic response or
contraindications to bevacizumab are present. Bevacizumab is treatment of choice if there is
priority for a symptomatic response and contraindications to bevacizumab are absent
2. Fit pts who have contraindications to bevacizumab (eg, recent stroke, myocardial infarction,
uncontrolled hypertension, recent bowel obstruction, thromboembolism), platinum doublets
without bevacizumab to be given; and these patients may be subsequently considered for
maintenance with PARPi if CR/PR to the PBC.
3. HRp patients may be more suitable for second-line maintenance rather than first-line
maintenance treatment with a PARP inhibitor..
4. Cancer histology- The use of PARP inhibitors in Europe is limited to patients with
HGSOC/HGEOC, whereas bevacizumab is not and so may be an option for patients with non-
high-grade ovarian cancer
Dr Shruthi Shivdas

56. Dr Shruthi Shivdas
ROC >2L
CR/PR to
patinum
based CT
Heavily
pretreated
not on CT
Pl / non Pl CT +/_ BEV
Restricted to 3L in Pl
resistant
Maintenance
with O/R/N
Monotherapy
with O/R/N if
BRCA m
(PS/PR)
N if HRd &PS
Trabectedin /
PLD

57. How long should systemic therapy be continued in ROC?
• Stopping chemotherapy
• For platinum-based chemotherapy, 6 cycles are recommended. More or fewer cycles have
not been shown to be beneficial, and consideration should be given to the toxicity.
• For non-platinum chemotherapies- treatment may be continued as long as there is clinical
benefit and treatment is well-tolerated.
• Stopping Bevacizumab:. Treatment is usually continued until disease progression.The
continuation of bevacizumab beyond progression has not been evaluated in the recurrent
setting.
• In the AURELIA trial , bevacizumab was not offered alone as a maintenance therapy;
chemotherapy in combination with bevacizumab was continued to progression.
• Stopping maintenance PARPi: Despite an increase inTFST demonstrated for olaparib and
niraparib, the benefit of continuing treatment beyond progression has not been demonstrated
conclusively to date; but may be considered.
ESMO ESGO 2019
Dr Shruthi Shivdas

58. Credits : Dr rajatharangini Dr Shruthi Shivdas
RCT Ph EOC Basket Trial HIGHLIGHT
Response,
% (n/N)
KEYNOTE-100 II
PROC
1-6 lines prior
PEMBROLIZUMAB ORR: 8.0
KEYNOTE-028
II
PROC
>2-3 therapy
26 PEMBROLIZUMAB
ORR: 11.5 (3/26)
CR: 3.8 (1/26) ,
PR: 7.7 (2/26)
KEYNOTE-162/
TAPACIO II/III PROC TN Breast
NIRAPARIB+
PEMBROLIZUMAB
ORR: 25% in ROC
NRG-GY003 II PROC -
NIVOLUMAB vs
Nivo +
IPILUMUMAB
ORR:12% vs 32%
JAVELIN III
PROC (refractory
+)
-
AVELUMAB alone
vs PLD alone vs
PLD + Avelumab
ORR:3 - 5% vs 15%
OS benefit if PDL1
+ Tr
MEDIOLA II PSOC --
OLAPARIB+
DURVALUMAB
ORR:72%
OVAREX II
FIRST LINE
CP vs CP + 4
oregovomab in
optimal Stage3/4
- OREGOVOMAB
Good PFS & OS
benefit
Immunotherapy in ROC
NO FDA
APPROVAL
for ICI in OC
at present
NCCN
recommended

59. • Systematic Review and Metaanalysis of Letrozole in various settings (Primary / rec / LGSOC/HGSOC)
• Most trials were conducted with patients who were heavily pre- treated and unselected for hormone
receptor expression.
• Letrozole was administered at a dose of 2.5mg/day until disease progression.
• Approximately 30% of patients demonstrated disease stabilization and an objective response
rate, including complete response and partial response, was recorded in approximately 15% of
patients
• Common letrozole-related side effects included nausea, fatigue, dyspepsia, headache, and hot
flashes.
• High levels of ER expression were associated with disease stabilization.
• Responders to letrozole had a significantly longer duration of response than responders to
tamoxifen (26 vs 11.5 months;p=0.03).
Dr Shruthi Shivdas
2020

60. Summary
ROC incurable
Changing definition of Platinum senstivity
SCRS – Selection vital; wrong choice worst prognosis
2L Chemo currently based onTFI
PRROC – minimal toxicity
Biological agents – significant prolongation of survival
Dr Shruthi Shivdas

61. Dr Shruthi Shivdas