Role of olaparib in breast and ovarian cancers

1. ROLE OF OLAPARIB IN BREAST
AND OVARIAN CANCERS

2. BRCA MUTATIONS
• Germline genetic testing guided by national/international guidelines
 Early stage with additional criteria (eg, younger age, family
history, male, personal cancer history)
 At diagnosis of HER2-negative metastatic disease
• At this time, only germline BRCA1/2 mutations have therapeutic
implications
 Ongoing clinical trials are evaluating PARP inhibitors in other DNA
damage response pathway genes (germline and somatic
mutations)
• Cardoso. Ann Oncol. 2020;[Epub]. Tung. JCO. 2020;[Epub].

3. BRCA ½ are TSG.
They encode proteins involved in the repair of DNA ds breaks via the homologous
recombination pathway.
Functional BRCA proteins regulate cell growth and prevent abnormal cell division that
might otherwise lead to tumor development

4. PARP(POLY ADP RIBOSE POLYMERASE)
• PARP : Family of enzymes composed
of 17 members.
• Found in nucleus of the cell
• Involved in cell processes ( cell
death, transcriptional regulation,
inflammation, chromatin
modification , dna repair)
• Most important components of base
excision repair pathway for ss DNA
breaks.
• PARP 1 is the best characterised
member of this family.
Primary enzyme involved in DNA
repair process

5. • Targeting the PARP pathway has been successfully exploited
as a new therapeutic approach in a number of cancers
• Effective PARP inhibitors trap PARP on DNA and prevent the
cellular DNA repair machinery from working

7. Early development of PARP INHIBITORS
• 1971 , Clarke et al described nicotinamide and its methyl
derivative as inhibitor of PARP formation after DNA damage
• First generation PARP inhibitors , nicotinamide analogues
developed 30 years ago
• Subsequently many compounds tried but they lacked antitumor
activity.

8. Olaparib in breast cancer
• First PARP inhibitor to enter into clinical practice
• Inhibition of PARP enzymes leads to synthetic lethality in
cells deficient in homologous recombination repair, such as
those with BRCA1/2 mutations
• Germline mutations in BRCA1 increase risk of developing
TNBC
• Germline mutations in BRCA2 increase risk of developing
estrogen receptor–positive breast cancer.
• A Phase II study (NCT00494234) showed that the oral PARP
inhibitor olaparib (400 mg bid; capsules) exerts
antitumouractivity in BC pts with a gBRCAm (Tutt et al Lancet 2010).

9. • Three Phase III trials of olaparib monotherapy have been
initiated in BC pts with a gBRCAm:
• OlympiA (NCT02032823),
• Neo-Olympia (D081EC00005),
• OlympiAD (NCT02000622).

10. olympiA
• Adjuvant Rx for high risk
primary TNBC
• 300mg BID (monotherapy arm)
• Compared with
• Placebo
• Primary end point : DFS
• Secondary end point : OS,
incidence of new cancers
Neo-Olympia
• Neo adjuvant Rx for primary
TNBC
• 300mg BID (Arm A)
• Compared with
• Placebo+weekly paclitaxel for 12
weeks (Arm B)
• Olaparib 100mg bid+ weekly
paclitaxel for 12 weeks (Arm C)
• Primary end point : pCR rate
• Secondary end point : OS, EFS,
ORR at 12 weeks
OlympiAD
• Metastatic breast cancer
• 300mg BID
• Compared with
• Physicians choice of drug
• Capecitabine 2500mg/m2, D1-
14 q 21 days ; Vinorelbine
30mg/m2 D1,8 q 21 days;
Eribulin 1.4mg/m2 D1,8 q 21
days
• Primary end point : PFS
• Secondary end point : OS, PFS,
ORR

11. Olympia trial
• Double-blind randomised trial
Arms : Olaparib 300 mg tablets bid or placebo for 12 months.
Eligible pts :
• Must have completed local treatment and at least 6 cycles of (neo)-adjuvant containing
anthracyclines and/or taxanes.
• Pts with triple negative BC (TNBC)
must have ≥ pT2 or pN1 in the adjuvant
and non-pCR in the neoadjuvant setting.
• Pts with hormone receptor (HR) positive BC must have ≥ 4 positive lymph nodes in the adjuvant and
non-pCR and CPS&EG score ≥ 3 in the neoadjuvant setting.
• Pts must also harbor a deleterious gBRCAm.
Primary objective : Invasive disease free survival (IDFS).
Secondary objectives : Overall survival, Distant DFS, Incidence of new non-BCs, QoL, safety and
tolerability.

12. Stratified by HR status (HR+ vs TNBC), prior CT (neoadjuvant
vs adjuvant), prior platinum-based CT (yes vs no)
Tutt. et al. N Engl J Med 2021;384:2394-405

13. Olympia : primary end point (idfs)_

14. Olympia : overall survival

15. Subgroup analysis

16. • Adjuvant olaparib significantly improved the primary endpoint of iDFS vs placebo
in patients with gBRCA1/2-mutated, HER2-, high-risk EBC
‒ 3-yr iDFS rate: 85.9% vs 77.1%; difference: 8.8% (HR: 0.58; 95% CI: 0.41-0.82; P
<.001)
‒ Distant DFS also significantly improved (HR: 0.57; P <.001)
• Despite fewer deaths occurring with olaparib vs placebo, OS was not significantly
improved in this analysis (HR: 0.68; P = .02 not crossing early-reporting efficacy
boundary of P = .01)
• Safety profile of olaparib consistent with prior reports, did not affect global health
quality
• Investigators concluded that positive results from this trial support use of
gBRCA1/2 sequencing to select optimal systemic therapy for patients with EBC

17. Latest update of olympia presentedin sabc 2021

19. Metastatic breast cancer … unmet need
• 5 year survival is only 22 % in MBC, hence there is an unmet
need for agents with acceptable safety and tolerability profile
that can improve outcome in MBC
• Ph III studies in MBC patients , med PFS with standard SA
chemotherapy drugs ( capecitabine, vinorelbine, eribulin) was
4 months. This is in addition to poor toxicity and tolerability
profile.

21. Olaparib in mbc ( Olympiad )

22. Study design

23. • Patients in Olaparib arm showed a 42 % reduction in risk of
progression or death

25. efficacy

26. safety

27. Treatment emergent ADR leading to discontinuation
• 10% Olaparib arm
• 7% in other arm

29. • In Asian subpopulation, PFS was prolonged in pts receiving
Olaparib compared with those in other arm
• Median 5.7 vs 4.2 months
• Fewer patients in Asian subpopulation required dose
modifications compared with overall population

30. Olympiad conclusions

31. • In India olapatib is yet approved for patients with deleterious
or suspected gBRCAm, her2 negative MBC who have been
treated with chemotherapy previously in NACT or metastatic
setting
• Patients with HR+ should have been treated with a prior ET or
be considered inappropriate for ET

32. Ongoing trials
• Harnessing olaparib, palbociclib, and endocrine therapy
(HOPE): Phase I/II trial of olaparib, palbociclib and fulvestrant
in patients with BRCA1/2-associated, hormone receptor-
positive, HER2-negative metastatic breast cancer
• PARTNER: Randomised, phase II/III trial to evaluate the
safety and efficacy of the addition of olaparib to platinum-
based neoadjuvant chemotherapy in triple negative and/or
germline BRCA mutated breast cancer patients

33. Role of olaparib in ovarian cancers

34. • 5-year survival for newly diagnosed advanced ovarian cancer is 30-50% and patients are
at high risk of relapse
• Till before approval of avastin in 2011, combination of debulking surgery And
chemotherapy had been the standard of care
• In 2011, GOG 0218 ,ICON 7 trials led to the addition of bevacizumab to first line
chemotherapy and continuation as maintenance therapy
• Despite high responses to first-line systemic therapy around 70% of women relapsed
within three years from completion of treatment
• Since 2018 there has been a shift in the management of newly diagnosed ovarian cancer
as a result of the substantial benefit with PARP INHIBITORS INHIBITORS
• Treatment goals in this setting include delay of recurrence and, for some patients,
increased chance of cure

35. Unmet need
There remains a significant unmet need
for newly diagnosed ovarian cancer

37. Guidelines for BRCA

38. • 15% ovarian cancer patients a gBRCAm
• while an additional 5-7% may have a sBRCAm
• 40% of patients with BRCAm OC may have no relevant
family history
• The use of family history, age and histology type alone for
patient selection in BRCAm testing would miss a significant
proportion of cases.
• Offering gBRCA test may also miss significant sBRCAm
population

39. • Four randomised phase 3 trials have led to the use of PARP
inhibitors in the first line setting in ovarian cancers
• SOLO-1
• PAOLA-1
• PRIMA
• VELIA

40. Solo 1 trial
• SOLO-1 is the first Phase III trial to investigate maintenance therapy with a PARP inhibitor in
newly diagnosed ovarian cancer

41. • PFS benefit of maintenance olaparib was sustained beyond the
end of treatment

42. • Recurrence-free survival in patients who achieved complete
response to chemotherapy

43. • Secondary efficacy outcomes support the observed PFS benefit

44. conclusions
• • The benefit derived from maintenance olaparib was sustained substantially
beyond the end of treatment in newly diagnosed , advanced ovarian cancer and
BRCA mutation– Median PFS was 56 months, whereas median treatment
duration was only 25 months •
• More than half of women in complete response at baseline who received
maintenance olaparib for 2 years remained free from relapse 5 years later
• No new safety signals were observed with long-term follow-up –
• No new cases of MDS/AML were reported and incidence of new primary
malignancies remained balanced between arms .
• These results provide further evidence to support the use of maintenance
olaparib as a standard of care for women with newly diagnosed advanced
ovarian cancer and a BRCA mutation, and suggest the possibility of long-term
remission or even cure for some patients

45. Solo 1 led Recommendations
• The results of the solo 1 trial led to the new standard of care of
2 years of maintenance olaparib quotations with newly
diagnosed BRCA ½ mutation associated advanced ovarian
cancers
• This study highlights the importance of timely germline and
tumor testing to identify BRC a associated ovarian cancers so
women can be offered maintenance olaparib therapy

46. PAOLA1 TRIAL
• first and only phase 3 trial to investigate a PARP inhibitor
combination regimen against an active and established
maintenance therapy: bevacizumab
• Rational of this trial was built on prior studies reporting
the efficacy of bevacizumab given during platinum and
taxane chemotherapy and after maintenance
• This trial adress the activity of adding elaborate or
placebo as maintenance therapy along with
bevacizumab and included patients with and without
brca1 mutation

48. Baseline patient characteristics : matched

49. • Significant improved PFS

52. Trials in relapsed setting
• Solo 2
• Study 19

53. recommendations
• For the maintenance treatment of adult patients with deleterious or suspected
deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced
epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete
or partial response to first-line platinum-based chemotherapy;
• For the maintenance treatment of adult patients with recurrent epithelial ovarian,
fallopian tube or primary peritoneal cancer, who are in a complete or partial
response to platinum-based chemotherapy ;
• For the treatment of adult patients with deleterious or suspected deleterious
germline BRCA-mutated advanced ovarian cancer who have been treated with
three or more prior lines of chemotherapy;
• Lynparza in combination with bevacizumab is indicated for the: maintenance
treatment of adult patients with advanced high-grade epithelial ovarian, fallopian
tube or primary peritoneal cancer who are in response (complete response or
partial response) to first-line platinum-based chemotherapy with bevacizumab

54. Nccn 2021