1. The intent to treat(ITT) population include all BRCA-wild type patients
which include HRD negative patients as well (Rubraca patient pool)(Source)
The final PFS results are as following(Source).
Treatment
Paclitaxel/carboplatin plus bevacizumab
Maintenance
Bevacizumab
Bevacizumab+ Durvalumab
Bevacizumab+ Durvalum
PFS In
Months(HRD+ve)
23.3
25.1
45.1
PFS in Months (ITT)
19.3
20.6
25.1
The PFS benefit in BRCA wild-type group is meaningful but there is no significant
OS benefit.
However, the PFS for HRD+ve subgroup is 45.1 Months which is highest ever
recorded PFS in this setting.
This suggest that the triple combination of chemotherapy, targeted therapy &
Immunotherapy achieves the best possible results in treatment of newly diagnosed,
BRCA wild type HRD+ advanced, high-grade epithelial OC.
Please find the full alert below. We have also attached the relevant links for your
reference. Please reach out to us if you have any query.
Progression-free survival benefit confirmed with triplet combination in BRCA
wild-type, HRD-positive ovarian cancer
Source: ASCO-POST 16/04/2024
Key Takeaways:

The combination of immunotherapy, targeted therapy, and chemotherapy could
be the new standard first-line treatment of patients with high-grade,
advanced ovarian cancer with BRCA wild-type, homologous recombination
deficiency (HRD)-positive tumours (Source).

The triple combination (Bevacizumab+ Durvalumab+Olaparib) has shown
significant efficacy in HRD+ group. The pfs is 45.1 Months(Highest in this
setting).

In the ITT- population, triple combination demonstrated an improvement in
median progression-free survival but no significant OS benefit(Source).

DUO-O study is ongoing, and further insights into the long-term benefits of
this novel combination will be provided in future follow ups.
Background:

DUO-O evaluated the benefit of incorporating both the PD-L1 antibody
durvalumab and the PARP inhibitor Olaparib to standard treatment with
paclitaxel/carboplatin and bevacizumab.

The cohort include patients with stage III or IV high-grade epithelial tumours
lacking somatic BRCA mutations. Patients(ITT-Population) were either HRDpositive (39%), HRD-negative (55%), or HRD-unknown (6%) (Source).
Implications

With PFS is 45.1 Months the triplet combination has established itself as a new
standard for therapy in untreated HRD +ve high-grade advanced ovarian
cancer patients.

In the ITT-population, a meaningful slight PFS benefit on addition of
durvalumab, but no significant OS benefit is recorded. However, if Olaparib
receives approval on basis of future follow-up results that will mean
potential entry of Olaparib in HRD-ve segment & challenges for other PARPs
including Rubraca.
2. Dear All,
Below, for your reference, is an article highlighting the first-in-human results for
saruparib, a next-generation PARP inhibitor, from the phase 1/2a PETRA module trial.
While the PETRA trial is in a type of breast cancer, it’s worth noting that according to
clinicaltrials.gov, AZD currently has three trials investigating saruparib in prostate,
mCRPC, and pan-tumor basket studies (including endometrial and aOC).
I would also like to highlight the article correctly refers to pharmaand as the
manufacturer of Rubraca – ‘Approved PARP inhibitors include AstraZeneca and Merck
& Co.’s Lynparza, pharmaand’s Rubraca and GSK’s Zejula.
Click on the link below to access the full article. I have also provided coverage from the
AACR newsroom. Many other outlets covered this data presentation, but these two
pieces provided a good overview of the broader coverage.
AACR 24: AstraZeneca PARP inhibitor gives 'bang for your buck' (fiercebiotech.com)
https://www.aacr.org/about-the-aacr/newsroom/news-releases/next-generation-parpinhibitor-demonstrates-clinical-benefit-in-patients-with-homologous-recombinationrepair-deficient-breast-cancer/
3. Repare Therapeutics RP-3467 demonstrated synergistic activity
preclinically in combination with PARP inhibitors. Expected Ph. 1 trial in
second half- 24
Source: Repare Therapeutics- Annual Report , February 28th, 2024
Key Takeaways:

Repare Therapeutics has recently reported an update on RP-3467 a Polθ
ATPase inhibitor.

RP-3467 demonstrated complete, sustained tumour regressions preclinically
in combination with PARP inhibitors. and compelling anti-tumor activity in
combination with radioligand therapy and chemotherapy.

Preclinical studies have shown that inactivation of Polθ, both on its own and in
combination with PARP inhibitors, reduces survival in BRCA-mutated cells,
but not in BRCA wild-type cells(source).

Combination with Olaparib achieved highly durable tumour regressions, for up
to 90 days post treatment, with no additive of synergistic toxicities.

RP-3467 is capable of synergism with PARPis and show complete regression
in PARPi resistance models(Source)

Ph-1 clinical trials expected in H 2 2024.
Background:

RP-3467 is a under development small molecule inhibitor of polymerase theta, or
Polθ, a target associated with BRCA mutations and other genomic alterations.

Polθ is a synthetic lethal target associated with homologous recombination
deficiency (HRD) tumors, including those with BRCA1/2 mutations or other
genomic alterations.

RP-3467 works effectively and synergistically with therapies that result in
double stranded DNA breaks, such as PARP inhibition, radioligand therapy
(RLT) and multiple chemotherapies and antibody-drug conjugates (ADCs).
Implications

Promising preclinical data suggest potential for development combinations with
PARPis for use in overcoming PARPi resistance in BRCA mutated patients.

Potential of strategic partnerships & collaboration for development of
combination of PARPis/Rubraca with Polθ ATPase inhibitors.

Potential competition from combinations (PARPi + Polθ ATPase inhibitor) in
future especially in PARPi reuse in advanced stages.
4. Dear all,
We would like to bring to your attention a recent news alert regarding (Bevacizumab+
Durvalumab+Olaparib) a combination currently in Ph.III trial for treatment of advanced
ovarian cancer(OC) in BRCA wild type population.
AstraZeneca has recently presented the interim results for its Ph.III clinical trial
DUO-O.
The Key highlights of results are as following.
The intent to treat(ITT) population include all BRCA-wild type patients which
include HRD negative patients as well (Rubraca patient pool)(Source)
The final PFS results are as following(Source).
Treatment
Paclitaxel/carboplatin plus bevacizumab
Maintenance
Bevacizumab
Bevacizumab+ Durvalumab
Bevacizumab+ Durvalum
PFS In
Months(HRD+ve)
23.3
25.1
45.1
PFS in Months (ITT)
19.3
20.6
25.1
The PFS benefit in BRCA wild-type group is meaningful but there is no significant
OS benefit.
However, the PFS for HRD+ve subgroup is 45.1 Months which is highest ever
recorded PFS in this setting.
This suggest that the triple combination of chemotherapy, targeted therapy &
Immunotherapy achieves the best possible results in treatment of newly diagnosed,
BRCA wild type HRD+ advanced, high-grade epithelial OC.
Please find the full alert below. We have also attached the relevant links for your
reference. Please reach out to us if you have any query.
Progression-free survival benefit confirmed with triplet combination in BRCA
wild-type, HRD-positive ovarian cancer
Source: ASCO-POST 16/04/2024
Key Takeaways:

The combination of immunotherapy, targeted therapy, and chemotherapy could
be the new standard first-line treatment of patients with high-grade,
advanced ovarian cancer with BRCA wild-type, homologous recombination
deficiency (HRD)-positive tumours (Source).

The triple combination (Bevacizumab+ Durvalumab+Olaparib) has shown
significant efficacy in HRD+ group. The pfs is 45.1 Months(Highest in this
setting).

In the ITT- population, triple combination demonstrated an improvement in
median progression-free survival but no significant OS benefit(Source).

DUO-O study is ongoing, and further insights into the long-term benefits of
this novel combination will be provided in future follow ups.
Background:

DUO-O evaluated the benefit of incorporating both the PD-L1 antibody
durvalumab and the PARP inhibitor Olaparib to standard treatment with
paclitaxel/carboplatin and bevacizumab.

The cohort include patients with stage III or IV high-grade epithelial tumours
lacking somatic BRCA mutations. Patients(ITT-Population) were either HRDpositive (39%), HRD-negative (55%), or HRD-unknown (6%) (Source).
Implications

With PFS is 45.1 Months the triplet combination has established itself as a new
standard for therapy in untreated HRD +ve high-grade advanced ovarian
cancer patients.

In the ITT-population, a meaningful slight PFS benefit on addition of
durvalumab, but no significant OS benefit is recorded. However, if Olaparib
receives approval on basis of future follow-up results that will mean
potential entry of Olaparib in HRD-ve segment & challenges for other PARPs
including Rubraca.