Claudia Marchetti
Policlinico A. Gemelli Foundation, Catholic University of the Sacred Heart, Rome, Italy
Advances in ovarian cancer systemic therapy
Gynecologic malignancies: EPIDEMIOLOGY
50% are HRd including BRCAm, BRCA1/2 and RAD51 promoter methylation, BRIP1, and other genes involved in homologous recombination
25% ate tBRCAm at diagnosis
15% are gBRCAm at diagnosis
ITALY
Site | Incidence | Mortality | % Mortality |
Cervix | 3,700 | 1,700 | 40% |
Ovary | 4,150 | 2,700 | 60% |
Endometrium | 5,400 | 1,600 | 20% |
Biomarkers play an important role in diagnosing and defining patient populations in ovarian cancer
Half of high-grade serous OC exhibits a high degree of genomic instability due to deficiencies in homologous recombination
50% are HRd including BRCAm, BRCA1/2 and RAD51 promoter methylation, BRIP1, and other genes involved in homologous recombination
25% are tBRCAm at diagnosis
15% are gBRCAm at diagnosis
50% are HRd including BRCAm, BRCA1/2 and RAD51 promoter methylation, BRIP1, and other genes involved in homologous recombination
25% ate tBRCAm at diagnosis
15% are gBRCAm at diagnosis
�1. Moore K, et al. NEJM 2018 2. Ray-Coquard !, et al. NEJM 2019 3. Gonzales-Martin A…Mirza MR, et al. NEJM 2019
PARP inhibitors are effective in patients with primary ovarian cancer
SOLO11 BRCAmut | PAOLA12 | PRIMA3 |
Olaparib | Olaparib + bevacizumab | Niraparib |
First-Line maintenance Studies in OC with PARPi
| SOLO1 | PRIMA | PAOLA1 |
ITT | HR 0.30 (0.23-0.41) | HR 0.62 (0.50-0.76) | HR 0.59 (0.49-0.72) |
HRd | - | HR 0.43 (0.31-0.59) | HR 0.33 (0.25-0.45) |
HRd + BRCAmut | HR 0.30 (0.23-0.41) | HR 0.40 (0.27-0.62) | HR 0.31 (0.20-0.47) |
HRd+ BRCAwt | - | HR 0.50 (0.31-0.83) | HR 0.43 (0.28-0.66) |
HRp | - | HR 0.68 (0.49-0.94) | HR 0.92 (0.72-1.17) |
Efficacy according to BRCA and Genomic Instability
…. And FROM ESMO….
SOLO 1-Update
Prof. Ray-Coquard
PAOLA -1 update
12
30%
70%
20%
50%
FIT ENOUGH FOR 3weekly? Evaluate!
Advanced EOC regardless of surgical strategy (upfront vs. neoadjuvant)
Biomarker based algorithm
Eligible Patients
Niraparib*
Placebo*
36 months or until disease progression or unacceptable toxicity
Stratified randomization
*Individualised starting dose (ISD) was adopted in ALL patients: �starting dose of 200 mg administered orally, once daily, but 300 mg for patients with body weight ≥77 kg AND platelet count ≥150,000/µL
2:1 Randomization
a There was no histological restriction for patients carrying gBRCA mutations.
b Tumor HRD status testing was conducted with BGI assay (BGI Genomics, Shenzhen, China). The positive stratum consisted of patients who tested positive for tumor HRD with the BGI assay, and the other patients were grouped as the negative stratum.
c The HRD subgroup consisted of patients with a gBRCA mutations and/or tumor with homologous recombination deficiency.
BICR: blinded independent central review; CR, complete response; HRD, homologous recombination deficiency; ITT, intention-to-treat; OS, overall survival; PFS, progression-free survival; PR, partial response; Pt, platinum; TFST, time to first subsequent anti-cancer therapy.
Primary Endpoint
Secondary Endpoints
PRIME TRIAL
Li N et al SGO 2022
PRIME: randomized, double-blind, placebo-controlled phase III trial (NCT 03709316)
BICR, blinded independent central review; CI, confidence interval; HR, hazard ratio; ITT, intention-to-treat;�mPFS, median progression-free survival; NE, not estimable; PD, progressive disease.
Median follow-up: 27.5 months
| Niraparib�(N=255)) | Placebo (N=129) | |
PFS (54.4% data maturity) | |||
Events, n (%) | 123 (48.2) | 86 (66.7) | |
mPFS (95% CI), months | 24.8�(19.2–NE) | 8.3 (7.3–11.1) | |
Patients without PD or death (%) | |||
24 months | 52.6 | 30.4 | |
Li N et al SGO 2022
PFS (by BICR) in the ITT Population PRIME Study Primary Endopoint
16.5 months longer median PFS with niraparib vs placebo
Subgroup | Events/patients (%) | Hazard ratio for PFS (95% CI) | ||
Niraparib | Placebo | |||
Overall | 123/255 (48.2) | 86/129 (66.7) | | 0.45 (0.34–0.60) |
Age | | | | |
<65 years | 108/229 (47.2) | 73/114 (64.0) | | 0.47 (0.34–0.63) |
≥65 years | 15/26 (57.7) | 13/15 (86.7) | | 0.24 (0.09–0.66) |
Neoadjuvant chemotherapy | | | | |
Yes | 62/121 (51.2) | 46/59 (78.0) | | 0.32 (0.21–0.48) |
No | 61/134 (45.5) | 40/70 (57.1) | | 0.63 (0.42–0.94) |
Response to Pt-based chemotherapy | | | | |
Complete response | 98/212 (46.2) | 66/103 (64.1) | | 0.45 (0.32–0.61) |
Partial response | 25/43 (58.1) | 20/26 (76.9) | | 0.45 (0.23–0.86) |
gBRCA mutation status | | | | |
gBRCAmut | 35/85 (41.2) | 25/40 (62.5) | | 0.40 (0.23–0.68) |
Non-gBRCAmut | 88/170 (51.8) | 61/89 (68.5) | | 0.48 (0.34–0.67) |
Homologous recombination | | | | |
Deficient | 75/170 (44.1) | 57/87 (65.5) | | 0.48 (0.34–0.68) |
Proficient | 48/85 (56.5) | 29/42 (69.0) | | 0.41 (0.25–0.65) |
Postoperative residual disease status | | | | |
Optimal | 94/193 (48.7) | 71/105 (67.6) | | 0.44 (0.32–0.61) |
Suboptimal or missing | 29/62 (46.8) | 15/24 (62.5) | | 0.43 (0.21–0.87) |
CI, confidence interval; FIGO, International Federation of Gynecology and Obstetric;�PFS, progression-free survival; Pt, platinum.
Li N et al SGO 2022
PFS Benefit in Pre-specified Subgroups
ATHENA–MONO Study Schema
ATHENA-MONO Study Schema
ITT Population
HRD Population
Primary Endpoint- Investigator-Assessed PFS
Investigator-Assessed PFS: Exploratory Subgroups
Investigator-Assessed PFS: Exploratory Subgroups
20
| SOLO 1 | PAOLA 1 | PRIMA | PRIME | ATHENA |
ITT | | 22.1 vs 16.6 HR 0.59 | 13.8 vs 8.2 HR 0.62 | 24.8 vs 8.3 HR 0.45 | 20.2 vs 9.2 HR 0.52 |
BRCA-mt | 56.0 vs 13.8 HR 0.33 | 37.2 vs 21.7 HR 0.31 | 22.1 vs 10.9 HR 0.4 | NR vs 10.8 HR 0.40 | NR vs 14.7 HR 0.40 |
HRD-Test Positive | | 37.2 vs 17.7 HR 0.33 | 21.9 vs 10.4 HR 0.43 | NR vs 11 HR 0.48 | 28.7 vs 11.3 HR 0.47 |
HRD-BRCA-wt | | 28.1 vs 16.6 HR 0.43 | 19.6 vs 8.2 HR 0.5 | 24.8 vs 11.1 HR 0.58 | 20.3 vs 9.2 HR 0.58 |
HRD Test Negative | | 16.6 vs 16.2 HR 1 | 8.1 vs 5.4 HR 0.68 | 14.0 vs 5.5 HR 0.41 | 12.1 vs 9.1 HR 0.65 |
Median Follow-up | 57.6 mos | 27.4 mos | 13.8 mos | 27.5 mos | 26.1 mos |
Primary Maintenance
| Stage IV disease | Visible residual disease | Neoadjuvant chemotherapy | PR to chemotherapy | BRCAwt |
PRIMA | 35% | 47% | 67% | 31% | 70% |
PAOLA-1 | 30% | 40% | 42% | 27% | 70% |
PRIME | 28% | 22% | 47% | 18% | 67% |
ATHENA-MONO | 25% | 25% | 51% | 18% | 79% |
SOLO1 | 17% | 24% | 35% | 18% | 0% |
HIGH-RISK FACTORS:
Gonzalez-Martin et al., 2019; Braicu et al., 2020; Ray-Coquard et al., 2019; Li et al., 2022; Monk et al., 2022; Moore et al., 2018.
PRIMA did not include patients with stage III R0 after PDS
Undestanding differences in patient population is critical for interpreting efficacy results in PARPi studies
Any steps beyond?
ANY STEPS BEYOND?
BRCA pts: PARPi alone or PARPi plus BEVA?
PARPi in HRP: any sense or not?
HRD test: is it enough and is it affordable?
Toxicity: does it matter?
ANY STEPS BEYOND?
BRCA pts: PARPi alone or PARPi plus BEVA?
PARPi in HRP: any sense or not?
HRD test: is it enough and is it affordable?
Toxicity: does it matter?
Vergote et al SGO 2020
Note: Head-to-head studies have not been conducted and indirect trial comparisons are not recommended. �*These results are based on weighted outcomes after matching tumour location status, ECOG status, FIGO stage, type of surgery (interval vs. upfront), residual disease status after surgery, response to first-line treatment and age to SOLO-1. †Confidence intervals generated via bootstrapping
In SOLO-1 median follow-up was 40.7 months in the olaparib arm and 41.2 months in the placebo arm. In PAOLA-1 median follow up was up was 22.7 months in the olaparib + bevacizumab arm and 24.0 months in the placebo + bevacizumab arm. BRCAm, BRCA1 or BRCA2 mutation; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; FIGO, Federation of Gynecology and Obstetrics; HR, hazard ratio; PFS, progression-free survival. 1. Vergote I, et al. Presented at SGO Annual Conference 2020
BRCA pts: PARPi alone or PARPi plus BEVA?
Patients receiving olaparib maintenance monotherapy had a 29% reduction in the risk of disease progression at 24 months compared with those receiving olaparib monotherapy.
ANY STEPS BEYOND?
BRCA pts: PARPi alone or PARPi plus BEVA?
PARPi in HRP: any sense or not?
HRD test: is it enough and is it affordable?
Toxicity: does it matter?
PAOLA1 HRp
ATHENA-MONO HRp
PRIMA HRp
Patients with HRp tumours who have a poor prognosis also derive clinical benefit from maintenance therapy
PRIME HRp
HR Proficient subgroups of PRIMA versus Bevacizumab
PRIME HRp
Gonzalez…Mirza NEJM 2019; Burger NEJM 2011
HRP in BEVA HR 0.71 (0.60-0.85)
Clin Can Res 2018
Niraparib
BRCAwt; HR proficient
Bevacizumab
GOG-2018
OS subgroups analysis by BRCAm and HRD status
ANY STEPS BEYOND?
BRCA pts: PARPi alone or PARPi plus BEVA?
PARPi in HRP: any sense or not?
HRD test: is it enough and is it affordable?
Toxicity: does it matter?
BRCAwt, HR proficient population
HRD test: is enough?
The TEST we want
BRCAwt, HR proficient population
PROGNOSTIC
PREDICTIVE ??
HRD test is
HRD test analysis from TCGA data set for which copy number data and survival information were available
PRIMA HRd
PRIME HRd
ATHEN-MONO HRd
PAOLA-1 HRd
Gonzalez-Martin et al., 2019; Ray-Coquard et al., 2019; Li et al., 2022; Monk et al., 2022;
1L trials show substantial PFS benefit with PARPi maintenance therapy in patients with HRd tumours
| SubGroup | PARPi | PLACEBO | HR |
|
| N of patients (%) | N of patients (%) |
|
ATHENA-MONO1* (rucaparib m) | HRD | 50/94 (53.1) | 17/25 (68) | 0.58 (0.33 -1.01) |
CR to CT | 44/73 (54.7) | 8/11 (72.7) | 0.48 (0.23-1.03) | |
PRIMA2 (niraparib m) | HRD | 32/95 (33.7) | 33/55 (60.0) | 0.50 (0.31–0.83) |
CR to CT* | 146/337 (43.3) | 100/172 (58.1) | 0.60 (0.46–0.77) | |
PRIME3 (niraparib m) | HRD | 40/85(47) | 32/47 (68) | 0.88 (0.36–0.93) |
CR to CT | 98/212 (46.2) | 66/103 (64.1) | 0.45 (0.32–0.61) | |
PAOLA16§ (bevacizumab and olaparib m) | HRD | 43/97 (44) | 40/55 (73) | 0.43 (0.28–0.66) |
CR to CT | 54/106 (51) | 42/53 (79) | 0.44 (0.29–0.66) |
HAZARD RATIO OF PROGRESSION FREE SURVIVAL IN PARPi TRIALS
HRD testing should NOT BE USED TO EXCLUDE the oppurtunity for a patient to be offered PARPi therapy
Study | PRIMA | PRIME | ATHENA-MONO | PAOLA-1 | SOLO1 |
BRCAwt/HRd | 0.50 | 0.58 | 0.58 | 0.43 | Not available |
HRp | 0.68 | 0.41 | 0.65 | 1.00 | Not available |
HRD test | myChoice test (Myriad Genetics) > 42 | BGI PARP inhibitor CDx-HRD test | FoundationOne CDx test LOH > 16% | myChoice HRD Plus assay (Myriad Genetics) > 42 | Not available (BRACAnalysis test; Myriad Genetics) |
HRnd/test failure % (n/N) | 15% | Not available | 12% | 18% | Not available |
However, HRD testing does not reliably exclude all patients who do not benefit from PARPi maintenance
ANY STEPS BEYOND?
BRCA pts: PARPi alone or PARPi plus BEVA?
PARPi in HRP: any sense or not?
HRD test: is it enough and is it affordable?
Toxicity: does it matter?
| PRIME | PRIMA | PAOLA-1 | |||
TEAEs, n (%) | Niraparib (N=255) | Placebo (N=129) | Niraparib (N=484) | Placebo (N=244) | Ola+Beva (N=535) | Placebo (N=267) |
TEAEs leading to discontinuation | 17 (6.7) | 7(5.4) | 58 (12.0) | 6(2.5) | 109 (20) | 15 (6) |
Safety Overview: PRIME vs PRIMA vs PAOLA-1
Long-term side effects of PARP inhibitors
Recurrent disease
NO NEW SIGNIFICANT DATA
Treatment of Recurrent Ovarian Cancer
| OCEANS | GOG 213 | PFISTERER 2022 |
Status | Reported | Reported | Reported |
Population | HGSOC | HGSOC | HGSOC |
Design | Phase III | Phase III | Phase III |
Regimen | Carboplatin + Gemcitabine + Bevacizumab vs Carboplatin Gemcitabine | Standard CT + Bevacizumab vs standard CT | Carboplatin + Gemcitabine + Bevacizumab vs Carboplatin + PLD + Bevacizumab |
Primary endpoint | PFS | OS | PFS |
N randomization | 484 1:1 | 674 1:1 | 682 1:1 |
PFS HR | 0.48 | 0.62 | 0.81 |
| | | |
OS HR | 0.75 | 0.82 | 0.81 |
BEVACIZUMAB IN ROC
| AZ 19 | ENGOT-OV16 NOVA | SOLO 2 | ARIEL 3 |
Status | Reported | Reported | Reported | Ongoing |
Population | HSGC | gBRCAmut or Non gBRCA HGSC | gBRCAmut | HGSC or Emdometrioid |
Design | Phase II | Phase III | Phase III | Phase III |
Regimen | Olaparib Vs placebo | Niraparib Vs placebo | Olaparib Vs placebo | Rucaparib Vs Placebo |
Primary endpoint | PFS | PFS | PFS | PFS |
N randomization | 265 (2:1) | 553 (2:1) | 440 (2:1) | 540 (2:1) |
| | | | |
PFS HR | 0.30 | gBRCAmut 0.24 (PR), 0.30 (CR) gBRCAWT 0.35 (PR), 0.58 (CR) | 0.30 | 0.36 |
| | | | |
OS HR | 0.95 | / | 0.74 | Ongoing |
PARPi IN ROC
| | Rate of PARTIALLY PLASTINUM SENSITIVE pts after maintenance therapy | Rate of PLATINUM RESISTANT pts after maintenance therapy |
ICON 7 | BEV+ BEV- | 25% 20% | 15% 30% |
SOLO-1 | BRCAmut / OLA- | 25-30% | 20% |
| BRCAmut /OLA+ | 10% | 5% |
PRIMA | All pts / NIRA- | 25% | 40% |
| All pts / NIRA+ | 15% | 20% |
PAOLA-1 | All pts / BEV+ | 20% | 15% |
| All pts / BEV+OLA+ | 10% | 10% |
| *HRD-/ukn /BEV+OLA- | 20% | 15% |
Matulonis UA et al. Ann Oncol 2016; Coleman RL et al. Gynecol Oncol 2015
I consideration: the earlier you give PARPi, the greater the benefit
ASCO Reccomend AGAINST PARPi retreatment at the present time
Tew , JCO, 2020
II consideration: PARPi rechallenge is not allowed
OReO/ENGOT Ov-38 trial: Maintenance olaparib rechallenge
Statistically significant PFS benefit with olaparib in the BRCAm and Non-BRCAm cohort
BRCAm cohort
Non-BRCAm cohort
HR 0.57
HR 0.43
OReO/ENGOT Ov-38 trial: Maintenance olaparib rechallenge
Non-BRCAm cohort: HRD-positive
Non-BRCAm cohort: HRD-negative
Benefit in the non-BRCAm cohort irrespective of HRD status
HR 0.52
HR 0.49
OReO/ENGOT Ov-38 trial: Maintenance olaparib rechallenge
ORR 9.5% PFI <6 mo
ORR 11.1% PFI 6-12 mo
ORR 22.2% PFI >12 mo
III consideration:PARPi resistance IS AN ISSUE
WHY?
Different roads, but lead to the same destination
Mechanisms of resistance:
How overcoming resistance to PARPi?
Targeting new vulnerabilities
Preventing resistance to PARPi: Combination
Trial | Treatments | Endpoints |
FIRS LINE | | |
AGO-DUO | Platinum CT + Bevacizumab +/- Durvalumab +/- Olaparib | PFS |
FIRST | Pacli-Carbo CT +/- Bevacizumab +/- Dostarlimab +/- Niraparib | PFS |
ENGOT OV 43 | Pacli-Carbo CT +/- Bevacizumab +/- Pembrolizumab +/- Olaparib | PFS-OS |
Athena | Platinum CT followed by maintenance +/- Nivolumab +/- Rucaparib | PFS |
LATE RELAPSE | | |
Anita | Platinum CT + Niraparib +/- Atezolizumab | OS-PFS |
Site of oligometastatic progression | |
Lymph node (supra- and sub-diaphragmatic) | 17 (61%) |
Parenchymal disease | 8 (29%) |
Peritoneal | 6 (21%) |
Observational, Retrospective, Single arm study
28 PATIENTS WITH OLIGO-METASTATIC METASTASES UNDER TREATMENT WITH PARPi
Palluzzi, 2022, IJGC
PARP-inhibitors beyond progression: a way to manage
oligo-metastatic ovarian cancer recurrence
Artificially Prolonged-TFI: OMP-further progression or the last FU
Overall TFI: start of PARPi -extensive progression of disease
7 months
29 months
6 mo surgery, 7 mo SBRT
p 0.84
36 mo surgery, 29 mo SBRT
p 0.49
Progression: No differences according to type of local treatment
(40% after surgery and 38.8% after SBRT )
Observational, Retrospective, Single arm study
Palluzzi, 2022, IJGC
PARP-inhibitors beyond progression: a way to manage
oligo-metastatic ovarian cancer recurrence
… the concept of OLIGOMETASTASIS has arrived in OC….
ESMO 2022
ESGO 2022
CONCLUSIONS