ASCO 2024 Updates in Ovarian Cancer

31 May - 4 Jun, 24

ASCO 2024

Chicago, IL

31 May - 4 Jun, 24

ASCO 2024

Chicago, IL

Atezolizumab versus Placebo in Combination with Bevacizumab and Non-Platinum-Based Chemotherapy in Recurrent Ovarian Cancer: Final Overall and Progression-Free Survival Results From The AGO-OVAR 2.29/ENGOT-ov34 Study.

Background

Paclitaxel or pegylated liposomal doxorubicin (PLD) in combination with bevacizumab (bev) are standard treatment options in patients with relapsed ovarian cancer not candidates for platinum, but responses are usually short-lived.
Recently, two trials have reported a numerical but non-significant advantage from the addition of atezolizumab (atezo) to chemo plus bev in the recurrent setting (ATALANTE, Kurtz JE et al., J Clin Oncol & NRG GY009, O'Cearbhaill et al, IGCS 2023).

Aim

To assess the efficacy of atezo in combination with bev and non-platinum-based chemo.

Methods

Randomized, double blind, phase III trial
N= 574 patients (pts) with recurrent ovarian cancer receiving atezo 840 mg q14 days plus bev or chemo (1:1 randomization) until progression or for a maximum duration of 24 months.
Eligible patients had a 1st/2nd relapse within 6 months after completing platinum-based chemo or a 3rd relapse regardless of treatment-free interval.
A fresh biopsy for central PD-L1 testing prior to randomization was mandatory.
Stratification factors - Number of prior lines, planned chemo, prior bev and PD-L1 status
Primary endpoints - Overall survival (OS), progression-free survival (PFS) in the intention to treat (ITT) population (both to be analyzed after observation of 391 deaths).
Data cut-off (DCO) occurred on 26/01/2024.
Safety is reported for pts who received at least one dose of study treatment.

Results

45.1% received PLD and 53.7% paclitaxel.
7 pts did not start study treatment.
Pts received 3 prior lines - 36.1%; Prior bev - 72.5%
PD-L1 positive - 25.8%
At DCO in atezo vs placebo arm –
1. OS events – 418; PFS events - 505
2. mOS - 14.3 vs 13.0 mos (HR 0.83, 95% CI 0.68-1.01; p=0.06)
3. mPFS 6.3 vs 6.6 mos (HR 0.88, 95% CI 0.73-1.05; p=0.15)
4. Similar HR were observed in PD-L1 positive and negative pts.
580 SAE and 141 AESI were reported.
≥ Grade 3 AEs - 71.5% vs 68.9%
Serious AEs - 63.7% vs 51.4%.

Conclusion

The addition of atezo to chemo plus bev did not significantly improve OS or PFS in pts. with recurrent ovarian cancer who are no candidates for platinum. Safety was within the expected range.

Reference

American Society of Clinical Oncology (ASCO) 2024 Congress. 31st May – 4th June 2024. Chicago, IL. Abstract No LBA5501.

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Omission of Lymphadenectomy in Patients with Advanced Epithelial Ovarian Cancer Treated with Primary or Interval Cytoreductive Surgery After Neoadjuvant Chemotherapy: The CARACO Phase III Randomized Trial.

Background

Lion trial demonstrated the lack of benefit of retroperitoneal pelvic and paraaortic lymphadenectomy (RPPL) in primary surgery in advanced epithelial ovarian cancer (AEOC) with clinically negative lymph nodes.

Aim

To assess the role of RPPL during interval cytoreductive surgery after neoadjuvant chemotherapy.

Methods

Prospective multi-institutional phase III trial
N= 379 patients with newly diagnosed AEOC FIGO III-IV, with no pre- and intra-operative suspicious lymph nodes
Randomized intra-operatively to RPPL (n=181) vs no-RPPL (n=187)
Stratified by surgical strategy (primary surgery, surgery after neoadjuvant chemotherapy).
Primary endpoint – PFS

Results

Required sample size was not reached because of a stop of inclusion after the publication of the Lion trial.
The median number of removed lymph nodes in patients randomized to RPPL was 27 [IQR=19-36].
Neoadjuvant chemotherapy - 75% patients (244 patients treated with 3 or 4 cycles before interval surgery and 41 patients treated with 6 cycles before delayed surgery)
83 patients treated with primary surgery followed with adjuvant platinum-based chemotherapy.
The rate of surgery with no residual was 86% and 88% respectively in the No RPPL and the RPPL arm.
Lymph node metastases - 49% patients in the RPPL arm, with a median of 3 involved lymph nodes [IQR=2-7].
Median follow up - 9 years
mPFS in the no-RPPL vs RPPL arm - 14.8 vs 18.5 mo respectively (HR 0.98, 95%CI 0.78-1.22, p=0.86)
mOS - 48.9 vs 58.0 mo (HR 0.96, 95%CI 0.75-1.22 p=0.72)
Results considering PFS & OS were not different in complete surgery or a neoadjuvant chemotherapy subgroup.
Serious post-operative complications - Re-laparotomies 8.3% vs 3.2% [p=0.03], transfusion rate (34% vs 25%, p=0.05).
Mortality within 60 days after surgery - 1.1 vs 0.5% [p=0.54]

Conclusion

CARACO trial is the first randomized trial showing that systematic lymphadenectomy should be omitted in AEOC with clinically negative lymph nodes also in patients undergoing neoadjuvant chemotherapy and interval complete surgery. This surgical de-escalation allows to significantly reduce serious post operative morbidity.

Reference

American Society of Clinical Oncology (ASCO) 2024 Congress. 31st May – 4th June 2024. Chicago, IL. Abstract No LBA5505.

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Phase II Randomized Multi-centre Study of Neoadjuvant Olaparib in Patients with Platinum Sensitive Relapsed High Grade Serous Ovarian Cancer: The NEO Trial.

Background

Recurrent Platinum sensitive (PS) high grade serous ovarian cancer (HGSOC) can be managed in selected patients (pts) with secondary cytoreductive surgery and systemic therapy.

Aim

To assess potential for de-escalation therapy postsurgery with the PARP inhibitor (PARPi) olaparib given prior to secondary cytoreductive surgery in PS HGSOC.

Methods

Phase II, open label, randomized study
N= 44 PARPi naïve pts with recurrent HGSOC ≥6 months following previous platinum therapy
Pts were suitable for secondary cytoreductive surgery and underwent tumor biopsy before neo-adjuvant therapy with olaparib 300mg po bid for 6 ± 2 weeks.
Post-operatively, pts were randomized 1:1 to –
1. Arm A (n=19) - 6 cycles of platinum chemotherapy followed by maintenance Olaparib
2. Arm B (n=17) - Olaparib alone 28 days cycle
Primary endpoint - PFS wit
Secondary endpoint - OS
Response was assessed by RECIST 1.1.
AEs were assessed with CTCAE v4.03.

Results

Median follow-up - 3.96 (2.23-5.29) years
Median age - 59 (53-66) years
Deleterious germline BRCA1/2 mutation - 31%
Median duration of neo-adjuvant - 40 (34-48) days, ranging from 20 to 120 days
Pts proceeded to surgery - 36
86% were surgically cytoreduced to no visible residual disease
Arm A vs Arm B:
1. Median cycles of all adjuvant therapy was similar in the two arms (21.5 vs 18 cycles, p=0.60)
2. Median time on adjuvant olaparib - 13.8 vs 14.7 mo
3. 3-year PFS rate – 84.2 % (69.3% - 100%)
4. 3-year OS rates - 75.1% (56.6%-99.7%) [HR: 0.90 (0.28, 2.83)]
5. No difference in PFS or OS between the arms (p=0.85).
6. Subjects with no visible residual disease had better OS (HR=0.23, p=0.0097).
7. No cases of MDS/AML were reported.
8. No grade >3 AEs during neoadjuvant therapy
9. Grade >3 AEs during first 6 months of adjuvant therapy - 16% vs 4% pts.

Conclusion

Neo-adjuvant olaparib followed by cytoreductive surgery was feasible and safe in PS HGSOC. In pts with resectable disease at secondary cytoreduction, olaparib alone post-surgery was as effective as chemotherapy followed by olaparib and less toxic, suggesting the potential for a chemo-free approach in this selected population. Translational research is on-going to assess biomarkers of response/resistance.

Reference

American Society of Clinical Oncology (ASCO) 2024 Congress. 31st May – 4th June 2024. Chicago, IL. Abstract No 5506.

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Intratumoral Ral-binding Protein 1 (RalBP1) Expression as a Potential Predictor of Bevacizumab Treatment Efficacy in Patients with Ovarian Cancer.

Background

The anti-VEGF antibody bevacizumab (Bev) has become part of the first-line treatment of patients with advanced ovarian cancer (OC) due to its significant impact on progression-free survival (PFS).

However, a significant effect on overall survival (OS) was not demonstrated.

Aim

It was hypothesized that the stress-responsive multidrug transporter and modulator of neovascularization Ral-binding protein 1 (RalBP1) might be prognostic for patient survival and patients were stratified according to their predicted Bev response.

Methods

N= 554 patients with epithelial OC
Tissue samples were obtained during first-line cytoreductive surgery
RalBP1 immunohistochemical staining was quantified using a mean staining intensity score (MSIS, 1-3) and a cut-off was defined as 2.5.
Correlation between MSIS and clinicopathologic data was assessed using two-sample t-tests.
Additional correlation measures - Spearman’s correlation, Chi2-test and ANOVA.
PFS and OS were visualized by Kaplan-Meier curves

Results

RalBP1 was present in the cytosol of almost all OC cells and independent of histopathologic subtype or grading:
1. RalBP1-low: n= 385
2. RalBP1-high: n= 169
Patients with elevated intratumoral RalBP1 expression showed significantly improved mPFS (73.5 vs. 35.8 months, HR=0.62, p=0.033) and mOS (120.1 vs. 71.7 months, HR=0.56, p=0.007) after complete tumor debulking and platin-based adjuvant chemotherapy (n=155).
In a comprehensive multivariate analysis, RalBP1 expression levels emerged as an independent prognostic marker for both OS (HR=0.67, p=0.031) and PFS (HR=0.72, p=0.033).
In the subgroup of all patients that received an adjuvant platinum-based chemotherapy (n=351), the RalBP1–low patient status was shown to be a predictive factor for response to Bev therapy for both PFS (median 26.4 vs. 18.1 months, HR=0.94, p=0.036) and OS (median 63.4 vs. 49.3 months, HR=0.72, p=0.041).

Conclusion

RALBP1 may serve as a prognostic biomarker for OC patients, helping to identify those who are likely to benefit not only in PFS but also in OS following Bev therapy. Its tumor biological role remains a matter of current investigations.

Reference

American Society of Clinical Oncology (ASCO) 2024 Congress. 31st May – 4th June 2024. Chicago, IL. Abstract No 5576.

Final Results of BrUOG 354: A Randomized Phase II Trial of Nivolumab Alone or in Combination with Ipilimumab for People with Ovarian and Other Extra-Renal Clear Cell Carcinomas

Background

Extra-renal clear cell cancer (CCC) are rare tumors that can arise from any organ. Gynecologic CCC can originate from the ovaries, endometrium, or cervix.

Compared to serous carcinomas, ovarian CCC is associated with poorer outcomes to standard chemotherapy, warranting a focused evaluation for innovative therapies.

Aim

To present the final results of treatment using nivolumab (N) monotherapy and in combination with ipilimumab (I) in extra-renal CCC.

Methods

Randomized two-stage phase II study
N= 44 patients with relapsed extra-renal CCC receiving single-agent N (240mg IV every two weeks) or in combination with I (1mg/kg every six weeks) (N/I) after at least one prior therapy (no prior immunotherapy).
Measurable disease was required.
In the first stage, volunteers were randomly assigned to N or N/I with stratification by tumor site (ovarian vs extra-ovarian).
Treatment was continued until disease progression or unacceptable toxicity.
Each arm was evaluated for overall response rate (ORR) separately at stage 1 using RECIST and iRECIST criteria.
In January 2022, the N arm was closed, and subsequent volunteers were treated with N/I.

Results

Median age - 57 (18-75) years
75% were White, 9.1% Black, 4.5% were Asian, and 11.4% were Hispanic.
All volunteers had a gynecologic primary, 36 (82%) with ovarian CCC.
Median number of prior lines - 1 (range, 1-7).
Overall Response Rate (ORR) –
1. N - 14.3% (2 Partial Responses)
2. N/I - 33% (4 Complete and 6 Partial Responses).
Four people continue on treatment with N/I as of December 2023.
Median follow up - 11.3 (1.6-46.4) months.
mPFS - 2.2 (95% CI 1.2-3.4) months with N and 5.6 (95% CI 1.6-29.1) months with N/I
mOS - 17 (95% CI 2.1-NR) and 24.6 (95% CI 5.9-NR) months
Serious treatment-related adverse events - 21% with N (all grade 3) and 47% with N/I (2 patients had grade 4 pancreatic enzyme elevations).
No new safety signals were noted, and no treatment-related deaths were observed in either arm.

Conclusion

Immunotherapy demonstrated important, meaningful, and durable activity in people with previously treated gynecologic CCC including four (12%) volunteers who achieved a complete response with N/I. N/I warrant further evaluation against standard treatment for people with ovarian CCC, given the historically chemotherapy-resistant nature of the disease.

Reference

American Society of Clinical Oncology (ASCO) 2024 Congress. 31st May – 4th June 2024. Chicago, IL. Abstract No LBA5500.

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Overall Survival (OS) in Patients with Platinum-Sensitive Relapsed Ovarian Cancer (PSROC) Treated with Olaparib Maintenance Monotherapy: Update from the L-MOCA Trial.

Background

The open-label, single-arm, L-MOCA trial (NCT03534453) was the first study to demonstrate promising efficacy and tolerability of olaparib maintenance monotherapy in Asian patients with PSROC (median progression-free survival 16.1 months).

Aim

To report the interim OS analysis.

Methods

The study enrolled Asian patients with high-grade epithelial PSROC who had received ≥2 prior lines (L) of platinum-based chemotherapy and achieved complete or partial response.
Patients were treated with oral olaparib (300 mg) twice daily until disease progression or unacceptable toxicity.
A prespecified descriptive analysis of OS, a secondary endpoint, was conducted after approximately 3 years of follow-up.
OS was analyzed in the full analysis set (FAS; defined as patients who received olaparib) and in subgroups defined by biomarker status (BRCA mutation/homologous recombination deficiency (HRD) status) and prior L of anticancer therapy.

Results

Data cutoff - 16 Nov 2023
Median duration of follow-up - 40.0 months (0.5–64.2)
Deaths - 105 (46.9%)
mOS
1. FAS (N=224)- 54.4 months (95% CI 43.8–not evaluable [NE])
2. BRCAm subgroup - Not reached (NR; 51.9–NE)
3. BRCAwt subgroup - 44.3 months (34.8–59.1)
4. Patients with HRD - 59.1 (43.5–NE)
  - HRD BRCAwt - 54.6 months (33.0–NE)
5. Homologous recombination proficiency (HRP) subgroup - 37.2 months (28.3–56.1).
Adverse events of any grade - 222 (99.1%) patients
Incidence of myelodysplastic syndrome and acute myeloid leukemia remained low (3 [1.3%]).
No new safety signals were identified.

	Patients with events, n/N (%)	Median OS, months, (95% CI)
FAS	105/224 (46.9	54.4 (43.8–NE)
**BRCAMutation Status^a**
BRCA_m	43/106 (40.6)	NR (51.9–NE)
BRCA_wt	61/117 (52.1)	44.3 (34.8–59.1)
HRD Status^a
HRD+	56/128 (43.8)	59.1 (43.5–NE)
HRD+BRCA_wt	13/22 (59.1)	54.6 (33.0-–NE)
HRP	48/95 (50.5)	37.2 (28.3-56.1)
Prior L of Anticancer Therapy
2 L	63/144 (43.8)	NR (48.7–NE)
>2 L	42/80 (52.5)	43.5 (29.6–59.1)
**BRCAMutation Status in Patients with 2 L Anticancer Therapy**
BRCA_m	24/67 (35.8)	NR (55.2–NE)
BRCA_wt	39/77 (50.6)	45.2 (33.5–NE)
**BRCAMutation Status in Patients with >2 L Anticancer Therapy**
BRCA_m	19/39 (48.7)	53.6 (29.3–NE)
BRCA_wt	22/40 (55.0)	38.0 (24.2–NE)

^aHRD status and BRCA mutations were detected in tumor tissue. 1 patient had unknown HRD/BRCA mutation status due to missing test results.

Conclusion

Olaparib showed promising OS benefit in Asian patients with PSROC, regardless of the BRCA mutation or HRD status, with a well-tolerated safety profile.