SOLO-1: Maintenance Olaparib in Newly Diagnosed Advanced Ovarian Cancer

Title: Maintenance Olaparib in Newly Diagnosed Advanced Ovarian Cancer

Hypothesis: Maintenance PARP-i after initial therapy in high-grade ovarian carcinoma improves progression free survival.

Standard Arm: Placebo

Experimental Arm: Olaparib 300 mg bid daily x 2 years

Design: Double blinded randomized controlled phase 3 study

Inclusion Criteria: High-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian-tube cancer with mutation in BRCA1, BRCA2 (germline or somatic)

Primary Endpoint: PFS or death at 3 years

Outcomes: Experimental vs. Standard arm (p-value)

PFS/death at 3 years: 60% vs. 27% (p<0.001)

Median time to subsequent therapy: 51.8 months vs. 15.1 months (HR – 0.30, p<0.001)

Serious Adverse Events:Experimental vs. Standard arm (p-value)

Anemia (G3/G4): 22% vs. 2% (p=s.s.)

Neutropenia (G3/G4): 9% vs. 5% (p=s.s.)

AML: 3/260 (1%) vs. 0/130 (0%) (p=n.s)

New Primary Cancer: 5/260 (2%) vs. 3/130 (2%) (p=n.s.)

Pneumonitis/Interstitial Lung Disease: 5/260 (2%) vs. 0 (p=n.s)

Conclusion: Addition of Olaparib 300mg bid for two years maintenance after completion of primary chemotherapy and debulking surgery in BRCA 1/2 (both germline or somatic) increases progression free survival or risk of death at 3 years.

GOG 218

Incorporation of bevacizumab in the primary treatment of ovarian cancer.

Pubmed

First Author: Burger RA

Hypothesis: Addition of bevacizumab improves progression free interval in previously untreated, incompletely resectable Stage III or any Stage IV EOC, surgery within 12 weeks. (PROTOCOL modification → Patients with Optimal debulking were included later in the trial)

Site: Ovary

Experimental arm – 1 (Bev-initiation): 175 mg/m2 paclitaxel (IV-3hrs) Carboplatin AUC 6 Bev 15 mg/m2 Cycle 2-6 followed by placebo cycle 7-22

Experimental arm – 2 (Bev-maintenance):175 mg/m2 paclitaxel (IV-3hrs) Carboplatin AUC 6 Bev 15 mg/m2 cycle 2-22

Standard Arm: 175 mg/m2 Paclitaxel (IV-3hrs) carboplatin AUC 6 IV x 6 cycle + placebo cycles 2-22

Primary Outcome: Originally planned was overall survival but changed to Progression free survival

Results:

Outcome Standard Bev-Inititation Bev-Maintenance p-value
PFS 10.3 11.2 14.1 SS
OS 39.3 38.7 39.7 NS
G3/4 – % cases
GI* 1.8 2.8 2.6 SS
HTN 7.2 16.5 23 SS
Neutropenia % 57 63 63 NS
VTE 5.8 5.3 6.7 NS
Arterial thrombosis 0.8 0.8 0.7 NS
CNS bleed 0 0 0.3 NS

*perforation, fistula, necrosis, or anastomotic leak

Conclusions: Marginal improvement in PFS, no significant improvement in OS

Important studies:

GOG Ancillary Study: Ascites predicts improved response to bevacizumab

Cost-effectiveness Study: Bevacizumab addition is not cost-effective

Other details

Arm Distribution:

Standard: 625 total - 83% serous,2.2% endometrioid, 3.7% clear cell and 10% other. 33% 1 cm disease, 26% stage IV


Experimental 1 (bev-inititation): 623 total - 84% serous,4% endometrioid, 3.2% clear cell, 1.3% mucinous, 7.5% other. 35%  1 cm disease, 26% stage IV


Experimental 2 (bev-maintenance): 625 total - 87% serous,3.4% endometrioid, 1.9% clear cell, 1% mucinous, 7.5% other. 35%  1 cm disease, 26% stage IV

GOG 152

Secondary surgical cytoreduction for advanced ovarian carcinoma

Pubmed

First Author: Rose PG

Hypothesis: Secondary debulking in sub optimally >1 cm tumor patients after 3 cycles of chemotherapy improves survival

Site: Ovary

Experimental arm: Suboptimal surgery –> 3 cycles of cisplatin 75 mg/m2 Paclitaxel 135 mg/m2 q-24 hr –>Secondary debulking –> 3 further cycles

Standard Arm: Suboptimal surgery –> 6 cycles of cisplatin 75 mg/m2 Paclitaxel 135 mg/m2 q-24 hr

Primary Outcome: OS

Arm Distribution:

Experimental arm (secondary debulking arm): N=208 (Serous 76%, Endometrioid 8%, Measurable disease at 3 cycles 1-2 cm 12%, 2-5 cm 43%, 5-10 cm 33%, > 10 cm 12%)

Standard arm (no secondary debulking): N=216 (Serous 76%, Endometrioid 5%, Measurable disease at 3 cycles 1-2 cm 12%, 2-5 cm 44%, 5-10 cm 38%, > 10 cm 6%)

Results:

Outcome Secondary debulking Chemotherapy only p-value
PFS (Months) 10.5 10.7 NS
OS 33.9 33.7 NS
Neuropathy G2/4 16% 26% SS
GI G2/4 7% 4% SS

Conclusions: If maximum surgical effort up front (by a gynecologic oncologist), no benefit to interval cytoreduction


GOG 172

Intraperitoneal cisplatin and paclitaxel in ovarian cancer

Pubmed

First Author: Armstrong DK

Hypothesis: IP chemotherapy improves overall survival in optimally debulked ovarian cancer

Site: Ovary

Experimental arm: 135 mg/m2 paclitaxel (IV-24hrs) cisplatin 100 mg/m2 IP day 2 60 mg Paclitaxel IP day 8 (All IP meds with 2 L warm saline)

Standard Arm: 135 mg/m2 Paclitaxel (IV-24hrs) cisplatin 75mg/m2 IV on day 2

Primary Outcome: Overall survival

Results:

Outcome IP/IV IV only p-value
PFS 23.8 18 SS
OS 65.6 49.7 SS
Completed all planned cycles 42% 83% SS
G3/G4Toxicity
GI 46% 24% SS
Neutropenia 76% 64% SS
Neuropathy 19% 9% SS
Fatigue 18% 4% SS

Conclusions: Significant improvement in PFS and OS in optimally debulked patients (<1 cm)

Controversies (Select editorials worth reading)

Pro IP chemotherapy

Against IP chemotherapy