Phase II study of aromatase inhibitors in women with potentially hormone responsive recurrent/metastatic gynaecological neoplasms

Phase 2

Completed

• Conditions: Hormone sensitive recurrent or metastatic gynecological cancers; Cancer - Ovarian and primary peritoneal; Cancer - Womb (Uterine or endometrial cancer)

• Registration Number: ACTRN12610000796088
• Lead Sponsor: niversity of Sydney

Brief Summary

Platinum resistant/refractory recurrent Ovarian Cancer subgroup Background: There is some evidence that a subset of patients with recurrent ovarian cancer may benefit from antiestrogen therapy. The Paragon study is a basket protocol that includes a series of phase 2 trials investigating the activity of anastrozole in patients with estrogen or progesterone receptor positive recurrent gynecological cancers. We report the results of treatment in patients with platinum-resistant or -refractory recurrent epithelial ovarian cancer. Methods: Postmenopausal women who had estrogen and/or progesterone receptor positive platinum-resistant or platinum-refractory recurrent ovarian cancer and disease measurable by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 or GCIG (Gynecologic Cancer Inter Group) CA-125 criteria were eligible. Patients received anastrozole 1 mg daily until progression or unacceptable toxicity. The study was prospectively registered (ACTRN12610000796088). Results: There were 49 evaluable patients, and clinical benefit was observed in 13 (27%; 95%confidence interval [CI], 16%Y40%). There were no complete or partial RECIST version 1.1 responses. Clinical benefit was associated with higher global quality-of-life scores. Median progression-free survival was 2.7 months (95% CI, 2.0Y2.8 months). The median duration of clinical benefit was 2.8 months (95% CI, 2.6Y5.7 months). Most patients (83%) progressed within 6months. Seven patients continued on treatment for longer than 6months. Anastrozole was well tolerated in most patients. Subgroup analysis suggested greater clinical benefit in patients with tumors with estrogen-receptor histoscore of more than 200, but this difference was not statistically significant. Conclusions: A subset of patients with estrogen- or progesterone-positive platinum-resistant or platinum-refractory recurrent epithelial ovarian cancers derives clinical benefit from anastrozole, with acceptable toxicity. The challenge remains how to identify them. Asymptomatic CA125 subgroup Objective: A subset of patients with recurrent ovarian cancer (ROC) may benefit from antiestrogen therapy with higher response rates reported in tumors that are strongly estrogen receptor (ER)-positive (ER+). PARAGON is a basket trial that incorporates 7 phase 2 trials investigating the activity of anastrozole in patients with ER+ and/or progesterone receptor (PR)-positive (PR+) recurrent/metastatic gynecological cancers. Methods: Postmenopausal women with ER+ and/or PR+ ROC, who were asymptomatic and had cancer antigen 125 (CA125) progression after response to first line chemotherapy, where chemotherapy was not clinically indicated. Patients received anastrozole 1 mg daily until progression or unacceptable toxicity. Results: Fifty-four patients were enrolled (52 evaluable). Clinical benefit at three months (primary endpoint) was observed in 18 patients (34.6%; 95% confidence interval [CI]=23%–48%). Median progression-free survival (PFS) was 2.7 months (95% CI=2.1–3.1). The median duration of clinical benefit was 6.5 months (95% CI=2.8–11.7). Most patients progressed within 6 months of starting anastrozole but 12 (22%) continued treatment for longer than 6months. Anastrozole was well tolerated. In the exploratory analysis, ER histoscores and the intensity of ER staining did not correlate with clinical benefit rate or PFS. Conclusion: A subset of asymptomatic patients with ER+ and/or PR+ ROC and CA125 progression had durable clinical benefit on anastrozole, with acceptable toxicity. Anastrozole may delay symptomatic progression and the time to subsequent chemotherapy. The future challenge is to identify the subset of patients most likely to benefit from an aromatase inhibitor and whether the clinical benefit could be increased by the addition of other agents. ER/PR positive Endometrial Cancer subgroup Background. The clinical benefit rate with aromatase inhibitors and the impact of treatment on quality of life (QOL) in endometrial cancer is unclear. We report the results of a phase 2 trial of anastrozole in endometrial cancer. Methods. Investigator initiated single-arm, open label trial of anastrozole, 1 mg/d in patients with ER and/or PR positive hormonal therapy naive metastatic endometrial cancer. Patients were treated until progressive disease (PD) or unacceptable toxicity. The primary end-point was clinical benefit (response + stable disease) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life (QOL) and toxicity. Results. Clinical benefit rate in 82 evaluable patients at 3 months was 44% (95% CI: 34–55%) with a best response by RECIST of partial response in 6 pts. (7%; 95% CI: 3–15%). The median PFS was 3.2 months (95% CI: 2.8–5.4). Median duration of clinical benefit was 5.6 months (95% CI: 3.0–13.7). Treatment was well tolerated. Patients who had clinical benefit at 3 months reported clinically significant improvements in several QOL domains compared to those with PD; this was evident by 2months including improvements in: emotional functioning (39 vs 6%: p=0.002), cognitive functioning (45 vs 19%: p=0.021), fatigue (47 vs 19%: p=0.015) and global health status (42 vs 9%: p=0.003). Low Grade Ovarian Cancers subgroup Objective. Treatment options are limited for patients with recurrent/metastatic low-grade ovarian cancers (LGOCs) and serous borderline ovarian tumors (SBOTs) as response rates to chemotherapy are low. A subset of patients appears to derive clinical benefit from antiestrogens, but most studies have been retrospective and clinical benefit rates (CBR) remain uncertain. The primary aim of PARAGON was to prospectively investigate the CBR of anastrozole, an aromatase inhibitor, in patients with estrogen receptor (ER) and/or progesterone receptor (PR) positive LGOC and SBOT. Methods. Post-menopausal women with ER-positive and/or PR-positive recurrent/metastatic LGOCs and SBOTs and evaluable disease by RECIST v1.1 or GCIG CA125 criteria were treated with anastrozole 1mgdaily until progression or unacceptable toxicity. Results. Thirty-six patients were enrolled. Clinical benefit at 3 months (primary endpoint) was observed in 23 patients (64%, 95% CI 48%–78%) andwas similar at 6 months (61%, 95% CI 43%–75%). The median duration of clinical benefit was 9.5 months (95% CI 8.3–25.8). Best study response was partial response by RECIST in 5 patients (14%), stable disease in 18 patients (50%) with progressive disease in 13 patients (36%).Median PFS was 11.1months (95% CI 3.2–11.9). Anastrozole was well-tolerated. Patients with evidence of clinical benefit at 3 months reported less pain, fatigue, and improved physical and role functioning as early as 1 month of commencing treatment. Conclusions. Anastrozole was associated with a CBR of 61% of patients with recurrent ER-positive and/or PR positive LGOC or SBOT for at least 6 months with acceptable toxicity. Endometrial Stromal Sarcoma subgroup Background: Aromatase inhibitors are standard of care for low-grade endometrial stromal sarcomas (LGESS), based on very high response rates reported in retrospective studies. We evaluated the activity of anastrozole in recurrent/metastatic LGESS patients enrolled in PARAGON, a basket trial of anastrozole in estrogen receptor (ER±)/progesterone receptor (PR+) gynecological cancers. Method: An investigator-initiated, single-arm, prospective open-label trial of anastrozole 1 mg/day in patients with ER±PR+ve LGESS with measurable disease, treated until progressive disease or unacceptable toxicity. Primary endpoint was clinical benefit (complete/partial response + stable disease) rate (CBR) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life and toxicity. Results: 15 eligible patients were enrolled. CBR at 3 months was 73% (95% CI: 48–89.1%); unchanged at 6 months. Best response was 26.7%, including complete response in one (6.7%; 95% CI 1.2–29.8%), partial response in three (20%, 95% CI 7.1–45.2%) and stable disease in seven (46.7%). Four patients ceased treatment by 3 months due to progression. Median PFS was not reached (25th percentile: 2.9 months (95% CI: 1.2–NR)). PFS was 73.3%, 73.3% and 66% at 6, 12, and 18 months, respectively. Six patients remained on treatment for an average of 44.2 months (range 34.5–63.6) up until data cut. Toxicity was as expected, with 3 patients stopping due to adverse effects. Conclusion: The 26.7% objective response rate with anastrozole is lower than reported in retrospective series, but the CBR was high and durable. The results underscore the importance of prospective trials in rare cancers. Granulosa/Sex-Cord Stromal Tumours subgroup Background: GCTs occur predominantly in postmenopausal women and arise from sex cord stromal cells of the ovary. They generally have a good prognosis but can metastasize / recur after surgery. Patients (pts) are commonly treated with antiestrogens as GCTs frequently express high ER and/or PR. The pooled response rates with a range of hormonal therapies in the literature are ~ 70 % based on case reports and small retrospective series which form the evidence base for clinical practice. Aromatase inhibitors (AIs) are reported to be particularly active. There are no reported phase 2 studies of antiestrogens in GCT. We report the results of a phase 2 trial of anastrozole, an AI in recurrent / metastatic GCT. To our knowledge this is the first prospective trial of hormonal therapy in GCTs. Methods: Postmenopausal women with ER/PR +ve metastatic GCT measurable by RECIST v1.1 and/or elevated Inhibin were eligible for inclusion. Pts received An 1 mg daily until progression or unacceptable toxicity. The primary endpoint was clinical benefit rate (CBR) at 12 weeks. Results: There were 41 pts entered. 3 pts without measureable disease had an elevated Inhibin. 1 pt received prior tamoxifen. 1 pt was not evaluable for 3-month (m) CBR. The CBR at 3m was 80.0% which included 1 (2.5%; 95% CI: 0.4 – 12.9%) partial response (PR) and 77.5% stable disease. 8 (20%) had progressive disease by 3m. Median PFS was 8.6 m (95% CI 5.5 – 13.5m). There were delayed responses beyond 3 m with a total 4 pts (9.8%; 95% CI 3.9% – 22.5%) with a RECIST PR. 23 (59%) pts were progression free at 6m (1 pt was censored at 3 m and 16 had progressed by 6 m). 2 pts remain on treatment at 14.8 m and 53.5 m. An was well-tolerated with only 1 grade 3 toxicity – arthralgia. 1 pt stopped An due to side effects. Conclusions: This is the first prospective trial of hormonal therapy in GCTs. Although there was a high CBR, the objective response rate to An was much lower than the pooled results of the response rate to hormonal therapy reported in retrospective series. Translational research on tumor specimens is underway for predictors of response/resistance to An which will inform future studies. Leiomyosarcomas & Carcinosarcomas subgroup Background: Aromatase inhibitors have been used empirically to treat a subset of patients with hormone receptor positive uterine leiomyosarcomas(LMS) and carcinosarcomas (UCS) mainly supported by retrospective data. We evaluated the activity of anastrozole in two rare cohorts; patients with recurrent/metastatic LMS and UCS enrolled in PARAGON, a basket trial of anastrozole in estrogen receptor (ER+)/progesterone receptor positive (PR+) gynecological cancers. Method: An investigator-initiated, single-arm, prospective open-label trial of anastrozole 1 mg/day in patients with ER &/or± PR + ve LMS or UCS with measurable disease, treated until progression or unacceptable toxicity. Primary endpoint was clinical benefit (complete/partial response + stable disease) rate (CBR) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life and toxicity. Results: 39 eligible patients were enrolled, 32 with LMS and 7 with UCS. For the LMS cohort CBR at 3 months was 35% (95% CI: 21-53%) with a median duration of clinical benefit of 5.8 months. Best response was a partial response in one patient. Two patients remained on treatment for more than one year. The median progression-free survival was 2.8 months (95% CI: 2.6-4.9). For the UCS cohort CBR at 3 months was 43% (95% CI: 16-75%) with a median duration of clinical benefit of 5.6 months. Stable disease was seen in 3 patients but no objective responses were seen. The median progression-free survival was 2.7 months (95% CI: 1.1-8.2). Safety was acceptable with 5/39 evaluable patients showing grade 3 toxicities Conclusion: Whilst objective response rates with anastrozole are low, the clinical benefit rate and good tolerance suggests that aromatase inhibitor therapy may have a role in a subset of patients with metastatic LMS and UCS.

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2010-09-24
• Study Completion: 2020-04-30
• Last Update Posted: 1 November 2021

Recruitment & Eligibility

• Status: Completed
• Sex: Female
• Target Recruitment: 333

Inclusion Criteria

Patients with recurrent or metastatic gynaecological cancers. The specific subgroups are outlined below. All patients will have central review and analyses of ER/PR at a later date to confirm receptor status, but entry to the study will be based on hormone receptor positivity according to local hormone receptor analyses.
A. Epithelial Ovarian Cancer, Primary Peritoneal Cancers and Cancers of the Fallopian Tube
(i) Asymptomatic patients with a rising CA125 after first line chemotherapy and GCIG defined CA125 progression (these patients should either have no measureable disease or small volume recurrence and the expectation they would not require chemotherapy within the next 12 weeks)
(ii) Borderline ovarian tumours, micro-invasive ovarian tumours and well differentiated low grade ovarian cancers. Apart from surgery, treatment options are very limited for these patients as these tumours are usually chemotherapy resistant but are also relatively indolent
(iii) Platinum resistant or refractory ovarian, fallopian tube and primary peritoneal cancer in patients in whom further chemotherapy is not indicated
B. Endometrial Cancer – patients that have measurable disease
C. Endometrial Stromal Sarcomas: patients that have measurable disease
D. Miscellaneous Sarcomas: Includes leiomyosarcomas, adenosarcomas, carcinosarcomas and undifferentiated uterine sarcomas with measurable disease and relapse following standard treatment such as chemotherapy or patients in whom chemotherapy is not clinically indicated.
E. Granulosa Cell Tumours and other Sex Cord Stromal Tumours: patients that have measurable disease and/or an elevated inhibin (total inhibin and/or inhibin B) level and in whom chemotherapy is not clinically indicated

All patients must have ER and/or PR positive tumours by immunohistochemical evaluation based on the assessment at individual sites. Hormone receptor staining should be carried out on the original tumour. If not available, but the recurrent tumour is hormone receptor positive, then these patients will also be eligible

Post-menopausal as defined by: (i) age 60 or more, or (ii) age 45–59 and satisfying the following criteria: Amenorrhoea for at least 12 months and FSH in postmenopausal range with an intact uterus, or (iii) age equal to 18 or more and having had a bilateral oophorectomy

Evaluable disease defined as; (i) measurable disease as per RECIST v1.1, OR (ii) CA125 as per GCIG criteria (for ovarian cancer subgroup) OR (iii) elevated total inhibin and/or inhibin B (for granulosa cell sub-group)

ECOG Performance status 0-2

Expected survival > 3months

Exclusion Criteria

Prior therapy with an aromatase inhibitor, tamoxifen or progestagens

Patients receiving any hormone replacement therapy

Inability to comply with study procedures

Unable to give informed consent

Other active malignancy or primary malignancy diagnosed within the previous 5 years, except for treated squamous or basal cell carcinoma of skin or in situ cervical carcinoma

Significant hepatic (bilirubin >2x ULN) or renal dysfunction (creatinine >3x ULN)

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Overall response to treatment as determined by Response Evaluation Criteria In Solid Tumors (RECIST) V1.1 criteria (all tumor sub-groups) or CA125 tumour marker response by Rustin criteria (ovarian sub-group) or inhibin (granulosa cell sub-group) as assessed at each visit by the Clinician[Assessed monthly for the first 3 months on trial then every 3 months until disease progression]