Overcoming Platinum Resistance in Ovarian Cancer – The PRECEDENT Trial

  • Date: 31 Jan 2014
  • Author: Rita Canario, Susana Banerjee
  • Affiliation: Rita Canario: ESO Fellow at the Gynecologic Unit, The Royal Marsden Hospital. Specialty trainee at Instituto Português de Oncologia de Coimbra, Portugal. Susana Banerjee: Consultant in Medical Oncology, Gynecologic Unit, The Royal Marsden Hospital, London, United Kingdom.
  • Link: Read the original article
  • Topic: Gynaecologic malignancies
Susana Banerjee
​Rita Canario

Ovarian cancer tends to recur despite the excellent response rates that can be achieved after primary standard treatment. The treatment of relapsed disease is challenging, especially in the setting of development of primary or secondary platinum resistance. Currently, the approved cytotoxic treatments in this setting includes pegylated liposomal doxorubicin (PLD), topotecan, paclitaxel and gemcitabine, with response rates of around 20-30% (1). Overcoming resistance to chemotherapy and personalising cancer care through target therapies are priorities for cancer research. In platinum-resistant ovarian cancer, several pathways are currently being studied, including inhibition of angiogenesis, DNA repair mechanisms and the folate pathway (2). New drugs targeting an isoform of the folate receptors alpha (FRα) take advantage their overexpression in epithelial tumours and scarce distribution in normal tissues. Vintafolide (EC145) is a folate conjugate with desacetylvinblastina hydrazine (DAVBLH), a potent vinca alkaloid.  Vintafolide is internalized to the cytoplasm by endocytosis through the FRα.

The PRECEDENT trial (3) is a randomised open-label multicenter phase II trial that aimed to evaluate the efficacy of vintafolide combined with PLD. This study enrolled women with platinum-resistant recurrent epithelial cancer of ovarian, tubal or peritoneal origin that had disease progression (PD) within 6 months after finishing platinum based treatment and up to 2 prior lines of treatment. A 2-arm parallel design of 2:1 stratified randomisation for vintafolide i.v. 3 times a week, on week 1 and 3, with 50mg/m2 of PLD i.v. every 28 days (arm 1) or PLD alone in the same schedule (arm 2). The primary endpoint was progression free survival (PFS). Disease progression (PD) was based on objective radiological PD (RECIST 1.0 criteria) or clinical progression. Secondary outcomes included objective response rates (ORR), disease control rate, safety and tolerability and overall survival (OS).

This trial enrolled a total of 149 women for the intention-to-treat (ITT) analysis (100 in arm 1, 49 in arm 2). The majority had high grade papillary serous histology. Median PFS was higher for vintafolide with PLD (5.0 months), vs. 2.7 months (hazard ratio 0.626, p=0.031) for PLD alone. The disease control rate (complete, partial response and stable disease) was higher in arm 1 (73% versus 53%, p=0.018). No differences were found in ORR between both arms (18% vs. 12%, p>0.05). A subgroup analysis in a group that underwent optional 99mTc-etarfolatide scan (63% of the ITT cohort) found that PFS was significantly higher in the experimental arm for those considered to express FR 100% (5.5months vs. 1.5months, p=0.013). The toxicity profile of the association of vintafolide with PLD had more haematologic toxicity and nausea (p<0.05); nevertheless, dose intensity was >90% in both arms. There was no difference in OS reported.

Some issues should be considered for reflection. The two groups were unbalanced in terms of platinum free interval (PFI) and the medium size of target lesions, with the experimental arm having the shortest PFI (<3 months) and larger lesions.  The use of PFS as the primary outcome for a trial assessing palliative chemotherapy has been debated (). Moreover, quality of life (QoL) and symptom control were not measured and these factors should be considered among the main outcomes for palliative chemotherapy. Finally, the relatively intensive schedule and route of administration needs to be taken into account in the palliative setting as well as their impact on QoL.

Overall, the results of this study are promising although the toxicity profile was somewhat higher than expected according to the rationale for targeted drug delivery. The differences noted on ORR for different expression of FRα on the 99mTc-etarfolatide scan could be an indicator of more aggressive behaviour, although the study was not powered to analyse this. Additionally, the baseline demographics suggest that the disease in the experimental arm may have had a more aggressive behaviour, which could be related to FRα expression. Correlation with the immunohistochemistry from the original tumour tissue with this scan was not made and could yield important information.

On the basis of results from the PRECEDENT study, a phase III trial (PROCEED trial) is underway and aims to assess the efficacy of vintafolide in combination with PLD in platinum-resistant FRα positive patients. The companion imaging diagnostic etarfolatide (EC20) will evaluate FRα status. Personalised medicine in ovarian cancer is becoming a reality and several factors are emerging as indicators to guide the choice for each drug such as the presence of BRCA mutations and receptor expression.

Discussion question:

In clinical practice, palliative chemotherapy in ovarian cancer is often triggered by the need to control symptoms. Should we be designing trials in the palliative setting with symptom control and QoL as primary outcomes?

References:

  1. Ledermann JA and Kristeleit RS. Optimal treatment for relapsing ovarian cancer. Ann Oncol 2010; 21(Suppl 7): vii218-22.
  2. Banerjee S, and Kaye SB. New strategies in the treatment of ovarian cancer: current clinical perspectives and future potential. Clin Cancer Res 2013; 19(5):  961-8.
  3. Naumann RW, Coleman RL, Burger RA, et al. PRECEDENT: a randomized phase II trial comparing vintafolide (EC145) and pegylated liposomal doxorubicin (PLD) in combination versus PLD alone in patients with platinum-resistant ovarian cancer. J Clin Oncol 2013; 31(35): 4400-6.
  4. Friedlander ML, Stockler MR, Butow P, et al. Clinical trials of palliative chemotherapy in platinum-resistant or -refractory ovarian cancer: time to think differently? J Clin Oncol 2013; 31(18): 2362.

The content of this article reflects the personal opinions of the authors and is not necessarily the official position of the European Society for Medical Oncology.

Overcoming Platinum Resistance in Ovarian Cancer – The PRECEDENT Trial
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