Study: More is not better: PARP dose can be safely reduced for people with ovarian cancer

Study background

Researchers of this study wanted to know

Researchers wanted to know whether the dose of the PARP inhibitor olaparib (Lynparza) during long-term maintenance therapy for ovarian cancer affects treatment outcomes. 

Populations looked at in this study

The study population was a subset of the SOLO2 study. Researchers enrolled 196 patients age 18 and older who had ovarian, fallopian tube, high-grade endometrioid or primary peritoneal cancer. All participants also had an inherited BRCA1 or BRCA2 mutation and received platinum-based chemotherapy for their cancer recurrence. 

After completing chemotherapy, participants were given maintenance therapy with the PARP inhibitor olaparib. If their tumor did not grow after 12 weeks of olaparib therapy, they were included in the subset evaluated in this study. Racial and ethnic demographic information of the study participants was not reported.

Study design

Researchers asked what dose of olaparib was prescribed and dispensed, as well as what dose was taken by the participants. Participants were divided into three categories based on the dose of olaparib they took relative to the standard dose of 300 mg twice a day in the first 12 weeks of the study:

• Category 1 - Minimal or no dose reduction. Participants took more than 98% of the standard dosage. Most people in this group took the full dose.
• Category 2 - Moderate dose reduction. Participants took more than 90 and up to 98% of the standard dosage.
• Category 3 – The greatest dose reduction in this study. Participants took 90% or less of the standard dosage. Half of this group took more than 76% of the dose and half took less than 76% of the dose.

The researchers looked at patients’ Eastern Cooperative Oncology Group (ECOG) performance status (a measure of how well a patient is able to perform ordinary tasks and carry out daily activities), age, body weight, time since the last platinum-containing chemotherapy treatment, baseline CA-125 level (a blood test for a cancer biomarker), the number of previous lines of cancer therapy, the time between chemotherapy completion and starting olaparib and the number of baseline tumors. Patients reported symptoms of nausea and vomiting and functional impairment at the start of the study.  Researchers tracked any adverse events during the study.

Study findings

After 12 weeks of olaparib treatment
Among participants, 185 of 196 who took olaparib during the SOLO2 study were progression free (had no cancer growth) after 12 weeks of olaparib treatment and were included in the remaining analysis.

• Most patients received a full dose of olaparib in their first 12 weeks of treatment.
• 26 (14%) had at least one dose reduction.
• 5 (3%) discontinued treatment.

However, among the 185 progression-free participants:

• 95% experienced an adverse event (side effect) in the first 12 weeks of treatment during SOLO2.
• 40 (22%) experienced a grade 3 (serious) or higher adverse effect.

• Among those with the greatest dose reduction (less than 90% of the full dose):
  •  43% of participants had anemia.
    • This was the most common grade 3 adverse event and the most common cause of a change or interruption in dose.
  • 21% of participants reported fatigue.
    • Fatigue was the second most common cause of dose reduction.
  • 13% of participants had leukopenia (low white blood cell count)

• Based on a participant's experience with their initial treatment with olaparib, they were assigned to one of three dose reduction categories. Researchers compared the outcomes of the people in the 3 dose reduction categories to determine whether there was a difference in their overall survival. At 12 weeks, there was no statistical difference in progression-free survival among the 3 groups of patients.

After 24 weeks of olaparib treatment
At 24 weeks after starting olaparib (and after 12 weeks of being on a reduced dose), 159 participants still had no disease progression.

Of these participants:

• 152 (98%) experienced an adverse event:
  • 51 (33%) experienced a grade 3 or higher adverse effect.
     
  • There was no statistical difference in progression-free survival or overall survival among the 3 groups of patients.

Strengths and Limitations

Strengths

• The patients were similar to each other. They all had the same disease, with the same past and current treatments.
• As a subset of a larger study, robust data collection resources as well as survival data were provided by the larger phase III study (SOLO2). 
• Analyzing data from specific time points helps to minimize time bias (e.g., survival bias).

Limitations

• Participants were categorized by total dose received compared to full dose. This measure does not look at how long patients took the maximum (full) dose, their peak blood levels or other ways of comparing them.
• Participants in this study were more likely to take the medication as prescribed than participants in other studies. Therefore, the dose reduction levels in this study may not be representative of all patients who take olaparib.
• The study cannot provide information on whether participants who need more significant dose reductions and treatment delays would have similar outcomes as these participants.
• The majority of participants were in category 1 with a full or minimally reduced dose. Participants were not randomly or evenly placed into different dose groups. This limits the ability to determine whether patients with lower dose reductions truly have similar outcomes as those with doses closer to category 1.
• There may be a difference in how dose reductions are decided for participants in the study compared to people taking olaparib who are not a part of a research study.
• Only participants who did not experience cancer progression at 12 and 24 weeks were included in the data analysis for these time points.
• Dose reduction adherence was calculated based on the number of olaparib tablets dispensed and returned, not firsthand knowledge of the number of pills taken. Olaparib blood concentration data were limited. Therefore, the dose reduction categories may not be an accurate representation of the actual amount of olaparib dosage taken by participants. 

Context

Maintenance olaparib therapy after chemotherapy for ovarian cancer is a long-term treatment and side effects occur in many patients. Side effects can lead to the need to reduce doses or interrupt therapy. Altering a treatment raises concerns about its effectiveness.

Other approaches with other PARP inhibitors have been studied. For example, with the PARP inhibitor niraparib (Zejula) a lower dose may be prescribed for patients with lower weight and lower platelets the so called “weight and plates” approach.  This approach could highlight patients that would benefit from starting at a lower dose but it is not widespread yet with olaparib use.

Patients and their health care providers need research that provides guidance not just at the onset of therapy, but also shows whether dose adjustments can lower the amount and severity of side effects without impacting efficacy.

Conclusions

Initial research on whether dose reductions and treatment interruptions interfere with the effectiveness of maintenance olaparib therapy for ovarian cancer is encouraging. This study found no evidence that dose reductions and treatment interruptions lead to worse outcomes, but further research is needed to better understand the implications of modifying olaparib maintenance therapy when needed to manage side effects.

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posted 11/8/22