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

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Contents

Study findings Guidelines
Strengths and limitations Clinical trials
What does this mean for me? Get Support
Questions for your doctor Related resources
   

STUDY AT A GLANCE
What is this study about?

This study is about whether the maintenance dose of the olaparib (Lynparza) can be reduced for people with ovarian cancer who have an inherited or mutation.

Why is this study important?

Dose reductions are common during using a due to significant adverse effects. It is important to understand whether dose reductions decrease the effectiveness of olaparib therapy and to identify the factors that cause dose reductions.

The SOLO2 trial looked at whether people who had recurrent ovarian cancer and an inherited or mutation benefited from olaparib. Following chemotherapy, participants took either the olaparib or a . Participants who received olaparib had significantly longer periods before their cancer progressed and better overall survival than those who received a .

However, almost all participants who received olaparib during SOLO2 experienced adverse effects that resulted in dose interruption, reduction or discontinuation. Researchers looked at a subset of people from the SOLO2 trial and asked whether those who had reduced doses of olaparib had different outcomes than those without dose changes.

Study findings

The researchers wanted to determine whether patients taking varying dosages of olaparib had different rates of disease progression (a relapse). Currently, the standard dosage of olaparib for is 300 mg twice a day. However, patients could have reduced, interrupted or discontinued olaparib treatment.

Throughout the SOLO2 study, almost all (95%) participants altered their dose of olaparib. Among participants, 50 percent interrupted treatment, 28 percent reduced their dosage and 17 percent discontinued treatment.

Among SOLO2 participants:

  • 40 (22%) experienced a grade 3 (serious) or higher adverse effect.
  • Among participants who had the greatest dose reduction (less than 90% of full dose):
    •  43% had anemia.
      • This was the most common grade 3 and the most common cause of a change or interruption in dose.
    • 21% reported fatigue.
      • Fatigue was the second most common cause of dose reduction13% had leukopenia (low white blood cell count).

Researchers divided participants into three groups based on how much their dose of olaparib was reduced compared to a standard dose during the first 12 weeks of treatment:

  • minimally reduced dose (participants took more than 98% of the standard dose).
  • mildly reduced dose (participants took more than 90% and up to 98% of the standard dose).
  • significantly reduced (participants took 90% or less of the standard dose).

Researchers followed these groups to determine whether patients taking different dosages of olaparib had different rates of disease progression (relapse). Individuals whose cancer does not progress or grow are said to have progression-free survival (PFS). Researchers also assessed overall survival (OS) of the participants. Researchers looked at the dose of olaparib that participants received at two time points: 12 weeks and 24 weeks after they began treatment.

Among the 196 participants assigned to receive olaparib, 185 had no disease progression after 12 weeks of olaparib treatment:

  • People who received a reduced dose of olaparib had similar progression-free survival and overall survival.

After 24 weeks of olaparib treatment, 159 participants still had no disease progression. Among these

  • 152 (98%) experienced an .
  • 51 (33%) experienced a grade 3 or higher adverse effect.
  • People who received a reduced dose of olaparib and whose cancer did not progress had similar progression-free survival and overall survival.

The researchers concluded that reducing the dose of olaparib does not change progression or overall survival.

Strengths and limitations

Strengths

  • This study was well designed. The relative dose was calculated similarly for participants, and data were collected at two defined time points.

Limitations

  • Participants in this study may not represent all patients who take olaparib for .
  • Researchers could not validate the doses of olaparib taken by all participants, as the amount of olaparib in blood samples was only calculated for a limited number of people.
  • Fewer participants took the lowest relative dose compared to those taking minimal or mildly reduces doses. This limits what can be concluded for those participants whose dose was reduced the most.
  • Researchers did not report whether side effects that resulted in dose reductions were resolved.

What does this mean for me?

If you have ovarian cancer, an inherited or gene mutation and a platinum-sensitive disease, olaparib after chemotherapy may be beneficial for you.

In this study, many people reduced their dose of olaparib because they experienced side effects, the most common of which was anemia. If you experience side effects from olaparib , reducing the dose of olaparib may be a helpful approach that does not seem to reduce the effectiveness of the treatment.

Reference

Francis K, Kim S, Friedlander M, et. al., The impact of olaparib dose reduction and treatment interruption on treatment outcome in the SOLO2/ENGOT-ov21 platinum-sensitive recurrent ovarian cancer. European Society for Medical Oncology 2022: 33(6). Published online February 24, 2022.

Disclosure: FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.

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posted 11/8/22

This article is relevant for:

People taking a PARP inhibitor for ovarian cancer maintenance therapy

This article is also relevant for:

People with ovarian cancer

People with platinum-sensitive ovarian cancer

People with a genetic mutation linked to cancer risk

People with metastatic or advanced cancer

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Study background

Researchers of this study wanted to know

Researchers wanted to know whether the dose of the olaparib (Lynparza) during long-term 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, , high-grade endometrioid or primary peritoneal cancer. All participants also had an inherited or mutation and received platinum-based chemotherapy for their cancer recurrence. 

After completing chemotherapy, participants were given with the 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 level (a blood test for a cancer ), 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 (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 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.

Category

Olaparib dose from start to 12 weeks

Number of people

Progression-Free Survival

(in months, p=0.37)

Overall survival

(in months, p=0.84)

1

>98%

111 (60%)

14.2

49.7

2

>90 – 98%

29 (16%)

19.3

49.5

3

<90%

45 (24%)

34.4

54.1

 

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.

Category

Olaparib dose from start to 24 weeks

Number of people

Progression Free Survival

(in months, p=0.60)

Overall survival

(months, p=0.91)

1

>98%

72

19.7

53.4

2

>90 – 98%

32

16.1

59.6

3

<90%

54

31.1

51.2

 

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 niraparib () 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 when needed to manage side effects.

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posted 11/8/22

 
 

Expert Guidelines
Expert Guidelines

The following NCCN recommendations are for for women with ovarian cancer who have had a complete or partial response to first-line therapy:

  • Women who have a mutation may benefit from a as .
  • Women who have a mutation and had Avastin as part of their first-line treatment may benefit from a alone or Lynparza and Avastin as .
  • Women who do not have a mutation and had Avastin as part of their first-line treatment may benefit from a alone or in combination with Avastin as , depending on their status.
  • Women who do not have a mutation and did not have Avastin as part of their first-line treatment may benefit from a as .

Updated: 12/07/2021

Questions To Ask Your Doctor
Questions To Ask Your Doctor

  • Is olaparib an option for me?
  • What side effects of olaparib therapy could lead to the need to reduce the dose or interrupt treatment?
  • How will the side effects of olaparib therapy be monitored and managed?
  • How will I know whether I should take my daily olaparib dose or not?

Open Clinical Trials
Open Clinical Trials

The following are studies looking at PARP inhibitors and similar agents for treating people with ovarian cancer.  

A number of other clinical trials for people with ovarian cancer can be found here.

Updated: 03/13/2022

Peer Support
Peer Support

The following organizations offer peer support services for people with or at high risk for ovarian cancer:

Updated: 02/05/2022

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