Homologous recombination deficiency positive advanced ovarian cancer is a complex condition that requires specialized testing and targeted treatment approaches. Understanding your tumor’s HRD status can open doors to personalized therapies that may help control disease progression and improve quality of life.

Understanding Treatment Goals for HRD-Positive Advanced Ovarian Cancer

When you or a loved one receives a diagnosis of advanced ovarian cancer that tests positive for homologous recombination deficiency, or HRD, the treatment journey becomes highly personalized. The main goals of treatment focus on slowing disease progression, managing symptoms, maintaining quality of life, and extending survival. Treatment decisions depend on several factors, including the stage of disease, your overall health, previous treatments received, and importantly, the specific genetic and molecular characteristics of your tumor.^[1]

HRD is a molecular characteristic present in nearly half of all advanced ovarian cancer cases. It means that cancer cells cannot efficiently repair breaks in their DNA through a process called homologous recombination repair. This deficiency can result from mutations in genes like BRCA1 and BRCA2, or from other genetic and molecular changes that affect the DNA repair pathway.^[1][2]

Medical societies and oncology guidelines recommend that all patients with advanced ovarian cancer undergo testing to determine their HRD status as early as possible after diagnosis. This testing helps doctors identify which treatments are most likely to be effective for each individual patient. Standard treatments approved by regulatory agencies exist for HRD-positive tumors, and ongoing clinical research continues to explore new therapeutic options that may offer additional benefits.^[3][6]

The treatment landscape for HRD-positive advanced ovarian cancer has evolved significantly. Beyond traditional chemotherapy and surgery, targeted therapies have emerged that specifically exploit the DNA repair deficiencies in these tumors. Understanding your HRD status empowers both you and your healthcare team to make informed decisions about which treatment path may be most appropriate for your unique situation.^[4]

Standard Treatment Approaches

Standard treatment for HRD-positive advanced ovarian cancer typically begins with a combination of surgery and platinum-based chemotherapy. The goal of surgery is to remove as much visible tumor as possible, a procedure called cytoreductive surgery or debulking. This is often followed by chemotherapy using platinum-containing drugs such as carboplatin or cisplatin, sometimes combined with other chemotherapy agents like paclitaxel. Platinum-based chemotherapy works by damaging the DNA in cancer cells, and HRD-positive tumors are often particularly sensitive to this type of treatment because they cannot efficiently repair the DNA damage caused by these drugs.^[8][9]

After completing initial chemotherapy, many patients with HRD-positive advanced ovarian cancer will receive maintenance therapy. Maintenance therapy means taking medication regularly after the initial treatment has achieved a response, with the goal of keeping the cancer from growing or coming back for as long as possible. For HRD-positive patients, this often involves a class of drugs called PARP inhibitors—which stands for poly (ADP-ribose) polymerase inhibitors. These targeted drugs work by blocking an enzyme that cancer cells need to repair certain types of DNA damage.^[9][12]

PARP inhibitors approved for use in HRD-positive advanced ovarian cancer include olaparib, niraparib, and rucaparib. These medications are typically taken as oral tablets once or twice daily. Olaparib, for example, is approved for use as maintenance treatment after first-line platinum-based chemotherapy in combination with another drug called bevacizumab, specifically for patients whose tumors are HRD-positive. Bevacizumab is a drug that works by blocking the formation of new blood vessels that tumors need to grow.^[3][10][11]

The duration of maintenance therapy varies from patient to patient. Some people continue taking PARP inhibitors for two years or more, while others may stop earlier if the cancer progresses or if side effects become too difficult to manage. Regular monitoring through imaging scans and blood tests helps doctors assess how well the treatment is working.^[3]

Clinical guidelines from organizations like the National Comprehensive Cancer Network (NCCN) recommend testing for BRCA1 and BRCA2 status in all patients with ovarian cancer. In the absence of BRCA mutations, testing for broader HRD status can provide information about the potential benefit of PARP inhibitor therapy. Both germline testing (using blood or saliva to look for inherited mutations) and tumor testing (using tissue from the tumor) are recommended.^[6]

For patients with recurrent ovarian cancer—meaning cancer that has come back after initial treatment—platinum-based chemotherapy may be used again if enough time has passed since the last treatment. PARP inhibitors are also approved as maintenance therapy after response to platinum-based chemotherapy in the recurrent setting, particularly for patients with BRCA mutations or HRD-positive tumors.^[3][16]

Testing for HRD Status

Determining whether your tumor is HRD-positive requires specialized laboratory testing. There are two main types of tests that help identify HRD status: genetic testing and genomic testing. Understanding the difference between these tests is important for making informed treatment decisions.^[4][13][14]

Genetic testing examines specific inherited genes in your DNA, such as BRCA1 and BRCA2. This type of test uses a blood or saliva sample and looks for mutations that you may have been born with and that are present in every cell of your body. These are called germline mutations. If you have a germline BRCA mutation, you may have inherited it from one of your parents, and it also means your family members might carry the same mutation and have increased cancer risk.^[3][16][18]

Tumor testing, also called genomic testing or biomarker testing, is different. This test looks at the DNA specifically from your tumor tissue. It can identify both inherited mutations and acquired mutations—changes in DNA that developed during your lifetime and are only present in the cancer cells. An HRD test is a type of tumor test that assesses the overall DNA profile of your tumor, including BRCA mutations and other changes that indicate HRD.^[4][13][14]

HRD testing looks for several markers of DNA damage and genomic instability. These markers are sometimes called genomic scars—permanent signatures in the tumor’s DNA that reflect past problems with DNA repair. The main markers measured include genomic loss of heterozygosity (gLOH) and large-scale state transitions (LST). These technical terms refer to specific patterns of chromosomal changes that accumulate when cells cannot properly repair DNA breaks.^[2][4][17]

A tumor is typically classified as HRD-positive if either a BRCA1 or BRCA2 mutation is detected, or if the genomic scar score is high. Different testing platforms calculate this score slightly differently, but the basic principle is the same: tumors with more genomic scarring are considered HRD-positive. A tumor that has no BRCA mutation and a low genomic scar score is classified as HRD-negative.^[2][17]

Several testing platforms are available for determining HRD status. One widely used test is the Myriad MyChoice CDx, which is approved by the U.S. Food and Drug Administration (FDA) as a companion diagnostic for certain PARP inhibitors. Companion diagnostics are tests that help identify which patients are most likely to benefit from a specific treatment. Other companies and laboratories also offer HRD testing using different methods and technologies.^[10][12]

To perform HRD testing, your healthcare team will need a sample of your tumor tissue. This is usually obtained during surgery to remove the tumor, or from a biopsy performed earlier in the diagnostic process. In many cases, tissue from your original biopsy can be used for HRD testing, so you may not need an additional procedure. The tissue sample is sent to a specialized laboratory where technicians analyze the DNA using advanced sequencing technologies.^[13][14]

About 50 percent of women with advanced ovarian cancer have tumors that test positive for HRD. Importantly, only about half of HRD-positive tumors have BRCA mutations—the other half are HRD-positive due to other genetic or molecular abnormalities. This means that even if you test negative for BRCA mutations, you could still have an HRD-positive tumor that may respond well to PARP inhibitors.^{[3][6][11][13]}

It is recommended that HRD testing be performed as early as possible after diagnosis, ideally before or shortly after starting first-line chemotherapy. Knowing your HRD status helps guide treatment decisions from the very beginning, including whether PARP inhibitor maintenance therapy may be appropriate after completing initial chemotherapy.^[3][13][14]

Treatment in Clinical Trials

Clinical trials are research studies that test new treatments or new ways of using existing treatments. For patients with HRD-positive advanced ovarian cancer, clinical trials offer access to cutting-edge therapies that may not yet be widely available. These trials are carefully designed to determine whether new treatments are safe and effective.^[7][12]

One of the landmark clinical trials for HRD-positive advanced ovarian cancer was the PAOLA-1 trial. This Phase 3 trial tested the combination of olaparib (a PARP inhibitor) plus bevacizumab as maintenance therapy after first-line platinum-based chemotherapy. The trial enrolled patients with newly diagnosed advanced ovarian cancer who had responded to initial chemotherapy. Results showed that patients with HRD-positive tumors who received the combination of olaparib and bevacizumab had significantly longer progression-free survival compared to those who received bevacizumab alone. This means the cancer took longer to start growing again in patients receiving the combination therapy.^[10][11]

In the PAOLA-1 trial, HRD status was determined retrospectively using the Myriad MyChoice CDx test. HRD-positive status was defined as having either a BRCA mutation or a high genomic instability score. Nearly half of the patients in the trial had HRD-positive tumors, which is consistent with what is seen in the general ovarian cancer population. The trial demonstrated that HRD testing can identify patients who are most likely to benefit from PARP inhibitor therapy.^[10]

Ongoing clinical trials continue to explore ways to improve outcomes for patients with HRD-positive ovarian cancer. Some trials are testing combinations of PARP inhibitors with other types of targeted therapies or immunotherapies. Immunotherapy drugs work by helping the body’s immune system recognize and attack cancer cells. Combining different types of treatments may produce better results than any single treatment alone.^[7][12]

Other clinical trials are investigating new PARP inhibitors or improved formulations of existing drugs. Researchers are also studying biomarkers beyond HRD that might help predict which patients will respond best to PARP inhibitors or other treatments. Understanding the molecular details of each patient’s tumor may eventually allow even more personalized treatment approaches.^[7][12]

Clinical trials are conducted in phases. Phase I trials primarily test the safety of a new treatment and determine the appropriate dose to use in larger studies. These trials typically enroll a small number of patients. Phase II trials evaluate whether the treatment shows signs of effectiveness against the cancer and continue to monitor safety. Phase III trials compare the new treatment to the current standard treatment in a large group of patients to determine which approach is better.^[12]

Eligibility for clinical trials depends on many factors, including the type and stage of cancer, previous treatments received, HRD status, overall health, and sometimes age. If you are interested in participating in a clinical trial, discuss this with your oncologist. They can help you understand which trials might be appropriate and available in your area. Clinical trials are conducted at many locations, including major cancer centers in the United States, Europe, Asia, and other regions around the world.^[7][12]

Advances in understanding HRD have directly informed clinical trial design. Researchers now routinely include HRD testing in ovarian cancer trials to identify which patients are most likely to benefit from investigational treatments. This precision medicine approach helps ensure that new therapies reach the patients who need them most.^[7][12]

Most Common Treatment Methods

• Platinum-based chemotherapy
  • First-line treatment typically combines carboplatin or cisplatin with paclitaxel
  • HRD-positive tumors often show particular sensitivity to platinum drugs
  • Used both in initial treatment and sometimes for recurrent disease
  • May be combined with bevacizumab in some cases
• PARP inhibitor maintenance therapy
  • Includes drugs such as olaparib, niraparib, and rucaparib
  • Taken orally, typically once or twice daily
  • Used as maintenance after response to platinum-based chemotherapy
  • Works by blocking DNA repair in cancer cells
  • Particularly effective in HRD-positive tumors
• Combination therapy with bevacizumab
  • Bevacizumab blocks formation of new blood vessels that feed tumors
  • May be combined with chemotherapy during initial treatment
  • Can be combined with PARP inhibitors like olaparib for maintenance therapy in HRD-positive patients
  • Given by intravenous infusion
• Cytoreductive surgery
  • Surgical removal of as much visible tumor as possible
  • Often performed as part of initial treatment
  • May be done before or after chemotherapy depending on individual circumstances
  • Goal is to leave behind minimal residual disease

How HRD Affects Treatment Response

The presence of HRD in ovarian cancer tumors has important implications for how patients respond to treatment. Studies have shown that patients with HRD-positive tumors tend to have higher response rates to platinum-based chemotherapy compared to those with HRD-negative tumors. In a study of Chinese patients with high-grade serous ovarian carcinoma, those with HRD-positive status showed significantly improved progression-free survival compared to HRD-negative patients when treated with first-line platinum-based chemotherapy.^[8]

The reason HRD-positive tumors respond better to platinum drugs relates to how these tumors handle DNA damage. Platinum chemotherapy works by creating cross-links in DNA that prevent cancer cells from dividing. Normal cells can repair this damage, but HRD-positive cancer cells cannot efficiently fix these breaks because their DNA repair machinery is already impaired. This makes them more vulnerable to platinum-based treatments.^[9]

Similarly, PARP inhibitors exploit the DNA repair deficiency in HRD-positive tumors. PARP is an enzyme that helps repair single-strand breaks in DNA. When PARP is blocked by a PARP inhibitor, these single-strand breaks accumulate and can convert into double-strand breaks—a more serious form of DNA damage. In normal cells, the homologous recombination repair pathway can fix double-strand breaks. But in HRD-positive cancer cells, this repair pathway doesn’t work properly, so the damage accumulates to lethal levels and the cancer cells die. This concept is called synthetic lethality.^[9][12][17]

Research has shown that patients with BRCA mutations or other HRR pathway gene mutations are more likely to be platinum-sensitive and have better progression-free survival. Even among patients without BRCA mutations, those with HRD-positive tumors still show benefits from PARP inhibitor therapy, though the magnitude of benefit may be somewhat less than in patients with BRCA mutations.^[8][10]

Beyond BRCA: Other Genes Involved in HRD

While BRCA1 and BRCA2 are the most well-known genes associated with HRD, they are not the only genes involved. The homologous recombination repair pathway involves many different proteins, and mutations in genes encoding any of these proteins can potentially lead to HRD. These genes are collectively referred to as HRR genes (homologous recombination repair genes).^[2][17]

Other genes associated with HRD include RAD51B, RAD51C, RAD51D, BRIP1, BARD1, PALB2, CDK12, CHEK1, CHEK2, ATM, FANCL, and H2AX, among others. Mutations in these genes can contribute to HRD and may make tumors more sensitive to platinum chemotherapy and PARP inhibitors. However, not all mutations in these genes necessarily cause HRD—the functional impact depends on the specific mutation and how it affects protein function.^[2][17]

In addition to genetic mutations, HRD can also result from epigenetic factors. Epigenetic changes are modifications that affect how genes are turned on or off without changing the underlying DNA sequence. For example, methylation of the BRCA1 promoter can silence the BRCA1 gene, leading to loss of BRCA1 protein function even though the gene sequence itself is normal. This type of epigenetic silencing can produce HRD just as effectively as a genetic mutation.^[2][9]

Because HRD can arise through multiple mechanisms—BRCA mutations, other HRR gene mutations, or epigenetic changes—testing that measures genomic scarring provides a more comprehensive assessment of HRD status than testing for BRCA mutations alone. This is why comprehensive HRD testing is recommended for guiding treatment decisions in advanced ovarian cancer.^[1][2][17]