New hope in PARP inhibitors

Dr Trudy Smith shares how advancements in genetics and targeted therapies, such as PARP inhibitors, are reshaping the landscape of ovarian cancer.

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Ovarian cancer is one of the most challenging malignancies to diagnose and treat, due in part to the lack of early symptoms and effective screening methods. By the time many women are diagnosed, the disease has often progressed to an advanced stage, which reduces the likelihood of successful treatment. 

However, with advancements in genetics and targeted therapies, there is increasing hope for patients, especially those with BRCA1/2 mutations or homologous recombination deficiency (HRD). These breakthroughs are reshaping the landscape of ovarian cancer diagnostics, treatment, and maintenance therapies.

Diagnostic approaches: The role of BRCA and HRD

Early detection remains a major obstacle, primarily because it’s often asymptomatic until it has reached an advanced stage. Traditional diagnostic techniques like imaging (ultrasound, CT scans) and blood tests (CA-125 marker) often fall short in identifying the disease early. 

However, there is growing recognition of the importance of genetic testing in diagnosing and managing ovarian cancer. Two key genetic factors have gained attention in ovarian cancer diagnosis and treatment: BRCA1/2 mutations and HRD.

BRCA1/2 mutations

BRCA1 and BRCA2 are tumour suppressor genes that help repair damaged DNA. Mutations in these genes, particularly BRCA1/2, significantly increase the risk of ovarian and breast cancers. Women with these mutations have a lifetime risk of developing ovarian cancer that is much higher than the general population, with estimates suggesting a risk of 15–40% for BRCA1 mutations and 10–20% for BRCA2 mutations.

Testing for BRCA1/2 mutations is now a routine part of the diagnostic process. If a woman tests positive for a BRCA1/2 mutation, she can be offered targeted therapies, including poly ADP-ribose polymerase (PARP) inhibitors, which are designed to exploit the DNA repair weaknesses in cancer cells caused by these mutations.

Homologous recombination deficiency (HRD)

In addition to BRCA mutations, HRD refers to a broader category of genetic defects that impair the DNA repair mechanism in cancer cells. HRD encompasses not just BRCA mutations but also other genetic alterations that affect the homologous recombination repair pathway. Testing for HRD is becoming increasingly important in ovarian cancer, as it helps identify patients who may benefit from specific therapies like PARP inhibitors.

HRD testing can be done through a variety of methods, including gene expression profiling and mutational analysis, providing valuable insight into the molecular landscape of the tumour. This information is crucial for tailoring treatment strategies and predicting the likelihood of a good therapeutic response.

Challenges of late diagnosis and relapse

Despite advances in genetic testing, ovarian cancer remains difficult to diagnose early. Most women are diagnosed only after the cancer has spread to other parts of the abdomen, leading to more complex and less favourable outcomes. 

The symptoms, such as bloating, abdominal pain, and changes in bowel habits, are often vague and can be mistaken for other less serious conditions. As a result, a significant percentage of women are diagnosed at later stages, where the cancer has already spread beyond the ovaries, complicating treatment options.

Even when diagnosed and treated early, ovarian cancer has a high relapse rate. Studies show that approximately 70% of patients with advanced-stage ovarian cancer will experience a recurrence within five years. The recurrence is often more difficult to treat, as the cancer may develop resistance to initial chemotherapy treatments, and the disease can become more aggressive.

PARP inhibitors in maintenance treatment

One of the most promising advancements is the use of PARP inhibitors, particularly for patients with BRCA1/2 mutations or HRD. PARP inhibitors work by blocking the PARP enzyme, which helps repair single-strand breaks in DNA. In cancer cells with BRCA mutations or HRD, DNA repair mechanisms are already compromised, and inhibiting PARP leads to the accumulation of DNA damage, ultimately causing cancer cell death.

PARP inhibitors are used as maintenance therapy following initial treatment to prolong progression-free survival (PFS). Maintenance treatment refers to the use of a drug to prevent the cancer from returning after initial chemotherapy or surgery. For patients with BRCA mutations or HRD, PARP inhibitors can significantly delay relapse and improve overall survival.

The advent of PARP inhibitors has transformed the management of ovarian cancer, offering patients with specific genetic profiles the opportunity for longer remission periods and a better quality of life. 

As research continues, the use of PARP inhibitors is expanding, with ongoing studies exploring their role in combination with other therapies and their potential to treat other cancers with similar genetic defects.

MEET THE EXPERT

Dr Trudy Smith is a gynaecology oncologist at Wits Donald Gordon Medical Centre and a senior lecturer at the University of Witwatersrand. She has a keen interest in teaching postgraduates and undergraduates.