Better late than never: targeted therapies reach ovarian cancer
March 12, 2019 | Disease
Targeted therapies, including lucrative immune-oncology (I-O) drugs such as Keytruda (pembrolizumab), have been slow to reach the ovarian cancer market. Ovarian cancer isn’t a single cancer; it encompasses a range of tumor-types that originate in the ovaries. Until recently, these weren’t considered to be immunogenic, so drugs that modulate the immune system were not thought to be effective. Indeed, small studies of I-O drugs in ovarian cancer have generally been disappointing, with response rates in the single digits or low teens. And in December 2018, two Phase III trials of Merck KGaA and Pfizer’s programmed death-ligand 1 (PD-L1)-targeted monoclonal Bavencio (avelumab), another I-O drug, failed to show any benefit in advanced ovarian cancer patients.
These challenges help explain why platinum-based chemotherapies have remained the standard first-line treatment for ovarian cancer in most markets. Chemotherapies are effective for many patients with early-stage disease, whose prognosis is good: five-year survival rates top 90% for this group. But ovarian cancer can be difficult to detect in its early-stages, when symptoms may be vague (tummy pain or bloating) or non-existent. Advanced disease is harder to treat, and some patients are or become resistant to platinum-based chemotherapy. These patients represent the most serious unmet need.
Fortunately, scientists now know that the picture for ovarian cancer – as for all other cancer-types – is much more complicated. Patients diagnosed with ovarian cancer may have tumors with very different genetic characteristics, requiring much narrower patient-segmentation and even a personalised approach. A small minority of patients’ tumors do react to immune-system modulators. The challenge is identifying which ones – and what to combine them with to greatest effect.
As experience with I-O drugs accumulates in other cancers, it is understood that these drugs’ true potential lies in their combination with other treatments (targeted or non-). These partner therapies may be able to ‘heat up’ the immune system, allowing the I-O drug to work more effectively.
Researchers are investigating immunotherapies in combination with anti-VEGF (vascular endothelial growth factor) strategies, such as Avastin, the first targeted (non-chemotherapy) drug approved for some patients with ovarian cancer, and still a key player in the ovarian cancer treatment market. (Avastin was first approved in Europe in 2011 and in the US three years later; it received a further green light in the US in 2018 for use post-surgery in advanced ovarian cancer patients.) A Phase III trial is underway of chemotherapy plus Avastin, followed by Avastin plus Roche’s PD-L1 immunotherapy antibody Tecentriq (atezolizumab).
Poly-ADP ribose polymerase (PARP) inhibitors like AstraZeneca/MSD’s Lynparza (olaparib) or Takeda/Tesaro’s Zejula (niraparib) are another important, relatively new targeted treatment class for patients with recurrent disease – especially those whose tumors have BRCA gene mutations. PARP inhibitors work by blocking enzymes that repair damaged cellular DNA, and are now being tested in combination with immunotherapy. Bavencio may yet find its utility in ovarian cancer alongside a PARP inhibitor, such as Pfizer’s Talzenna (talazoparib) – trials are underway.
PARP inhibitors are also working their way earlier up the treatment pathway. Lynparza was first approved in 2014 in the US for patients with advanced, heavily pre-treated cancer linked to BCRA mutations; in December 2018 that was expanded to first-line maintenance therapy (preventing or delaying recurrence) for BRCA-mutated advanced ovarian cancer.
Patients have a lot to gain as targeted therapy approaches and combinations find their place in ovarian cancer treatment. As approvals accumulate – including in earlier-stage cancers, where targeted therapies can have the greatest effect – payers will also start to pay more attention, however. Historically, reimbursement restrictions have been low in this area, due to the widespread use of cheaper chemotherapies. That may soon begin to change.
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