Some of the first data from trials of Parp inhibitors in combination with checkpoint antibodies should emerge next week. With question marks hanging over the size of the opportunity for these drugs, strong data could mark something of a turning point for the small players in this space – Tesaro and Clovis.
The impending results are in various ovarian cancer subsets that, if positive, could move these targeted agents into new patient niches (see table below). Supportive evidence for the combination of these two mechanisms, in general, is especially important as developers strive to prove that Parps have big potential.
This is particularly true for Tesaro and Clovis, whose valuations largely depend on the fate of their candidates, Zejula and Rubraca respectively.
Combinations with novel agents are considered vital to extend the reach of Parp inhibitors. For Tesaro the Topacio trial is a major plank in this strategy.
The study tests Zejula in combination with Keytruda in patients with triple negative breast and platinum-resistant ovarian cancers. Enrolment has not been restricted to patients with a BRCA mutation – where Parps are most effective – but stratification by PD-L1 and BRCA mutation status, among other biomarkers, will be carried out.
Mechanistically, it is hoped that combining a Parp with a checkpoint inhibitor like Keytruda will increase a patient’s susceptibility to the immunotherapy; inhibition of Parp can increase tumour mutational burden, as well as boost immunogenicity.
|Parp plus I-O – selected ovarian cancer studies|
|Trial||Combination assets||Setting||Notes||Trial ID|
|Topacio (ph II)||Keytruda (anti-PD-1)||TNBC and recurrent, platinum-resistant ovarian cancers||Data in platinum-resistant ovarian due at SGO in Mar; further data at Asco||NCT02657889|
|First (ph III)||TSR-042 (anti-PD-1)||Newly diagnosed ovarian||Due to start Q2 2018||tbc|
|Roche study (ph Ia/b)||Tecentriq (anti-PD-L1)||Advanced ovarian or TNBC||Primary completion date Jan 2019||NCT03101280|
|Athena (ph III)||Opdivo (anti-PD-1)||First-line maintenance, ovarian||Due to start early 2018||tbc|
|Mediola (ph II)||Imfinzi (anti-PD-L1)||SCLC; BRCA+ Her2- breast; BRCA+ relapsed ovarian, gastric||Ovarian data at SGO in Mar 2018||NCT02734004|
Data from the ovarian cohort in Topacio have been chosen as a late breaking abstract at the Society of Gynecological Oncology meeting next week. Patients whose ovarian cancer fails to respond to platinum-based chemotherapies have a very poor prognosis – response rates to Parp inhibition in these subjects, even if they carry a BRCA mutation, only amounts to around 25%. Responses fall to single digits in BRCA wildtype.
However, earlier data from Topacio released at Esmo last year intriguingly hinted at response rates independent of either BRCA or PD-L1 status. At that point the study, which is open label and single arm, was yielding a response rate of 21% among the 29 ovarian cancer patients.
Tesaro has made no secret of its desire to seek accelerated approval on the back of these data, so any improvement on this number will bolster this strategy. Further information on responses by mutation status is also eagerly awaited, to help gauge the wider potential of Parp plus I-O.
Important insights could also come from a second trial at the SGO conference – the ovarian cohort of Astra’s Mediola study of Lynparza plus Imfinzi, which has also won late-breaker status.
This recruited a different patient population – germline BRCA mutation, platinum-sensitive, relapsed ovarian patients. It is known that Parps are effective here – Lynparza monotherapy was approved on the basis of a 34% response rate in BRCA patients who had received three or more lines of chemotherapy.
A signal that adding anti-PD-L1 can boost the effectiveness of Parp inhibition – with tolerable toxicity – will be positive for these end-of-life patients.
Positive data from both of these studies could help add weight to all of these developers’ substantial investments in combination strategies in other tumour types, as they seek to prove the wider potential of Parp inhibitors.
Clovis too has I-O combinations ongoing, although is further behind in ovarian; a Roche-sponsored study pairing Rubraca with Tecentriq should report later this year.
As Morgan Stanley analysts have described: “We maintain that the I-O combination opportunity is the most important lever determining the potential magnitude of the Parp class in general, as well as being viewed as a potential driver of strategic optionality.”
Strategic optionality is analyst speak for takeover interest – something that has been long rumoured but failed to materialise for Tesaro or Clovis. Proving that Parps can surf the I-O wave could make all the difference.