Lynparza Matches Tesaro's Superstar Status

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Includes: AZN, CLVS, TSRO
by: EP Vantage

AstraZeneca’s (NYSE:AZN) disclosure of stronger-than-expected data from its Solo-2 study of Lynparza in ovarian cancer surprised the market yesterday by equalling, if not even slightly bettering, rival Tesaro’s (NASDAQ:TSRO) Parp inhibitor, niraparib. A clear match on efficacy and some potential side effect advantages give the Astra drug a highly competitive profile in the germline BRCA (gBRCA) mutant subgroup (see tables below).

Tesaro retains an advantage in the broader non-BRCA mutant segment where Lynparza was not tested, but the impact on its stock was nonetheless predictable. Tesaro’s shares fell by almost 15% at one point yesterday and closed down 10%, as the US biotech saw its Parp superstar status shared with a competitor.

Astra had previously released a positive result in the Solo-2 study, which tested Lynparza as second or later-line maintenance therapy in relapsed, platinum-sensitive gBRCA mutant ovarian cancer in October last year but retained details for the presentation made yesterday at the Society of Gynecologic Oncology's annual meeting. Astra had previously said only that results were clinically meaningful, statistically significant and substantially exceeded those in a similar Phase II known as study 19 (Lynparza shows that Parp competitors have it all to do, October 26, 2016).

As it turned out, the data were better than anticipated. On the primary endpoint, Solo-2 showed a hazard ratio for progression free survival (PFS), as assessed by investigators, of 0.3, equivalent to a 70% improvement in the relative risk of progression. Median PFS, as assessed by the trial investigators, was 19.1 months versus 5.5 months for placebo.

By comparison, the gBRCA mutant cohort of Tesaro’s Nova study, which tested niraparib in the first-line maintenance setting, showed a hazard ratio for centrally assessed PFS of 0.27, equivalent to a 73% improvement in relative risk of progression. Median PFS here was 21.0 months, versus 5.5 months for placebo; exactly the same figure as in Solo-2, suggesting that a cross-trial comparison is legitimate.

Central assessment

But Astra also disclosed centrally-assessed PFS, a pre-specified secondary, and on this measure, Lynparza comes out even better. These data showed a hazard ratio of 0.25 and a jaw-dropping median PFS of 30.2 months. This finding is surprising because central assessments almost always reduce the treatment effect relative to investigator assessments.

Head-to-head comparison: Solo-2 vs. Nova

Solo-2 (gBRCAmut only)

Lynparza

Placebo

Statistics

PFS (investigator assessed)

19.1 mos

5.5 mos

HR=0.30 (0.22-0.41), p<0.0001

PFS (central review)

30.2 mos

5.5 mos

HR=0.25 (0.18-0.35); p<0.0001

PFS2*

NR

18.4 mos

HR=0.50 (0.34-0.72); p=0.0002

Nova, gBRCAmut cohort

Niraparib

Placebo

Statistics

PFS (central review)

21 mos

5.5 mos

HR=0.27 (0.173-0.410), p<0.0001

PFS2*

N/A

N/A

HR=0.48 (0.242-0.687)

CFI**

22.8 mos

9.4 mos

HR=0.26 (0.166-0.409), p<0.0001

TFST***

N/A

N/A

HR=0.31 (0.205-0.481), p<0.0001

*Time to second progression or death; **chemotherapy free interval; ***time to first subsequent treatment

NR = not reached; N/A = not available as data are still immature

Tesaro disclosed some new data of its own from Nova at the SGO meeting, such as time to second progression (PFS2), which are similar to those seen with Lynparza.

But it will be hard for physicians to ignore the almost nine-month relative advantage in centrally confirmed PFS for Lynparza in gBRCA mutants and it is unlikely that Astra will overlook this strict like-for-like comparison.

An interesting question is what caused Lynparza to perform so much better in Solo-2 relative to Study 19, where median PFS was 11.2 months. It seems the answer lies in a switch from capsules to tablets that both improved bioavailability and reduced the pill burden.

This planned formulation switch with the new indication is one thing that plays in Tesaro’s favor, as it will probably limit the off-label use of the approved Lynparza capsule in the maintenance setting ahead of approval. The capsules are currently approved for gBRCA-mutated ovarian cancer after three or more lines of therapy.

Niraparib has a June 30 PDUFA action date and assuming it is approved for all patients, Tesaro will still be able to target a much larger patient population than Astra, even if it has to share the gBRCA mutants, which account for only around one third of patients. Data on the other patient segments have been previously reported (Esmo–Tesaro enjoys a ta-dah moment, October 9, 2016).

Clovis gains

The third ranked Parp player, Clovis (NASDAQ:CLVS), saw its stock rise 10% yesterday, as its contender Rubraca now seems more competitive in an environment where the two class leaders are more equally matched. Clovis will shortly reveal results of its Ariel-3 Phase III study of Rubraca in the first-line maintenance setting, which may indeed even prove that all Parps are created equal. This will be the first of three Phase III readouts for Parp inhibitors in ovarian cancer this year.

Phase III trials of Parp inhibitors in ovarian cancer

Project

Trial

Setting

Comparator

Primary endpoint

Data

Trial ID

Rubraca

Ariel3

1L maintenance, Pt-sensitive, BRCAmut and HRD+

vs. placebo

PFS (inv assessed)

Mar-17

NCT01968213

Lynparza

Solo-1

1L maintenance, BRCAmut

vs. placebo

PFS (inv assessed)

Sep -17

NCT01844986

Lynparza

Solo-3

>3L, relapsed gBRACAmut, progression >6 mos

vs. single agent chemo

PFS (central assessed)

Dec-17

NCT02282020

Niraparib

Prima

1L maintenance, HRD+ve

vs. placebo

PFS

Aug-19

NCT02655016

Rubraca

Ariel4

>3L, BRCAmut

vs. chemo

PFS (inv assessed)

Jun-22

NCT02855944

Clovis investors are probably hoping that a positive result will inject some of the takeover speculation that has fueled Tesaro’s meteoric stock price over the past year. Ironically, Tesaro’s share price fall yesterday might make it a more likely target – at a more sensible price.

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