Lynparza: Expanding into Prostate Cancer

Conclusion: Lynparza shows significant clinical benefit in its newest indication, second-line HRR-mutated metastatic castration-resistant prostate cancer.  Even when competing against generically priced Zytiga, Lynparza’s efficacy advantages support its current price.

On April 24th, Lynparza (olaparib, AstraZeneca/Merck) announced positive data in second-line homologous recombination repair gene mutated (HRRm) metastatic castration-resistant prostate cancer (mCRPC). Assuming approval, this is the PARP inhibitor’s sixth indication, joining BRCA-mutated pancreatic, ovarian, and breast cancer.

An FDA approval is expected to follow the data published from the PROfound study, a prospective, multicenter, randomized, open-label, Phase III trial testing Lynparza versus enzalutamide or abiraterone in HRRm patients. The trial was broken out into two cohorts, BRCA- and ATM- mutated patients, and other HRR mutations. Lynparza showed significant clinical efficacy over the control arm in both groups, more than doubling progression-free survival (7.8 vs. 3.6 months in HRRm writ-large).  These improvements come to a high-need population—patients with HRR-mutated prostate cancer are on average younger and have more aggressive disease than non-mutated patients.

The waterfall chart below illustrates how Lynparza compares to Zytiga/Xtandi across the different domains of unmet need in HRRm writ-large. Looking at the chart, it’s clear that Lynparza’s efficacy and reduction of mortality offset its higher cost; in the HRRm population the overall improvement as measured by our Clinical Innovation score of 9.1% suggests a well differentiated agent (at the high end of our medium range). In BRCA/ATM mutated patients, Lynparza performs even better, with an overall improvement of 16.6%, which qualifies as high Clinical Innovation.

We can plot Lynparza’s clinical benefit over Zytiga/Xtandi against its increase in price. Doing so, we see that in both HRRm writ-large (top) and BRCA/ATM mutated (bottom) mCRPC Lynparza falls neatly into the “cloud,” a set of exemplars that have achieved good market access. This is good news for AstraZeneca and Merck— with generic Zytiga now widely available, Lynparza needed to show significant benefit to battle a drug with generic pricing, and it does just that.

Given Lynparza’s significant reduction in overall unmet need in second-line HRRm mCRPC, we expect it to be approved and adopted quickly.

PARP Inhibitors: Promise in New Maintenance Indications

Conclusion: PARP inhibitors Zejula and Lynparza both show significant clinical benefit in new maintenance populations in ovarian and pancreatic cancers, respectively. Fortunately for both assets, their clinical benefit in the new indications supports their current prices.

PARP inhibitors are advancing into more indications after their initial approvals in later-line ovarian and breast cancer.  While the cancers that the PARP inhibitors are pursuing differ significantly in unmet need, our analyses suggest that both Zejula and Lynparza are unlikely to encounter market access friction in their latest indications.

Results were recently published for Zejula (niraparib, GlaxoSmithKline) in the maintenance setting for newly diagnosed stage III and IV ovarian cancer patients who respond to platinum-based chemotherapy. Zejula is still awaiting approval in this indication, but there are no maintenance options for most of these patients, leaving a wide window of opportunity. Lynparza (olaparib, AstraZeneca/Merck) is the only PARP inhibitor currently playing in first-line ovarian maintenance, and only for the 15% of patients who have a BRCA mutation. Should Zejula receive its sought-after label expansion, its new maintenance data includes results for both BRCA-positives and “all comers”. Zejula is already approved in both ovarian cancer patients with refractory disease who have homologous recombination deficiencies (HRDs) and in second-line maintenance.

Fortunately for GSK, adding Zejula as maintenance therapy for first-line ovarian cancer patients (regardless of BRCA mutation) offers a tremendous clinical benefit of 39% in our framework, largely driven by improvements in both efficacy and mortality. The benefit is even greater in HRD patients, in whom Zejula provides a 56% clinical benefit.

Like Zejula, AstraZeneca/Merck’s PARP inhibitor, Lynparza, recently sought out and received approval as maintenance therapy in pancreatic cancer patients with a BRCA mutation. This is Lynparza’s fifth approval and the first approved therapy for maintenance following first-line therapy in pancreatic cancer. While BRCA-mutated pancreatic cancer has a smaller overall population than Lynparza’s other indications (ovarian and breast cancer), the low level of competition makes for an attractive opportunity, especially among BRCA-mutated patients.

Lynparza offers a significant clinical benefit of 16.6% as maintenance in BRCA-mutated pancreatic cancer. While it didn’t show a significant survival benefit, Lynparza nearly doubled time to progression from 3.8 months to 7.4 months in a recent phase 3 trial.

Using our Cost vs. Benefit tool, we can plot both Zejula and Lynparza in their respective indications within a historical data set of new oncology drugs that achieved favorable market access. Incremental cost (inverted) is plotted along the y-axis and clinical benefit along the x-axis, showing a clear relationship between clinical benefit in successful therapies and cost.  We believe that drugs that fall within the resulting cloud are priced appropriately given their clinical benefit.

While Zejula and Lynparza are priced slightly higher than other agents offering similar levels of clinical benefit, they are within range of historical analogs.  We consider them appropriately priced in these indications and expect them to receive favorable market access.

U.S. WAC prices are $372/day for Zejula and $472/day for Lynparza.

While our analysis predicts strong market access for Zejula, the competition for this indication is likely to be fierce. Avastin/Lynparza dual therapy and veliparib monotherapy have both recently released positive results in maintenance clinical trials. Though capturing the market will be no easy feat for GSK, Equinox Group believes Zejula is well positioned to become the market leader. This is largely due to the fact that the PRIMA trial (Zejula maintenance vs placebo) included patients who responded to any chemotherapy regimen, while the trials for Avastin/Lynparza and veliparib maintenance only included patients who received induction with, respectively, Avastin-containing and veliparib-containing regimens, limiting the potential patient populations they can tap into.

Contrastingly, Lynparza faces only one potential competitor, Rubraca (rucaparib, Clovis Oncology). Given the low level of competition and the clinical benefit that Lynparza offers compared to its price, we believe that Lynparza will also achieve considerable market share.

Our analysis incorporated data from the PRIMA, VELIA, PAOLA-1 and POLO trials, as well as prescribing information for Zejula and Lynparza.