Investors have been fixating on a new class cancer drugs known as PARP inhibitors that has shown great promise in treating women with ovarian cancer. Wall Street's interest stems, in part, because a PARP inhibitor played a contributory role in Pfizer's (PFE) - Get Pfizer Inc. Report decision to spend $14 billion on the acquisition of Medivation (MDVN) .
A cancer research meeting beginning on Friday in Copenhagen will provide investors with the next opportunity to inspect updated clinical data on two competing PARP inhibitors from Clovis Oncology (CLVS) - Get Clovis Oncology, Inc. Report and Tesaro (TSRO) - Get TESARO, Inc. Report . The market value of both companies has already soared ahead of the meeting.
PARP inhibitors are pills which work by blocking an enzyme, poly ADP-ribose polymerase, that cancer cells use to repair their DNA after being damaged by chemotherapy. PARP inhibitors are believed to have the greatest potential effect in ovarian and breast cancers because these tumors can contain a mutation to a gene known as BRCA, which also inhibits DNA repair.
Analysts have projected multi-billion dollar peak sales for the PARP inhibitor class. Approximately 22,000 women in the U.S. are diagnosed with ovarian cancer each year and 196,000 U.S. women live with ovarian cancer, according to the National Cancer Institute.
Clovis and Tesaro are initially targeting ovarian cancer patients with BRCA mutations -- thought to be approximately 15% of all cases. However, the PARP inhibitors may also work in tumors containing different genetic mutations.
The European Society of Medical Oncology, or ESMO, kicks off its closely followed annual meeting on Friday. Here's a preview of the PARP inhibitor presentations expected from Clovis and Tesaro, as well as a summary look at Lynparza, the only approved PARP inhibitor, marketed by AstraZeneca (AZN) - Get Astrazeneca PLC Sponsored ADR Report .
PARP name: Rucaparib. Nickname: "ruca." Clovis owns full worldwide rights to ruca.
Key ESMO presentation slot: Friday, Oct. 7
What do we know about ruca already? A new drug application for ruca was submitted and accepted by the FDA with an approval decision date of Feb. 23, 2017. The initial proposed indication for ruca is the treatment of advanced ovarian cancer in patients with BRCA-mutated tumors (germline and somatic), who have been treated previously with two or more chemotherapies.
Ruca's efficacy data comes from two single-arm phase II studies which enrolled 106 ovarian cancer patients, treated with a 600 mg, twice-daily dose. The pooled objective response rate was 54%, including 9% complete response and 45% partial response. The median duration of response was 9.2 months.
Response rate to ruca was "similar" in patients with germline and somatic BRCA mutations, as well in patients with BRCA1 and BRCA2 mutations.
Ruca's safety database comprises 377 ovarian cancer patients treated with different doses. Notable grade 3/4 adverse events reported by patients include anemia (25%), fatigue (11%) and increased ALT/AST liver enzymes (11%). The observed increases in ALT and AST were asymptomatic, reversible and "rarely associated" with increases in bilirubin. The discontinuation rate for ruca-treated ovarian cancer patients in the two studies was 8%.
One case of myelodysplastic syndrome, or MDS, was reported in the 377 ruca-treated patients. In a separate and still-ongoing blinded and randomized clinical trial of ruca as a maintenance treatment for ovarian cancer, two cases of acute myeloid leukemia, or AML, have been reported. One of these AML cases was fatal. Both patients had received prior treatment with chemotherapy which could have contributed to the AML.
Stock performance: Clovis' stock price essentially doubled from $18 to $36 since the end of August, when Pfizer announced the acquisition of Medivation and FDA accepted the ruca new drug application. On Monday, the stock closed at $35.35, with a market cap of $1.36 billion.
What should investors look for from the ruca presentation at ESMO? More detailed ruca data that will flesh out the top-line results already disclosed. On efficacy, it would be nice to see the ruca response rates parsed by prior lines of therapy, platinum chemo sensitivity and BRCA mutation status. Clovis might also present progression-free survival data.
This would help investors evaluate ruca relative to AstraZeneca's Lynparza, which is approved based on a 34% response rate and median duration of response of 7.9 months, but in a sicker patient population with germline, BRCA-mutated ovarian cancer no longer responsive to three or more prior lines of therapy.
On safety, investors will be looking for more clarity on the ruca-related ALT/AST increases, particularly when associated with increases in bilirubin, since this is a warning sign of serious liver toxicity.
After ESMO, what's next for ruca? The Feb. 23, 2017, FDA approval decision date. So far, the FDA has not indicated whether it will convene an advisory panel to review the ruca data prior to making an approval decision. Clovis is conducting a phase III study of ruca for second-line maintenance treatment of ovarian cancer, with results expected in the latter part of 2017.
Key ESMO presentation slot: Saturday, Oct. 8.
What do we know about niraparib already? In June, Tesaro announced that niraparib successfully achieved the primary endpoint of a randomized, placebo-controlled phase III study of second-line maintenance therapy in ovarian cancer patients. The study enrolled 500 patients with ovarian cancer which relapsed following initial platinum chemotherapy but was successfully retreated with second-line platinum chemotherapy. The patients were randomized to receive maintenance therapy of niraparib or a placebo on top of their second-line platinum chemotherapy. The primary endpoint was progression-free survival, or PFS, or the time (measured in months) before the ovarian cancer started to grow again.
In patients with germline BRCA mutated ovarian cancer, niraparib reduced the risk of tumor progression by 73% compared to placebo. At the median, niraparib PFS was 21 months vs. 5.5 months for placebo.
In ovarian cancer patients with non-germline BRCA mutations but whose tumors were positive for another DNA repair deficiency known as HRD, niraparib reduced the risk of tumor progression by 62%. At the median, niraparib PFS was 12.9 months compared to 3.8 months for placebo.
In ovarian cancer patients with non-germline BRCA mutations that were either positive or negative for the DNA repair deficiency HRD, niraparib reduced the risk of tumor progression by 55%. At the median, niraparib PFS was 9.3 months compared to 3.9 months for placebo.
The most commonly reported side effect of niraparib was thrombocytopenia (28%), anemia (25%) and neutropenia (11%.) The discontinuation rate from the study was 15% for niraparib and 2% for placebo. The rates of myelodysplastic syndrome and acute myeloid leukemia were 1.3% for niraparib and 1.2% for placebo.
Stock performance: The niraparib data reported from the phase III study in June were better than the Street expected, which fueled a massive move in Tesaro's stock price from $37 to $84 over two trading days. Maintenance therapy in ovarian cancer is a larger commercial market opportunity than treating patients with more advanced disease. The value of Tesaro shares continue to rise throughout the summer and fall, boosted by takeover speculation. The stock closed Monday at $100.54 with a market cap of $5.16 billion.
What should investors look for from the niraparib presentation at ESMO? The data from the phase III study announced to date have been impressive, so investors are eager to see more details presented in the setting of a medical meeting. The potential for niraparib to be effective in a broader-than-expected population of ovarian cancer patients, including those with non-germline BRCA mutations/HRD negative tumors, will be closely scrutinized.
Tesaro has disclosed PFS data only to date, but additional data on patient reported outcomes and overall survival (preliminary) might be presented at the meeting.
Niraparib's safety profile looks good based on the data disclosed to date, but of course, the detailed results presented at ESMO will be important.
After ESMO, what's next for niraparib? Tesaro expects to file a new drug application before the end of the year for niraparib as a second-line maintenance therapy for ovarian cancer. This filing will be based on the data from the phase III study being presented at ESMO.
Tesaro is conducting a phase II (but registrational quality) study of niraparib in ovarian cancer patients no longer responsive to three or more prior therapies. Results from this study, which is similar to the Clovis studies, are expected by the end of the year or in early 2017. The company is also conducting a phase III study of niraparib as a first-line maintenance therapy in ovarian cancer, but results aren't expected until 2018. The drug is also being studied against breast and prostate cancer.
PARP name: Lynparza (scientific name olaparib.)
Key ESMO presentation slot: No Lynparza data in ovarian cancer is being presented, but there will be a presentation of results from a negative, previously disclosed phase III study in gastric cancer on Saturday, Oct. 8.
What do we know about Lynparza already? Lynparza is approved in the U.S. as a treatment for ovarian cancer patients with germline BRCA mutant tumors no longer responsive to three or more prior therapies. In these patients, the Lynparza overall response rate was 34%, with a median duration of response of 7.9 months. In a subset of platinum-sensitive patients, the response rate was 46%. In platinum-refractory patients, the response rate was 14%.
In Europe, Lynparza is approved as a second-line maintenance therapy for ovarian cancer patients with germline BRCA mutated tumors. Treatment with Lynparza demonstrated an 82% reduction in the risk of tumor progression compared to placebo. At the median, Lynparza PFS was 11.2 months compared to 4.3 months for placebo. It's important to note that these maintenance ovarian cancer therapy data came from a retrospective analysis of a larger phase II study. AstraZeneca sought approval in the U.S. based on these data but was denied by the FDA.
What should investors look for from Lynparza at ESMO? It's difficult to make accurate comparisons of all the competing PARPs because of differences in the ovarian cancer patients enrolled into the different studies. There won't be any new Lynparza ovarian cancer data at ESMO, however. As the only approved PARP to date, Lynparza will be used as a measuring stick by investors considering Clovis' ruca and Tesaro's nirpaparib.
After ESMO, what's next for Lynparza? Results from a phase III study of Lynparza as a maintenance therapy in ovarian cancer are expected before the end of 2016 or early in 2017. Another phase III study of Lynparza in the treatment of relapsed ovarian cancer is expected to have results in 2018.
Adam Feuerstein writes regularly for TheStreet. In keeping with company editorial policy, he doesn't own or short individual stocks, although he owns stock in TheStreet. He also doesn't invest in hedge funds or other private investment partnerships. Feuerstein appreciates your feedback; click here to send him an email.