Clovis Oncology Inc (CLVS) 2017 Q1 法說會逐字稿

Good day, ladies and gentlemen, and thank you, for standing by. Welcome to Clovis Oncology Incorporated First Quarter 2017 Earnings Conference Call. (Operator Instructions)

I would now like to introduce your host for today's presentation, Ms. Anna Sussman. Ma'am please begin.

Thank you, Howard. Good afternoon, everyone. Welcome to the Clovis Oncology first quarter 2017 conference call. You should have received the news release announcing our first quarter results, if not, it's available on our website at www.clovisoncology.com. As a reminder, this conference call is being recorded and webcast. Remarks may be accessed live on our website during the call and will be available in our archive for the next several weeks. The agenda for today's call is as follows: Patrick Mahaffy, Clovis President and CEO, will discuss the key components of our corporate update provided in today's news release, as well as an update on our clinical development programs; and Dan Muehl, Clovis Senior Vice President of Finance and Principal Financial and Accounting Officer will cover the financial results for the quarter in greater detail.

I will make a few closing remarks and then we'll open the call for Q&A.

Before we begin, please note that during today's conference call, we may make forward-looking statements within the meaning of the federal securities laws, including statements concerning our financial outlook and expected business plans. All of these statements are subject to risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. Please refer to our recent filings with the SEC for a full review of the risks and uncertainties associated with our business. Forward-looking statements speak only as of the date on which they are made, and Clovis undertakes no obligation to update or revise any forward-looking statements.

Now, I'll turn the call over to Patrick Mahaffy.

All right. Thanks, Anna. Welcome everybody for joining us. I'd like to start with an update on the launch of Rubraca. We were very pleased with our first full quarter of sales for Rubraca, which as you know was approved on December 19, 2016 by the FDA as monotherapy for the treatment of patients with deleterious BRCA mutations associated advanced ovarian cancer, who have been treated with 2 or more chemotherapies. We had our first Rubraca prescription, written the day after approval and in our first full launch quarter, we achieved $7 million on net sales, with over 350 new patients on therapy and, equally impressive, we have over 300 unique healthcare providers who prescribed Rubraca during the first quarter.

In patients who have refilled their prescription, the average time to refill was 29 days. These and other initial patient data suggest a high adherence to the recommended dose and limited dose reductions that we've seen to date. In fact, 94% of dispensed volume in the quarter were 300 milligram tablets, and less than 10% of refills were down dosed from 300 milligram to 200 milligram dose. These metrics of course have been observed early in the launch and may move around a bit.

As we know, in fact, we will see some dose reductions as is common for all oral oncolytics. We are therefore pleased to announce today, that the FDA has now approved a 250 milligram Rubraca tablet. As a result, we have 3 tablets strengths approved in the United States: 200, 250 and 300 milligram strengths, each of which is priced equivalently and provides physicians with maximum flexibility and options to reduce the dose if and as needed. Payor coverage has been quite positive. As with other oral oncolytic launches, Rubraca generally requires a prior authorization and, to date, 96% of new prescriptions have been efficiently processed and filled.

Let me review a selection of prescription and utilization patterns to date. You may remember from our February call, that at that time 70% of Rubraca prescriptions were written by clinicians at academic institutions. And about 30% were generated from community based practices. The shift to a majority of community based prescriptions is occurring and for the first quarter, 45% of Rubraca prescriptions were from academic institutions and 55% through community based practices. We anticipate that the percentage of prescriptions from community-based practices will continue to grow over time. 80% of our prescribers to date are clinicians who have previously prescribed olaparib but approximately 20% of clinicians who treat advanced ovarian cancer, but had not used a PARP inhibitor prior to Rubraca's approval. We are pleased to have seen this degree of market expansion this early in our launch.

Overall, we're happy with the initial quarterly Rubraca launch and in particular, the feedback we are receiving from the field. We look forward to providing further updates each quarter.

Let me provide a quick update on our European submission for rucaparib which is under review by the EMA for the same ovarian cancer treatment indication we submitted to the FDA. The review is progressing as we expected, thus far, and we anticipate an opinion from the CHMP in late 2017. Pending a favorable opinion, we would expect a formal approval in early 2018. Given this timing, we're actively building out our European commercial and medical affairs infrastructure. Of course, we already have regulatory clinical safety and supply chain teams in place at our Cambridge U.K. office.

Turning now to the rucaparib development program. I'll start with our 2 confirmatory trials, with the focus of course on ARIEL3. As announced in our news release this afternoon, we were notified by the independent data monitoring committee for IDMC that the ARIEL3 target progression events were achieved in mid-April. Having received this notification, we have initiated final activities in preparation for the data base lock and the release of topline results for ARIEL3.

As we have stated before and as is common, we anticipate it will take approximately 2 months to conduct these final activities and to lock the database. As a result, we anticipate ARIEL3 topline results to be released by the end of June. We are well aware of the significant interest in these results, which we share, and we'll seek to release sufficient information to inform investors about the results from this trial when we release the topline data, while preserving enough information to ensure acceptance for presentation at a scientific meeting this fall, hopefully at ESMO in early September. I know you know this, but we and all others involved in this study, other than the IDMC, remain completely blinded to these results and will remain blinded for this approximately 2 months period. Pending positive data, we intend to submit a supplemental NDA for the second line or later maintenance treatment indication for advanced ovarian cancer patients within 4 months or less of the database lock. Given the evident focus on this trial, I'll briefly review the trial design of ARIEL3 again. The ARIEL3 pivotal study is a randomized double blind study, comparing the effects of rucaparib against placebo to evaluate whether rucaparib, given as maintenance treatment to platinum sensitive patients, can extend the period of time for which the disease is controlled after a partial or complete response for platinum-based therapy. Patients with high-grade serious ovarian cancer and who have received 2 or more prior lines of platinum-based chemotherapy are randomized 2 to 1 to receive either rucaparib or placebo and the primary end point of the study is progression free survival or PFS. Overall survival is a secondary endpoint. Enrollment in the trial required a partial or complete response to the most recent platinum-based therapy. Enrollment in the trial took approximately 2 years, with half of the patients enrolled in the first year and the second half enrolled in the second year. In fact, within months of study start, monthly enrollment was very consistent over the entire course of the trial. Of course, we were blinded as well to the BRCA or biomarker status of the patients, as they enrolled in the trial, and we remained blinded to their status today. The trial was designed to enroll between 180 and 200 patients with BRCA mutated tumors. Based on IDMC guidance, we believe that the 180 patient number was exceeded, our estimate is that approximately 200 patients in the ARIEL3 trial are tissue BRCA positive. Based on data from ARIEL2, we estimate that of the remaining 364 patients enrolled, approximately half are HRD positive and the other half are biomarker negative. The primary efficacy analysis will evaluate in a step down manner. First, BRCA mutant patients, including both germline and somatic mutations. Second, all HRD positive patients, including in a nested manner, the BRCA mutant patients. And finally all patients enrolled in the trial, including biomarker negative patients, all of them of course are platinum sensitive, which may itself be a biomarker of activity for a PARP inhibitor such as rucaparib.

In addition, a prespecified subgroup analysis is planned to evaluate patients with low volume or no residual disease at baseline to determine the impact of disease burden on PFS. Importantly this analysis will also estimate the size of the population with tumor lesions greater than 2 centimeters still present after a partial response to a second or a later line platinum therapy.

As just discussed, ARIEL3 will evaluate mutant BRCA, HRD and finally the pooled population of platinum sensitive women with ovarian cancer enrolled in the trial, including biomarker negative patients. This means that ARIEL3, if successful, could lead to a label for maintenance treatment in all platinum sensitive second line ovarian cancer patients, who are responding to the most recent platinum.

Now briefly on ARIEL4. This is our Phase III multicenter randomized confirmatory study of rucaparib versus chemotherapy in relapsed ovarian cancer patients with BRCA mutations, who have failed 2 prior lines of therapy. Primary endpoint of the study is PFS. We anticipate data from this study in 2022. As we have mentioned previously, after ovarian cancer, prostate cancer is our next area of focus. Prostate cancer is a high priority indication for us as a meaningful number of patients, with advanced prostate cancer possess mutations of BRCA and other mutations that may be responsive to rucaparib. There are 2 Clovis sponsored prostate cancer trials that are actively enrolling patients today. The first Clovis sponsored trial is TRITON2. Our Phase II single arm study, inclusive of patients who have a germline of somatic BRCA or ATM mutation or other deleterious mutations in HR repair genes, who have progressed after receiving 1 line of taxane based chemotherapy and 1 or 2 lines of androgen receptor targeted therapy in the castrate resistant setting. Planned primary endpoints are radiologic overall response rate in patients with measurable disease, PSA response rate in patients without measurable disease. Our second Clovis sponsored study is TRITON3, a Phase III comparative study inclusive of patients who have a germline or somatic BRCA or ATM mutation, who have progressed on AR targeted therapy and not yet received chemotherapy in the castrate resistant setting. The study will compare rucaparib to physician's choice of AR targeted therapy or chemotherapy. The planned primary endpoint is radiological progression free survival.

Later this year, we are also planning to begin an earlier line study in castrate resistant prostate cancer. And we'll provide further details as we finalize the design. In February, we announced an agreement with Strata Oncology to accelerate patient identification and enrollment for the Triton program. The Strata trial is a nationwide observation study sponsored by Strata that provides no-cost tumor sequencing to advanced cancer patients at Strata trial sites and, under this agreement, matches BRCA and ATM mutated advanced prostate cancer patients to our Triton studies. Strata has agreed not to provide similar matching services on behalf of any other Strata collaborator for any other metastatic castrate resistant prostate cancer clinical trial with respect to patients with those same genetic mutations.

We are optimistic that by working with Strata, we will accelerate enrollment in the Triton studies. In addition to the Clovis sponsored prostate cancer studies, we are working in collaboration with the Medical Research Council in the U.K. to study rucaparib in what is known as the STRAT-STAMPEDE study, a newly diagnosed castrate sensitive metastatic tumor BRCA mutant and BRCA-like prostate cancer patients. This cooperative group study is expected to begin later this year. Beyond the ovarian and prostate studies I've described, there are several clinical studies in ovarian, breast and gastroesophageal cancers which are opened for enrollment or anticipated to open during 2017. These include Clovis sponsored, collaborator sponsored and investigator initiated studies.

I'd like to focus on 2 of these studies to highlight our strategy and approach to the first-line maintenance treatment opportunity in ovarian cancer. We believe there is greater potential to achieve a meaningful progression free survival benefit, potentially even a curative result in some patients by combining rucaparib with either bevacizumab or an anti-PD-1 or anti-PD-L1, following first-line platinum therapy. 2 trials have followed this approach includes MITO-25, a cooperative group study, evaluating rucaparib versus rucaparib plus bevacizumab, as first-line maintenance treatment for advanced ovarian cancer. The MITO-25 study has planned enrollment of over 350 patients with mutations of BRCA or HRD signature and PFS as the primary endpoint. The 3 arms of this study include carbo, paclitaxel, and bevacizumab, followed by bevacizumab maintenance. Carbo, paclitaxel and bevacizumab followed by bevacizumab plus rucaparib maintenance and Carbo plus paclitaxel followed by rucaparib maintenance. In addition, there is increasing pre-clinical and clinical evidence that an anti-PD-1 or PD-L1 combination with a PARP inhibitor could be meaningfully additive to clinical benefit without synergistic side effects.

Accordingly, in collaboration with Genentech, a member of the Roche group, the Phase Ib trial will enroll its first patient tomorrow to evaluate a novel combination therapy of their cancer immunotherapy TECENTRIQ or atezolizumab and rucaparib for the treatment of gynecological cancers, with a focus on ovarian cancer. This is initially a Phase Ib study to determine the dose and which we then expect to expand to explore activity in select patient cohorts.

As noted above, we know that in the ovarian community they are extremely optimistic of the potential of rucaparib and an anti-PD-L1 or PD-1 combination to provide meaningful benefit to women with ovarian cancer. As a result, we plan to initiate a Clovis-sponsored Phase III trial of rucaparib plus an anti-PD-1 or PD-L1 in front line ovarian cancer maintenance treatments around the end of this year. We will describe this trial in more detail later in the year.

In addition to these trials, we have a number of investigator initiated trials underway or planned, including studies in ovarian, prostate, breast, gastroesophageal, pancreatic, lung and urothelial cancers.

Now let me to turn the call over to Dan to discuss first quarter financial results.

Thanks, Patrick. And good afternoon, everyone. Our first quarter 2017 financial results are included in this afternoon's press release. I'll review the highlights of our financial results and provide some additional commentary. Net product revenue was $7 million for our first full quarter of sales. We ended the first quarter with $408.8 million in cash, cash equivalents and available for sale securities, including net proceeds of $221.2 million from an offering of 5.75 million shares of common stock in January, 2017. Cash used in operating activities was $80.4 million for the first quarter of 2017, $3.3 million lower than the prior-year quarter. We reported a net loss of $58.5 million or $1.33 per share for the first quarter of 2017. This compares to $83.4 million or $2.17 per share for the comparable period in 2016. The reduction in net loss year-over-year was primarily due to lower R&D spending, including balance sheet classification of rucaparib API or drug substance, payments and prepaid deposits on future production, which were previously expensed prior to product approval in December of 2016. And higher net product revenues, compared to the same quarter in 2016.

Our first quarter 2017 R&D expenses totaled $32.4 million, this compares to $74.6 million for the comparable period in 2016. The decrease year-over-year is primarily due to lower spending on rucaparib and rociletinib development activities, and classifying as selling, general and administrative, certain expenses related to commercialization of Rubraca that had been classified as research and development prior to FDA approval.

Selling, general and administrative expenses totaled $29.2 million for the first quarter of 2017. This compares to $9.8 million for the comparable period in 2016. The increase year-over-year is primarily due to classifying as selling general and administrative, certain expenses related to commercialization of Rubraca that had been classified as research and development prior to FDA approval. Operating expenses for the first quarter of 2017 include share-based compensation totaling $8.9 million, compared with $11 million in the comparable period of 2016.

Now I'll provide a further color on Rubraca from a finance perspective. We distribute our product principally, through a limited number of specialty distributor and specialty pharmacy providers. These customers subsequently resell products to patients and healthcare providers. Separately, we have arrangements with certain payers and other third parties that provide for government mandated and privately negotiated rebates, chargebacks and discounts. As noted previously, net product revenue was $7 million for the quarter. Revenue was recorded net of estimated rebates, charge backs, discounts and other deductions, as well as estimated product returns, known as gross to net, GTN adjustments, which total approximately 11% of gross revenue for the quarter. As revenues rise, the gross to net adjustments are expected to decrease to high single digits as a percentage of gross revenue as the year progresses assuming that the distribution and payer mix remain constant. We only recognize revenue on product sales once the product is resold to the patient or healthcare provider by the specialty distributor or specialty pharmacy provider.

Our distribution mix for the quarter was approximately 75% specialty pharmacy and 25% specialty distributor consistent with our expectations, and our payer mix was approximately 66% commercial, 30% Medicare and 4% Medicaid and other, also consistent with our expectations. Cost of sales for the quarter ended March 31, 2017 was $1.5 million or approximately 22% of net revenue and consists of costs associated with the sale of Rubraca, mainly freight, royalties and amortization of capitalized acquired intangible license right and milestone payments related to Rubraca.

Based on our policy to expense cost associated with the manufacture of our products prior to regulatory approval, certain of the cost that Rubraca recognizes revenue during the year -- during the quarter, I'm sorry during the year ended December 31, 2016 were expensed prior to December 19, 2016 FDA approval and, therefore, are not included in the cost of sales during the current period. We expect cost of sales to remain generally consistent in relation to product revenues, as we deplete these inventories and amortize capitalized acquired intangible license rates and milestone payments related to Rubraca.

We expect to use the remaining pre-commercialization inventory for product sales through the third quarter of 2017. With the FDA approval of Rubraca, all sales and marketing expenses associated with Rubraca are included in selling, general and administrative expenses and no longer in R&D. This will have the impact of lowering R&D expenses on a comparable basis from 2016 to 2017. Clinical trial expenses will shift in composition in 2017 as well, with the completion of all rociletinib trials and the winding down of ARIEL2, ARIEL3 and Study 10 for rucaparib. The initiation of TRITON2 and TRITON3 and ARIEL4 and other company-sponsored and investigator initiated trials Pat mentioned earlier will begin to add to higher levels of spending as 2017 progresses.

Now I'll turn the call back to Patrick for some closing remarks. Then we'll open it up for Q&A.

Thanks, Dan. It's a very exciting time here, with our initial launch of Rubraca underway, ARIEL3 data on the near-term horizon and an anticipated CHMP opinion late this year, followed by a potential EU approval and launch early next year. And it's hard not to reflect upon the fact that after many of these calls, turns out the next time we will likely all be on the phone together will be to discuss ARIEL3 top line results.

With that, I'll be happy to answer any questions you may have.

(Operator Instructions) Our first question or comment comes from the line of Cory Kasimov from JPMorgan.

I have 2 of them for you. First one is do you plan to disclose the results specifically for the biomarker negative patients, in addition to the 3 primary analyses in that top line release in June?

We haven't fully landed on what all we're going to provide. But I would imagine that in addition to the 3 groups that we have already prespecified in the statistical analysis plan, I am aware that there would be an interest, including by us, in activity in the biomarker negative population uniquely. And I would expect that we would provide those data.

Okay. And then my follow-up question is obviously the PARP market has just evolved very, very rapidly. I'm curious, how you think this kind of continued evolution or the impact the continued evolution that we get once you get the results from a first line maintenance later this year from studies like SOLO1?

Well again, SOLO1 is going to be limited to germline BRCA, but it's also going to tell a story about whether the pronounced activity others at least have seen in the maintenance setting in more advanced patients we have so clearly seen in the treatment setting might even be more impressive in patients with -- less advanced in their disease progression. So we look forward to seeing those results. I can tell you that we and collaborators are incredibly excited about the combination studies we're running in our European study with Avastin. And in our planned PD-1 PD-L1 study. And one of the things that has happened, a lot of it is I-O driven but some of it is while rucaparib or PARP inhibitor driven is that there's a greater expectation that these combination, at least in some patients could be curative. And this includes patients who had really no thought of curative regimens, only 2, 3, 4, 5 years ago. And so I think the evolution is going to be, first, in earlier line patients in ovarian, then to include early line patients, including a PD-1 or PD-L1, and the enthusiasm for that is hard to describe. And then obviously, we and others are seeking to pretty substantially advance PARP inhibitor therapy into other indications, either as monotherapy or increasingly at our planned studies in combination with the PD-1 or PD-L1. That -- I would say that in my career, obviously, the most exciting thing that has happened has been I-O. But right now, at least at this moment in time, the second most talked about class of compounds is PARP inhibitors and the enthusiasm we see, the interest we see is incredibly high.

Our next question comes from the line of Alethia Young from Credit Suisse.

Two for me, just on the launch, I'm curious if you've seen kind of any differences in like use between the academics and the community physicians? And then second, I'm just curious, if you can run through with us kind of your thoughts again on LOH versus HRD and then are they more similar than different and have we had any incremental point kind of evidence on your side to kind of make you feel more comfortable or have greater confidence or the same confidence there?

Sure. So first, I don't think we've seen much difference in the use, between academics and the community setting. It's pretty early days, it's 3 months or so. But I don't have any evidence that there's markedly different prescribing patterns in the community versus academic settings. So the quick answer to that, I think is, more to come as the launch evolves. As to LOH versus HRD, I probably have 15 answers to that, but I'll try to make it quick. So we do not believe that there is going to be a meaningful difference in the patients identified as HRD from the Myriad tests versus LOH from the Foundation test with the one exception, that patients with somatic mutations of BRCA are included in our definition of BRCA and the tissue BRCA test that is conducted by Foundation, and those patients are included in the definition of HRD and in the definition by Myriad and used by TESARO in the NOVA study but broken out, so you can see the pure HRD, which was helpful. Interestingly enough, given the label, it appears that while we clearly will describe to you HRD outcomes and LOH outcomes, as I think Cory was noting, there's probably going to be more attention to what the outcomes are in the non-BRCA patients versus the BRCA patients because that's the way the label for TESARO is delineated. So while I don't anticipate much of a difference, I think the greater interest is going to be on the all comers non-BRCA population.

Our next question or comment comes from the line of Peter Lawson from SunTrust Robinson.

I wonder if you could give us any details about how Rubraca is being used with -- whether you're seeing also in the maintenance from being used in treatment or second line versus later lines? That would be great.

We don't capture perfect data but, and we tend to live off more anecdotes than we do perfect data. We do get a lot of questions about, given that it's 2 prior chemotherapies that can be used in patients who may only have had some combination of carbo and Taxol or maybe with bev. We certainly have physicians who don't really believe that there is a well delineated in the real world population of maintenance versus treatment. And we get physicians who are quite open to using it when they feel the patient is going to benefit, having followed a platinum-based regimen and benefited from a platinum-based regimen, which could be pretty early, which I guess would classify more as maintenance, and we know it's been used in that setting or patients who clearly are progressing where it would be absolutely defined as treatment. I do think this is a well delineated zone for the purposes of regulators and clinical trials, but a much less well delineated zone. And in the world of treatment, especially of women who now have been through 2 rounds of chemotherapy and who are clearly inevitably, sadly likely to progress.

Got you. And then just, are you seeing physicians switching from LYNPARZA use?

We have heard that patients have switched. And again, I don't have data, I have anecdotes, but clearly several of our -- I tend to go out and meet with our local commercial teams whether I'm in New York, L.A. or Boston or wherever. And clearly there are patients who switch from olaparib to rucaparib, I think that's driven by 2 things. One, is as you know, at this moment in time, and this will change, when they have approval for their tablet, but at this moment in time, the pill burden or capsule burden for olaparib is fairly difficult for many women to tolerate, so that can drive a decision to change. We are still going to see patients who are beginning to progress on a PARP inhibitor, consider an alternative PARP inhibitor, the data suggests expectations should be relatively low for a meaningful effect in those patients. But obviously, at that moment, physicians and patients are desirous of trying whatever they can.

Our next question or comment comes from the line of Debjit Chattopadhyay from Janney.

So first of all, there is a subgroup analysis in patients with low residual disease burden, which in many ways could be similar to the NOVA population. Would you be putting that out initially? Or is that kind of being benchmarked for the ESMO meeting?

Yes. I'm determined as much as possible not to tell everybody what we plan to put in that press release because -- partly because we don't really know what we're going to put in that press release. But having made clear that we think that could be important in the event, it is important we will likely have it in the press release, if the results are largely similar to the intent to treat population, we would probably save that, we would say so and save that for the scientific presentation.

Great. And then any thoughts on, because obviously, it's a slightly different test in terms of the loss of heterozygosity, 16% in the Phase II versus 14% here. Do you think a companion diagnostic comes at play? Or do you expect the label to be very similar to TESARO without a companion diagnostic burden?

Well, that's an important question that is unanswerable today. So in the event that we show a similar outcome in both the HRD population, but also as stated in the all comers population. I would expect that we would follow a very similar path as they did in their interactions with the regulator. So it's highly dependent on the data, but if our data are equally robust, in the all comers, non-BRCA population, then I think it would probably follow a similar pattern.

And in terms of the checkpoint inhibitor combos, this might be a weird question, but does -- any feedback from KOLs regarding the somatic mutation burden has? Does that increase with the number of chemo regimens that patients have had before. You've seen some of that in prostate cancer. Does that also happen here in ovarian cancer? And in which case, what makes more sense, up above with PD-1s earlier on or later down the road?

Well, it clearly works for in the earlier on in the maintenance setting. We uniquely, I think, or maybe not uniquely, as far as I know uniquely have fairly good data where, because in ARIEL2, we mandated that not only would we get archival tissue, but we would also get tissue at the time of enrollment in the trial. We were concerned or curious or some word about whether or not there would be a large increase in the number of somatic mutations or even in the definition of HRD in relationship to disease progression and to the effect of rounds of chemotherapy. And we did not see very much at all in the way of differences between those mutations and archival tissue, which would have been an initial diagnosis and following several rounds of therapy. So we don't think in ovarian, there are likely to be a meaningful number of differences. It may be that it is pronounced in prostate, and you're right, both the percentage of germline and somatic patients in prostate cancer increases pretty significantly by round of therapy. But what physicians believe is that is less likely to be in response to therapy, but that those somatic and germline mutations of BRCA in prostate cancer patients are a really poor prognostic factor. And so you're seeing an enrichment in later line and progressing patients, for those who have that poor prognostic factor. And so the cause of it may not be exactly what you think, it may just be there's an enrichment for these patients who, unfortunately, are more likely to progress and progress into metastatic disease.

Great, and one last question. In terms of timing of the data and powering of the bev plus chemo plus Rubraca study?

Okay. I think that was a question to me. I can't say for sure when the timing of that study will be, and I don't have full knowledge on the powering. I'm pretty sure it was 80% powered, potential hazard ratio of at least [0.5%], but we'll figure out a way to make that clear to you in the next couple of days. We don't control enrollment or timing of that trial because it's a cooperative group in Italy that is running it. But we know and, in fact, I just met with the investigator, the PI in the last month or so that there's a tremendous amount of enthusiasm for enrollment in that trial, participation in that trial. And I know that you can do that because this woman happens to be the highest individual enroller in the ARIEL3 study. So they are good enrollers.

Our next question or comment comes from the line of Steven Breazzano from Piper Jaffray.

From me, how long from the data release would we expect for publication in the scientific journal and incorporation into NCCN guidelines? And could this be concurrent with presentation at a scientific conference like ESMO?

Well, we have an impressive precedent. We were impressed that TESARO was able to get to New England Journal publication at exactly the same time as their ESMO presentation. And it goes without saying that we here are challenged to deliver a similar outcome. So we are going to do our best. I mean I can't predict it. I suspect the robustness of the data will drive the enthusiasm for publication. But we clearly are going to try to be in that similar zone. As to the timing of potential NCCN guidelines, I'm sure you're aware that NCCN guidelines do require a publication so we're highly incented to have that publication as rapidly as we can. And I would hope that within a matter of relatively small number of months following publication, again, if the data is robust, as we all hope, that it would make it into NCCN guidelines.

Our next question or comment comes from the line of Terence Flynn from Goldman Sachs.

Maybe 2 from me. First, just wondering, Pat, if you can remind us on just where your confidence on the prostate cancer opportunity comes from, give us a sense of what data is out there that drives that. And then the second question, I might have missed it at the beginning was the breadth of prescribing for rucaparib. What have you seen so far with respect to your target population in the U.S.?

Sure. For prostate, I'll say a couple of things. We have, as others do, pretty impressive anecdotes of efficacy in our Phase I study as well in certain patients who under a compassionate use availability of rucaparib, where it was used to treat prostate cancer patients. And in fact, this is clearly an anecdote Terence, but it was a really great moment when a physician forwarded me a letter that a patient wrote where he called himself the comeback kid. And he wanted it sent to me for sharing with me and my colleagues here, where he was a PS2, effectively a PS3, he was on oxygen, he was in a wheelchair, he was about to be sent to a hospice, and after 6 weeks of being with prostate cancer. And after about 4 weeks or 5 weeks of therapy, he walked into the clinic, no oxygen, fully mobile and had a dramatically lower PSA response. It goes without saying that, that impressed the physician to the point that he is our European PI now in the TRITON2 and TRITON3 study. More importantly, the DeBono paper that was published in December of '15, which looked at [alacrative] outcomes with a somewhat complicated definition of response, including PSA response and CDC response, but also in a small number of patients that they do this for a RECIST response, so the really pronounced effect. That was in the New England Journal. It clearly has activated the prostate cancer community to the point wherein interest and enthusiasm to participate in this trial is incredibly exciting. And I know that the Prostate Cancer Foundation which wields an enormous influence in this setting has prioritized the importance of both BRCA testing and the possible use of PARP inhibitors in the treatment of prostate cancer. So this is a well regarded opportunity and class of compound in the treatment of at least BRCA mutated, ATM mutated and potentially other HR related mutations in prostate cancer.

And I will say one last thing about that. I think that the relationship of a PARP inhibitor to activity in BRCA mutated patients now is really well established, at least for this group of very active PARP inhibitors, of course, rucaparib amongst those. With regard to the breadth of the prescribers, I think I may have mentioned that in the script. I was really happy. We had 350 independent or unique prescribers of rucaparib just in the first quarter alone. So I think our reach is impressive, and I anticipate that, that will be, of course, higher as we continue in our launch.

Our next question or comment comes from the line of Tom Shrader from Stifel.

I couldn't tell if you answered this question earlier, so I want to try again. Is line of treatment driving a lot of your use. And I guess what I'm really asking is are you treating a lot of mostly early patients because they can get the drug on label earlier? Or is that kind of irrelevant to physicians and they just like the drug?

I think they like the drug. I think that we don't have perfect information about -- we get questions from physicians. We don't know with perfection or with detail of whether the patient would have had 2 prior chemotherapies or 2 prior lines of therapy. We know what our label says. I think, over time, we'll follow a pattern that is pretty common in the launch of new drugs where frankly, early in the launch, you tend to get more later line patients, where the physicians really challenge the drug in patients who've been through multiple rounds of therapy and where they may think they have alternatives at earlier line. And if they like what they see, they tend to move it up into earlier line, even on label patients. So I think that transition may occur over time. It doesn't necessarily happen 3 months in the launch.

And can you just remind us, in your clinical trials with the drug, would you have seen most dose reductions at the first refill? Is that the major point? Do they happen early?

In our experience, they can happen at anytime. In our experience, most of the dose reductions would occur -- I wouldn't necessarily say just after the first cycle, but certainly after the first 1 or 2 cycles. But remembering that with 3 months, a number of our patients who may have been dosed in March haven't even had their refill yet. So while I'm pleased thus far with adherence, as I pointed out in the script, it's a little early to make -- to -- we must acknowledge that, that's going to move around some over the course of the launch.

Our next question or comment comes from the line of Tazeen Ahmad from Bank of America, Merill Lynch.

Pat, I just joined the call a few minutes in, so forgive me if I'm asking you something you already talked about. But you have talked about getting some use in earlier lines of therapy. But are you also seeing any use by doctors in the maintenance setting per se? And then a second question would be on the studies that are being conducted in combination with PD-1 or PD-L1s. I guess, just given the idea about cost here that would be a potentially expensive combo. What kind of efficacy would you ideally like to see

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to justify advancing into more advanced trials, just based on what you think would be, and are they clinically meaningful but commercially viable?

Yes. Good question. With regard first to are we getting some use in maintenance, I did address this earlier, and the answer is yes. And the answer is yes because the definitions of maintenance and the definitions of treatment gray area for women who already progressed now or have been treated with 2 prior lines of therapy are a little less -- the definitions are a little less robust than they are for regulatory or for clinical development purposes. And we're well aware physicians who have used it somewhat might formally be called a maintenance setting and then reimbursed. I can't quantify that, but I certainly have heard it. With regard to the potential financial toxicity, of the PD-1, PD-L1 plus rucaparib, all of us in Oncology are focused on developing combinations products. And in fact there are a number of PD-1, PD-L1 products that are already used in combination with (inaudible) combination immunotherapy agents that are already combining the 2 relatively expensive drugs. I have been predicting for about 15 years that there's going to be more issue with pricing. I have been wrong for about 15 years. Ultimately, there will be a more focus on this. I do think that, given the pronounced effect seen with some of these combinations, and given that, as I said earlier, what the expectation is from this trial or the hope I should say from this maintenance study at least in the front line setting of PD-L1, is we see a market increase in the number of patients who would be described as having been cured. I think that meaningful results of that nature, including a meaningful increase in the PFS versus what's available today would be reimbursable.

Okay. And then maybe just one question about the importance of being able to get a full label without the need for gene testing should ARIEL3 be positive. Some of the feedback we've been getting from physicians about the TESARO launch is that at least on the KOL front, they would still like to do gene status testing for patients. And I don't know if you're hearing the same thing in general from physicians, but that does that in any way, in your mind, change the importance of having a label without the need for gene testing?

Yes, this is -- it's a good dialogue to have, and a dialogue that is currently occurring in the community. The academic community for sure is very focused on ensuring they have the availability of testing both for BRCA mutations and for HRD. And in addition to the ongoing debate about maintenance versus treatment and when best to use a PARP inhibitor, because that debate continues both in the academic and community setting, there remains as well a conversation about the relative merit in a patient who is neither defined as HRD or BRCA. And we all know from the ESMO data that there was a descending benefit first pronounced in BRCA, very good in HRD, less so in the biomarker negative. And I would anticipate ours would follow the same path, I'm not saying it would be any different. And I think it's extremely important that we as a community ensure that patients and physicians know their options for testing and important that they consider testing to determine which of the classifications they are. And I think it's important that as a marketer, we don't try to say, assuming we had great data in the biomarker negative, that testing isn't important. Testing is important because there are varying results here and varying alternatives. And most important, anything we do that would take away from testing for mutant BRCA has pronounced effects on the availability of that information, not just to a patient but to her family. And in fact, we're embarking on a program now the product to increase testing in other tumor types where it turns out it is just as relevant, prostate being a very good example. So yes, we hear that dialogue, yes we participate in that dialogue, and I will say that there will be a delineation of those who may prefer to use it in all comers, but certainly going to be a population but a population who will limit it to either BRCA or HRD.

We have time for one more question. Our final question comes from the line of Andrew Berens from Morgan Stanley.

Maybe a question on commercial and then on ARIEL3 also. In terms of the usage, I know, AstraZeneca saw some usage out of ovarian cancer without a formal label. And are you guys seeing that? Or any usage also outside of just the BRCA patients?

The data we have, and again, this is unrelated to our promotional activities, which are very focused on our label, but the data we have suggests that around 10% of our scripts would be formally described as off label primarily in other tumor types.

Okay, thanks. And what about outside of BRCA patients?

Well, I think far less of that. I think for now, the majority of our use is going to be in somatic or germline BRCA patients. We do know of some patients who have been treated and reimbursed, I guess I should add this, who are defined as HRD, that we do know, primarily in the academic setting.

Okay. And then in terms of ARIEL3, is there a marker for clinical progression like CA125 in the trial? And was that used by the independent review, the data monitoring board to assess the trigger, the 70% trigger?

No, the trigger is entirely driven by progression events as determined by RECIST . At the local clinic, a physician of course would monitor CA125 and in the event that they were monitoring the CA125 and saw a meaningful rise, they have the ability to call for a scan earlier. So that was a role of CA125, but the independent data monitoring committee had no visibility to CA125 response, not that I am aware of. If they did, it had nothing to do with the timing of the call.

Okay, and progression events for the trigger were driven by the central review?

No, the progression events for the trigger were driven by local review.

Okay, and then just last one question, I know you're trying to wrap up the call. But can you help us understand -- I know people have been trying to benchmark the enrollment and the last patient in to the trigger with some of the other trials that have read out previously. Could you help us put that in context?

Well, I could take an hour on this or I could try to do it in a little shorter period of time. So I'll try and do it in a shorter period of time. First, I'm highly sympathetic to the desire investors have to try to rank order where we are compared to the AstraZeneca data for SOLO2 and to the TESARO data for NOVA. And so first I'm sympathetic. Second, it turns out, it's really hard to do. Each of these trials, now it turns out, are going to have a complete time from first patient in to release of data of just around 3 years. So that is true. So these are all, I think, pretty narrow confidence intervals. Going to be 3 years, in our case, it's going to be 3 years plus 2 months, that's exactly our timeline. The difficulty is that, one, in the TESARO study, because they added the HRD patients later than they did the original trial which didn't include a focused patient group in HRD, our understanding is that they delayed the results until they had appropriately hit the number of events in the HRD population. So it's not a great benchmark because we don't know what that timing would have been if they had, like us, just enrolled everybody at the same time. For AstraZeneca, it turns out, and I only recently learned this, that they concluded enrollment in the first part of the trial at the end of '14. But in early '15, they reopened the trial to add a Japanese cohort of around 30 or 40 patients, and then I think delayed the analysis of that trial until they had achieved some trigger of progression events in that Japanese cohort. It would be kind of foolish to enroll them but not use them in the analysis, particularly because it's hard not to believe the decision to enroll them was driven by a regulatory dialogue about how many Japanese patients the regulator would like to see in that trial. So in both cases, there was not kind of a linear enrollment that both companies, in theory, could have read out their results earlier than they did if they have not elected to add additional patients, in the one case, Japanese patients, in the one case, HRD patients. So it just turns out that much as we all and hell we like to do it too. We'd like to have some clarity on how it feels at this moment likely compare, you cannot make this apples-to-apples comparison because it's an apple to a pear to an orange. Further, the enrollment in our trial was completely linear, and as I mentioned earlier in the script, I am not sure if you've heard this Andrew, but we had a really interesting trial. Half of our patients did enroll in the first year, half in the second year of the trial. And after the first few months, where we were getting IRB approvals in new sites. Our monthly enrollment was almost exactly the same month to month to month. Truly interesting to see, you don't see it quite that linear in these trials like we did. But it was really interesting. However, we don't know the biomarker status of those patients. So since our trigger is driven by a sub-population, BRCA, we have no idea if our last BRCA patient enrolled in February of '15 or March of '15 or January of '15 or April of '15, we just don't know. And so it makes it even harder to make these comparisons. So it's -- I gave you not quite the hour long one, but I got close. But it's just -- I get that people want to do it, I will tell you that it is impossible to do it.

I'd now like to turn the conference back over to Ms. Anna Sussman for any closing remarks.

Thanks, Howard. Thanks everyone for your interest in Clovis today. If you have any follow-up questions, you can call me at (303) 625 5022 or Breanna at (303) 625 5023. This call can be accessed via replay at clovisoncology.com beginning in about an hour, and it will be available for 30 days. We appreciate your interest and time. Thank you, and have a good evening.

Ladies and gentlemen, thank you for participating in today's conference. This concludes the program. You may now disconnect. Everyone, have a wonderful day.