J&J's Apalutamide, Astellas/Pfizer's Xtandi On Par For Non-Metastatic Prostate Cancer

Phase III data at ASCO GU meeting impress, but raise questions about safety in new non-metastatic CRPC indication – rash, fractures and falls for Erleada (apalutamide) and unexplained deaths after termination of treatment for Xtandi (enzalutamide).

Astellas Pharma Inc./Pfizer Inc.'s Xtandi (enzalutamide) and Johnson & Johnson's investigational apalutamide both demonstrated profound benefits over placebo in high-risk, non-metastatic castration resistant prostate cancer with similar results in Phase III trials, but both raised questions about safety.

Data from the PROSPER study of Xtandi and the SPARTAN study apalutamide, now dubbed Erleada, were presented on Feb. 8 at the American Society of Clinical Oncology Genitourinary Cancers (ASCO GU) symposium in San Francisco.

Both studies evaluated the drugs in non-metastatic castration resistant prostate cancer (nmCRPC) patients on hormonal therapy who have a rising level of prostate-specific antigen (PSA), but no other symptoms of progression.

ASCO said in a statement that the findings may be relevant to some 100,000 patients in the United States. Nothing is currently FDA approved for this nmCPRC.

The clinical community has expressed a lot of excitement about the prospect for having an effective treatment of these earlier-stage prostate cancer patients, Steven Benner, senior vice president and global therapeutic area head of oncology development at Astellas, told Scrip in an interview before the meeting.

"When the PSA is rising like this you know that the patients are on a path towards metastases and that has been a source of frustration, as there haven't been effective therapies that could be given in that setting. So we think these results are clinically very meaningful," Benner said.

Both studies measured metastasis-free survival (MFS), the time that passes until a cancer can be radiographically detected as having metastasized, or until death.

In addition to demonstrating a highly statistically significant improvement in time to development of metastases vs. placebo on top of background hormonal therapy, both drugs showed significant benefits on secondary endpoints, like median time to progression, as well as a trend for an overall survival benefit (see table below).

Philip Kantoff, the discussant for both trials at the ASCO GU meeting, described the MFS efficacy data for both drugs as "very impressive" and a clear signal that the drugs "are very biologically active."

The studies haven't been compared directly, but the data presented at the meeting suggest that efficacy is similar and there is a "hint" of a difference in toxicity, said Kantoff, who chairs the department of medicine at Memorial-Sloan Kettering.

Flagging safety issues for each study, he questioned whether there was enough evidence of a clinical benefit for patients, particularly given that they are asymptomatic, so the safety bar is higher.

Rash, Falls Fractures

J&J's SPARTAN study tested apalutamide against placebo on top of androgen deprivation therapy (ADT) in 1,207 men with non-metastatic CRPC at high risk of metastasis based on PSA tests.

Erleada is new androgen receptor inhibitor that is being positioned as a successor to J&J's Zytiga (abiraterone), which had $2.5bn in sales for 2017. (Also see "J&J Shows Grace Under Pressure From Biosimilars And Other Threats" - Scrip, 23 Jan, 2018.)

The study was unblinded early based on a recommendation by the independent data monitoring committee in July 2017, and patients on placebo were permitted to cross over to treatment with apalutamide.

Apalutamide decreased the risk of metastasis and death by 72% compared with placebo and significantly prolonged median metastasis-free survival by two years (40.5 months for apalutamide vs. 16.2 months for placebo).

Data for overall survival – a secondary endpoint – were not mature but there was a trend toward a benefit, with a 30% reduction in risk of death for the apalutamide arm.

The treatment related dropout rate was 10.7% for apalutamide vs. 6.3% for placebo.

Kantoff expressed concern for data on three particular side effects – rash, falls and fractures. Overall and Grade 3/4 rates were as follows: Rash (23.8%/5.2% for apalutamide vs. 5.5%/0.3% for placebo; falls (15.6%/1.7% for apalutamide vs. 9%/0.8% for placebo) and fractures (11.7%/2.7% for apalutamide and 6.5%/0.8% for placebo).

Looking at Grade 3/4 rates and noting "twice as many falls" and "three times as many fractures," Kantoff said: "Yes, these are low frequency events but nonetheless they are important for patients."

There was a significant improvement on the secondary endpoint related to time to development of symptomatic progression in the SPARTAN study (a 55% reduced risk for the test drug arm), "which looks like a hint of some clinical benefit," but it's unclear what symptoms exactly are driving this result and whether in clinical practice the patients would have been treated with an alternative therapy before they occurred.

Deaths Post-Treatment

Pfizer/Astellas' PROSPER study tested Xtandi vs placebo on top of ADT in 1,401 patients with nmCRPC. The ASCO GU presentation followed a positive topline release in September 2017. (Also see "Pfizer Poised To PROSPER From Xtandi In Expanded Indication" - Scrip, 14 Sep, 2017.)

Metastasis-free survival in the Xtandi/ADT arm was 36.6 months vs. 14.7 months for ADT/placebo, a highly significant result with a 0.29 hazard ratio, meaning a 71% reduction in the risk of progressing to metastases (p-value <0.0001).

The magnitude of the impact on MFS was really striking and exceeded the companies' expectations going into the study, Astellas' Benner said.

On the secondary endpoint of time to PSA progression, there was a 93% reduction in risk for the Xtandi arm vs. the control arm (37.2 months vs. 3.9 months, p-value of 0.0001).

Overall survival data are not mature yet but there was a trend toward an improvement for the Xtandi arm, with a 20% reduction in risk of death.

"The profound PFS benefit suggests that an OS benefit is also probable, in our view," BMO Capital Markets Alex Arfaei said in a Feb. 5 note on Pfizer.

The most common Grade 3+ events included hypertension (5% vs. 2%), fatigue (3% vs. 1%) and major adverse cardiovascular events (5% vs. 3%). "Three seizures (<1%) were reported with Xtandi plus ADT patients and none were reported for those who received ADT alone," the companies reported. The dropout rate due to adverse events was 9% for the Xtandi/ADT arm vs. 6% for ADT/placebo.

Kantoff drew attention to the difference in the rates of death without documented radiographic progression within 112 days of treatment continuation – 32 (15%) for Xtandi vs. 4 (2%) for placebo – and said the causes of death for the patients in the test drug arm should be explained.

"This is a little concerning to me and I think we need to dissect this further," he said.

During the Q&A session after the presentation, PROSPER presenter Maha Hussain, Northwestern University, explained that there were no specific trends for these deaths; the causes included malignancy and pneumonitis. However, on a percentage basis, there were more related to cardiovascular problems. Investigators are looking further into the data, she said.

Expanding To Earlier Use

Reception of the study data by regulators and prescribers is important. Non-metastatic CRPC is one of the indications that will allow sponsors of to move into earlier lines of treatment, amid competitive pressures.

Xtandi was initially approved for treating advanced metastatic prostate cancer after chemotherapy in 2012, then later for patients prior to chemo. In the first nine months of the fiscal year 2017 (ending March 31, 2018), Xtandi had sales of Y219.9bn (about $2bn), up 16.2% from the year-ago period, Astellas reported Jan. 31. Pfizer reported $168m in royalty revenue for Xtandi in the fourth quarter of 2017.

Pfizer and Astellas noted in a Feb. 5 ASCO GU announcement that Xtandi has been filed with FDA in non-metastatic CRPC, with an expected user fee date in November. The drug was also submitted for approval in Europe.

J&J's Zytiga could face generic competition in the US in October, following a Jan. 17 decision by the US Patent and Trademark Office's Patent Trial and Appeal Board, but J&J is fighting this ruling. (Also see "PTAB Clears Path For Earlier Generic Zytiga Launch" - Scrip, 18 Jan, 2018.) In addition to developing follow-ons, J&J has been moving Zytiga into new indications beyond metastatic CRPC. On Feb. 8, FDA approved a new use for use in combination with prednisone for metastatic high-risk castration sensitive prostate cancer, a filing supported by the LATITUDE study.

Apalutamide has priority review in the US for non-metastatic CRPC, with a user fee date in April, so it is set to become the first androgen receptor inhibitor approved for this indication.

But Is The Data Enough?

However, that may not be good enough for Johnson & Johnson. BTIG analyst Dane Leone said in a Feb. 6 note that for JNJ’s prostate cancer franchise, the "SPARTAN dataset for apalutamide needed a clear win over Xtandi to improve investor sentiment around the aggregate growth outlook for JNJ’s cancer drug portfolio, due to the coming generic launches against Zytiga by YE2018."

Leone concluded that "efficacy looks identical between Xtandi and apalutamide" for nmCRPC.

"The hazard ratio for risk of distant metastasis or death for Xtandi (PROSPER) was 0.29 vs. 0.28 for the apalutamide (SPARTAN) study. Although the differentiation against placebo on median metastasis-free survival was ~24.3 months for SPARTAN versus ~21.9 months for PROSPER, given the study designs, the margin is likely too thin to claim any clinical superiority," the analyst said.

As for Xtandi, BMO Capital Markets is forecasting peak revenue of $2.6bn by 2027, with 30% to 40% coming from the non-metastatic CRPC indication.

Although nmCRPC is currently viewed as an area of high unmet need, the population size may shrink in the future, ASCO expert Sumanta Pal said during a Feb. 5 press briefing that featured the SPARTAN study of apalutamide, among other datasets.

The SPARTAN study used conventional imaging methods – CT and technetium bone scans – to assess whether cancer had metastasized. This is the current standard of care but there are better modalities, like advanced PET imaging, which improve the ability to detect disease spread earlier, thereby changing the management strategy, explained Pal, a genitourinary specialist at the City of Hope in Duarte, Calif. PET is becoming more widely available. Conventional imaging methods were also used in PROSPER.

During the Q&A session at the meeting, Nicholas David James, lead investigator of the Cancer Research UK-funded STAMPEDE study, said that from the UK perspective, the SPARTAN and PROSPER data were not practice changing. Asymptomatic men with rising PSA are no longer put on long-term ADT, which is quite toxic and should be avoided; rather they are imaged with PET to detect metastases and managed with short-term ADT, he said.

"These trials are very important but they relate to a segment of the disease that certainly in Europe is going to disappear quite soon. It already has disappeared in my practice already," James said.

Comparison Of Phase III Data For Androgen Receptor Inhibitors In Non-Metastatic CRPC
Phase III studies for non-metastatic CRPC tested androgen receptor inhibitors in men whose prostate specific antigen (PSA) was rising, despite androgen deprivation therapy (ADT), and were at high risk for developing metastases. Both used metastasis-free survival (MFS) as a primary endpoint. Full data were presented at the ASCO GU meeting in San Francisco on Feb. 8.
Sponsor/Drug	Trial/Design	Primary Endpoint	Key Secondary Endpoints	Safety Highlights	Filing Status
Janssen's Erleada (apalutamide)	SPARTAN (n=1,297), apalutamide (APA) vs. placebo, both with ADT	APA/ADT arm decreased risk of metastasis and death, 40.5 months vs. 16.2 months for ADT/placebo (hazard ratio 0.28, p-value < 0.0001)	Significant improvement in time to symptomatic progression for APA/ADT (HR 0.45); APA significantly reduced risk of progression (HR 0.49). Trend for OS benefit with APA (HR 0.70).	Serious event rate 25% for APA/ADT vs. 23% placebo/ADT. Grade 3/4 events of note: rash, falls, fracture. Treatment-related dropout rate: 10.7% for APA vs. 6.3% for placebo. Two seizures in APA arm vs. 0 placebo.	Priority review with US FDA, April user fee date; also filed in Europe
Pfizer/Astellas' Xtandi (enzalutamide)	PROSPER (n=1,401), Xtandi vs. placebo, both with ADT	Xtandi combo improved MFS: 36.6 months vs.14.7 months (hazard ratio 0.29, p-value <0.0001)	Time to PSA progression reduced by 93% in Xtandi/ADT arm (p<0.0001). Trend for OS benefit with Xtandi, hazard ratio 0.80.	Major Grade 3+ CV events (5% Xtandi vs. 3% placebo). Three seizures in Xtandi arm, 0 placebo. Treatment-related dropout rate 9% for Xtandi vs. 6%.	Newly filed in US and Europe