Randy Dotinga

In November 2018, the FDA issued a draft guidance recommending metastasis-free survival (MFS) as an endpoint in drug trials for nonmetastatic castration-resistant prostate cancer (nmCRPC), suggesting a major change in expectations for treatment of this tumor type.

&ldquo;Whereas radiographic progression-free survival has been standardized as an endpoint in metastatic settings, there was previously no earlier endpoint for nmCRPC trials. The FDA has now recognized that a prolonged delay in development of metastatic disease is an objective and clinically relevant measure,&rdquo; officials from the FDA wrote in a perspective summary.

&ldquo;Future agents may be approved on the basis of MFS only if substantial effects on this transition are demonstrated and the safety profile is acceptable for a medication taken long term.&rdquo;

James Mohler, MD, associate director and senior vice president for Translational Research at Roswell Park Comprehensive Cancer Center in Buffalo, New York, described the FDA&rsquo;s move as &ldquo;a landmark change&rdquo; considering the agency&rsquo;s tendency to favor overall survival (OS) as an endpoint.

&ldquo;There is great value in delaying the development of metastasis,&rdquo; said Mohler in an interview with

. &ldquo;I applaud the FDA for looking at an intermediate endpoint that is really meaningful for patients. This is a tremendous breakthrough.&rdquo;

Prior to the approval of apalutamide (Erleada), in February 2018, no therapies existed exclusively for the treatment of nmCRPC. As a result, many patients were unprotected against disease progression once androgen-deprivation therapy (ADT) had failed.

This approval was based on the results of the double-blind, phase III SPARTAN trial, in which MFS was used as the primary endpoint. Administration of apalutamide was associated with a median MFS of 40.5 months compared with 16.2 months in patients taking placebo, representing roughly a 2-year improvement (HR 0.28; 95% CI, 0.23-0.35;

Participants (n = 1207) were randomized 2:1 to receive oral apalutamide at 240 mg daily or placebo in conjunction with ADT. High-risk, castration-resistant disease was defined as occuring with a PSA doubling time of 10 months or less during ADT.

Officials said the drug was &ldquo;well-tolerated&rdquo; and had similar incidence rates of serious adverse outcomes in the apalutamide and control groups.

They added that patient-reported outcomes showed &ldquo;no notable adverse signals in symptom or functional effects despite the long treatment duration.&rdquo;

In the interview, Mohler said too little attention has been paid to an important adverse event statistic in the study: the any-grade bone fracture rate of 11.7% in the apalutamide group compared with 6.5% in the placebo group.

Investigators on the apalutamide trial determined that &ldquo;MFS has a significant association with OS and is predictive of OS in high-risk nmCRPC&rdquo; and is therefore &ldquo;a meaningful and valid intermediate clinical [endpoint] for OS.&rdquo;

Recognizing that the evolution from nmCRPC to metastatic disease is a clinically relevant event, the FDA Oncologic Drugs Advisory Committee (ODAC) discussed endpoints in therapies for nmCRPC in a 2011 meeting. Although they recommended that MFS could reasonably be used as an endpoint in clinical trials, they added that &ldquo;ensuring clinical benefit of a drug would require a substantial magnitude of improvement and a favorable benefitrisk evaluation.&rdquo;

Another ODAC examined a randomized, placebo-controlled trial of denosumab in nmCRPC that reported an improvement of 4 months in bone-only MFS. ODAC members concluded that longer MFS would be required to justify an approval based on this endpoint.

Enzalutamide Enters the Picture for nmCRPC

Another option in nmCRPC came in July 2018 when the FDA granted enzalutamide (Xtandi) approval for a new indication after the phase III PROSPER trial in which 1401 patients were randomized 2:1 to oral enzalutamide at 160 mg or placebo once daily. All patients had been previously treated with ADT or bilateral orchiectomy. Median MFS was higher in the enzalutamide group than in the placebo cohort, at 36.6 and 14.7 months, respectively (HR 0.29; 95% CI, 0.24-0.35;

Enzalutamide was previously recommended for the treatment of patients with metastatic disease only. Meanwhile, dozens of trials are exploring the use of apalutamide and enzalutamide in conjunction with other forms of treatment such as medication and surgery.

FDA officials hypothesized that the use of MFS could require significant adjustment. They commented that &ldquo;increasing sensitivity [of medical imaging] may increase the sensitivity and specificity of metastasis detection, potentially affecting the interpretation of study results and even changing the baseline characteristics of enrollees over time.&rdquo;

Data about OS in apalutamide and enzalutamide are not yet available. &ldquo;It will be interesting if apalutamide does not result in a change in OS,&rdquo; Mohler said. &ldquo;Even if OS does not differ, the value of delaying metastatic disease and its morbidity is probably worth use of the drug.&rdquo;

Analyses of the drug&rsquo;s long-term impact will need to consider its high cost, its adverse effects, and perhaps factors such as quality-adjusted life years gained, Mohler concluded.

Beaver JA, Kluetz PG, Padzur R. Metastasis-free survival  a new endpoint in prostate cancer trials.

2018;378(26):2458-2460. doi: 10.1056/NEJMp1805966.

Smith MR, Saad F, Chowdhury S, et al; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer.

2018;378(15):1408-1418. doi: 10.1056/NEJMoa1715546.

Smith MR, Mehra M, Nair S, Lawson J, Small EJ. Association of metastasis-free survival (MFS) and overall survival (OS) in nonmetastatic castration-resistant prostate cancer (nmCRPC).

2018;36(suppl 15):5032. doi: 10.1200/JCO.2018.36.15_suppl.5032.

Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer.

2018;378(26):2465-2474. doi: 10.1056/NEJ- Moa1800536.

Articles

In November 2018, the FDA issued a draft guidance recommending metastasis-free survival as an endpoint in drug trials for nonmetastatic castration-resistant prostate cancer, suggesting a major change in expectations for treatment of this tumor type.

FDA Advances the Use of Metastasis-Free Survival as an Endpoint in nmCRPC

Long-term metastatic control is an important goal for patients with high-risk renal cell carcinoma (RCC) after nephrectomy. In recent years, adjuvant therapy with tyrosine kinase inhibitors (TKIs) has entered the picture to potentially fill this unmet need.

The FDA found the evidence in 1 trial so convincing that it approved sunitinib malate (Sutent) for these patients in November 2017. But recent early studies in this population have provided conflicting results, and the European Medicine Agency&rsquo;s Committee for Medicinal Products for Human Use decided to go in the opposite direction of the FDA. It recommended against expanding sunitinib&rsquo;s use to treat this patient population.

Meanwhile, sharp dispute has arisen among US oncologists over whether TKIs are appropriate for these patients at this time.

A pair of Emory University physicians with opposing views on the issue discussed findings for adjuvant TKI therapy after surgery in high-risk RCC during the 2018 Debates and Didactics in Hematology and Oncology conference, held in Sea Island, Georgia.

Viraj Master, MD, PhD, argued in favor of adjuvant TKI use. He is a professor, the associate chair for clinical affairs and quality, and the director of the Clinical Research Unit in Emory University&rsquo;s Department of Urology.

In his talk, Master pointed to evidence supporting a disease-free survival (DFS) advantage in patients who receive adjuvant TKIs. He also noted that patients are less concerned about toxicity than survival and are &ldquo;highly interested in adjuvant therapy.&rdquo; Also, he added, patients do not differentiate between DFS and overall survival (OS).

Mehmet Asim Bilen, MD, argued against the use of TKIs at this point. Bilen is an assistant professor with the Department of Hematology and Medical Oncology in the School of Medicine and the associate medical director of the Phase I Unit at Winship Cancer Institute of Emory University.

Bilen noted that the drugs are not cheap, are &ldquo;definitely&rdquo; not easy to tolerate, and have not shown a benefit in OS in this population. &ldquo;I&rsquo;m not convinced that patients are getting a benefit, but I&rsquo;m pretty sure they&rsquo;re getting significant [adverse] effects,&rdquo; he said in an interview with

Both speakers discussed the phase III ASSURE/ ECOG-ACRIN E2805 trial, although they took different lessons from its findings.

The trial tracked 1943 patients with resected nonmetastatic RCC at a high risk for recurrence who were treated with adjuvant sunitinib, sorafenib (Nexavar), or placebo for 1 year.

Investigators did not find any evidence of a statistically significant DFS advantage with either TKI over placebo. A follow-up analysis also found no DFS advantage in a high-risk subset of patients with clear cell RCC (ccRCC) at 5 years.

The study authors noted that &ldquo;neither prognostic category of the tumor nor dose intensity of therapy altered the lack of difference in DFS or OS in this population of patients with high-risk ccRCC.&rdquo;

Bilen emphasized the negative findings of the ASSURE study, but Master rejected it as &ldquo;not the right trial.&rdquo;

Master identified weaknesses in the trial beyond the lack of patients with high-risk cancer and ccRCC: He said the study had an &ldquo;extremely high&rdquo; attrition rate of 44% and many of the patients were inadequately dosed.

However, Master was not entirely dismissive. He also noted that the study&rsquo;s findings suggested positive treatment effects on DFS with sorafenib in 3 subgroups: patients at pathologic stage T3 or T4, those with American Joint Committee on Cancer stage III/IV disease, and patients who started treatment at the full dose.

Master referred to the S-TRAC study as a &ldquo;much better trial.&rdquo; Indeed, the study persuaded the FDA to approve sunitinib malate. However, the approval came despite a 6-6 vote on the potential approval from the FDA&rsquo;s Oncologic Drugs Advisory Committee.

The phase III S-TRAC trial looked at 1 year of adjuvant sunitinib or placebo in 610 patients with high-risk ccRCC.

According to Master, the findings regarding DFS are promising. The study found a DFS benefit for sunitinib (6.8 vs 5.6 years; HR, 0.76; 95% CI, 0.59-0.98;&nbsp;

= .03), and Master said the study is more reliable than ASSURE because it had lower rates of dose reduction and discontinuation. He also noted that S-TRAC subjects were at &ldquo;much higher risk.&rdquo;

A follow-up phase III study that sought to validate the 16-gene Recurrence Score in 193 patients with stage III disease from S-TRAC &ldquo;may help identify which patients are most likely to benefit from adjuvant TKI therapy,&rdquo; Master added.

Bilen noted the S-TRAC study in his presentation but pointed out that it included only pT3-4 patients with positive lymph nodes. The treatment group in the S-TRAC study received 50 mg of sunitinib daily for 1 year on a 4-weeks-on, 2-weeks-off schedule, and Bilen pointed to the expense of this treatment.

He also pointed to the expense of TKI drugs. According to goodrx.com, the retail price for 28 capsules of sunitinib 50 mg is around $17,300.

Medicare covers sunitinib, and co-pays can range from $4,900 to $19,600.

Both physicians took different lessons from the PROTECT trial. This study examined patients with locally advanced RCC following surgery who were treated with pazopanib (Votrient) or placebo.

Patients in the treatment arm initially received 800 mg of pazopanib, which was lowered to 600 mg due to adverse effects (AEs).

Bilen noted no difference in DFS or OS in the primary analysis of the 600-mg intention-to-treat (ITT) group compared with placebo. He also noted high levels of grade 3/4 AEs in the 600-mg pazopanib group compared with the placebo group (60% vs 21%).

For his part, Master focused on a 31% reduction in the risk of recurrence with pazopanib in an analysis of the 800-mg ITT group.

Bilen highlighted the ATLAS trial, which was stopped earlier in 2018 due to futility. In that phase III trial, 724 patients with high-risk RCC were randomized to adjuvant axitinib (Inlyta) or placebo for 1 or 2 years.

He also pointed to a 2018 systematic review/pooled analysis of 3 trials: ASSURE (n = 1943), S-TRAC (n = 615), and PROTECT (n = 1135). The analysis found that adjuvant TKI use was not associated with improved DFS (HR, 0.92; 95% CI, 0.83-1.03;

but was associated with higher odds of grade 3/4 AEs (OR, 5.89; 95% CI, 4.85-7.15;

&ldquo;Vascular endothelial growth factor receptor-targeted therapy after nephrectomy for localized kidney cancer is not associated with consistent improvements in delaying cancer recurrence or prolonging life, and comes at the expense of potentially significant side effects,&rdquo; the analysis notes.

In his presentation, Master pointed to survey findings that suggest that patients do not consider AEs a top priority when they make treatment choices regarding recurrence: &ldquo;Toxicity is not a main driver of decision making.&rdquo;

Among 450 patients with RCC surveyed in a recent study, 63% and 60%, respectively, said prolonged OS and DFS were important; 43% pointed to toxicity as important.

Master said extended survival data are expected from the S-TRAC trial, and further insight is still to come regarding the use of tools such as highest grade/stage, 16-gene Recurrence Score, and other biomarkers to identify patients who would benefit most from adjuvant TKIs.

Bilen strongly urged physicians to support clinical trials. &ldquo;Those patients need therapy,&rdquo; he added. &ldquo;They have a very high chance for tumor recurrence. If there is any drug that can help them, it will be a great addition for our therapy.&rdquo;

Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal- cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-con- trolled, randomised, phase 3 trial.

2016;387(10032):2008-2016. doi: 10.1016/ S0140-6736(16)00559-6.

Haas NB, Manola J, Dutcher JP, et al. Adjuvant treatment for high-risk clear cell renal cancer: updated results of a high-risk subset of the ASSURE randomized trial.

2017;3(9):1249-1252. doi: 10.1001/jamaoncol.2017.0076.

3. FDA Center for Drug Evaluation and Research. Summary minutes of Oncologic Drugs Advisory Committee meeting. FDA website. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/ UCM580666.pdf. Published October 15, 2017. Accessed August 29, 2018.

Ravaud A, Motzer RJ, Pandha HS, et al; S-TRAC Investigators. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy.

2016;375(23):2246- 2254. doi: 10.1056/NEJMoa1611406.

Escudier BJ, Rini BI, Martini J-F, et al. Phase III trial of adjuvant sunitinib in patients with high-risk renal cell carcinoma (RCC): validation of the 16-gene Recurrence Score in stage III patients.

2017;35(suppl; abstr 4508). meetinglibrary.asco.org/ record/144686/abstract.

Sutent. GoodRx website. www.goodrx.com/sutent?form=capsule&dosage=50mg&quan- tity=28&days_supply=&label_override=Sutent. Accessed August 29, 2018.

Motzer RJ, Haas NB, Donskov F, et al. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with locally advanced renal cell carcinoma (RCC) (PROTECT).

2017;35(suppl; abstr 4507). meetinglibrary.asco.org/ record/144687/abstract.

Pfizer Provides Update on Phase 3 Trial of Axitinib as Adjuvant Treatment for Patients at High Risk of Renal Cell Carcinoma Recurrence After Surgery [press release]. New York, NY; Pfizer Inc; April 10, 2018. press.pfizer.com/press-release/pfizer-provides-update-phase-3- trial-axitinib-adjuvant-treatment-patients-high-risk-re. Accessed August 29, 2018.

Sun M, Marconi L, Eisen T, et al. Adjuvant Vascular Endothelial Growth Factor-targeted Therapy in Renal Cell Carcinoma: A Systematic Review and Pooled Analysis [published online May 18, 2018].

Battle D, Jonasch E, Hammers H, et al. Patients perspectives on adjuvant therapy in renal cell carcinoma.

2018;36(suppl 6; abstr 644). meetinglibrary.asco.org/ record/156950/abstract.

Long-term metastatic control is an important goal for patients with high-risk renal cell carcinoma after nephrectomy. In recent years, adjuvant therapy with tyrosine kinase inhibitors has entered the picture to potentially fill this unmet need.

Randy Dotinga | Authors

Articles

FDA Advances the Use of Metastasis-Free Survival as an Endpoint in nmCRPC

Are Adjuvant TKIs in High-Risk RCC Ready for Prime Time?