Andrew D. Smith

It took many years for investigators to find an effective treatment that could extend survival beyond androgen deprivation therapy (ADT) for patients with metastatic castration-resistant prostate cancer (CRPC). The answer was found in the chemotherapy docetaxel (Taxotere) in 2004. The next 13 years saw the approval of 8 treatments for the same disease: the chemotherapies cabazitaxel (Jevtana) and mitoxantrone (Novantrone), the immunotherapy sipuleucel-T (Provenge), the anti-androgen abiraterone acetate (Zytiga), the androgen receptor blocker enzalutamide (Xtandi), external-beam radiation, radium-223 (Xofigo), and the RANKL inhibitor denosumab (Prolia and Xgeva).

The same period, however, saw no successful trials against nonmetastatic CRPC, so the number of proven treatments remained, at least in the opening months of this year, where it had begun in 2004: at zero.

Patients with the localized form of CRPC (FIGURE) still have no options that are proven to extend overall survival (OS), but preliminary results from the PROSPER trial of enzalutamide and the SPARTAN trial of apalutamide (Erleada) offer them unprecedented hope. Both drugs, used in conjunction with androgen deprivation therapy (ADT), have demonstrated the ability to delay the metastasis that ultimately kill patients with prostate cancer by an average of about 24 months.

These 2 trials may be remembered as the first in a long line of breakthroughs against nonmetastatic CRPC. The FDA approved both apalutamide and enzalutamide for patients with nonmetastatis CRPC in February and July 2018, respectively. Other experimental compounds are currently being tested as monotherapies against the condition, and both enzalutamide and apalutamide are being tested as part of experimental combinations. Nothing is guaranteed just yet, however, not even the wisdom of using enzalutamide or apalutamide against nonmetastatic CRPC.

&ldquo;Although it&rsquo;s clear that there is [an] unprecedented delay in the development of metastasis with the use of enzalutamide or apalutamide in patients with nonmetastatic castration-resistant disease, we can&rsquo;t be certain that we are prolonging life until we see the final overall survival results from PROSPER and SPARTAN,&rdquo; said Maha H. Hussain, MD, the lead investigator of the PROSPER trial, in an interview with

&ldquo;We do know, though, that metastases precede diseaserelated death in the majority of patients, so the delay of metastases, which is the terminal phase of the disease, by a median time of 2 years is truly a landmark achievement against this disease. We also know that both drugs produce significant improvements in a range of secondary outcomes, which further supports their clinical benefit,&rdquo; said Hussain, who is the deputy director and genitourinary oncology program leader at Northwestern University&rsquo;s Robert H. Lurie Comprehensive Cancer Center. &ldquo;All those considerations have led the FDA to approve both drugs for nonmetastatic castration-resistant prostate cancer and professional organizations such as the American Urological Association to update their treatment guidelines, even in the absence of overall survival data.&rdquo;

Charles Huggins, MD, and Clarence Hodges, MD, outlined the first effective treatment for systemic prostate cancerwhich was also the first effective treatment for any systemic cancer&mdash;in 1941, when they published a seminal paper on patients with prostate cancer treated via either physical castration or chemical castration with estrogen therapy.

A follow-up paper from Huggins et al in the same year confirmed the dramatic benefits of testosterone deprivation in a larger patient population.

Huggins knew when he published that first paper that some patients developed castration-resistant disease, but it took 63 years to find a viable treatment that extended survival once patients progressed on ADT. Huggins actually discovered, and later research confirmed, that removal of the adrenal gland, which produces low levels of androgens, can improve outcomes in castration-resistant cancers, but the complexity of the procedure and paucity of the benefit prevented widespread adoption.

Even before the 2004 trials with docetaxel in patients with metastatic CRPC, chemotherapy was known to reduce levels of prostate-specific antigen (PSA) and to reduce cancer-related pain in some patients with hormone-refractory prostate cancer, but concerns about toxicities prevented its use in such patients, who received ADT monotherapy instead.

The 2004 trials showed not only that docetaxel extended life in patients with castration-resistant disease but also that the reduction in cancer burden outweighed the chemotherapy toxicity. That said, the survival benefits were modest. Men receiving the most effective regimen of docetaxel every 3 weeks and prednisone survived a median of 18.9 months, which was just 2.4 months more than the median with the comparator regimen of mitoxantrone and prednisone.

A 2010 trial showed a similarly robust-but-modest survival benefit for cabazitaxel and prednisone in patients who failed on docetaxel, the median survival was 15.1 months for the combination.

The years that followed saw half a dozen agents approved for metastatic CRPC, but few of those were tested in the setting of nonmetastatic CRPC. Radium-223 and external beam radiation all treat cancer in the bone, so there was little push to test them in patients whose cancer had not spread to the bone. Observers can only guess why the others were never tested in nonmetastatic CRPC.

Whatever the reason, it certainly wasn&rsquo;t lack of need. One patient-flow model has suggested that the prevalence of nonmetastatic CRPC in the United States amounted to about 40,000 cases in 2013 and will increase over the next 10 years.

In Enzalutamide and apalutamide seemed likely to help such patients because they both block the androgen receptors that somehow develop castration resistance and resume their ability to drive tumor growth, despite the lack of androgens in patients who continue on ADT. Both drugs also had fewer adverse effects (AEs) than chemotherapeutics. PROSPER and SPARTAN both started in October 2013, but they were not the first trials of anti-androgens against nonmetastatic CRPC.

First-generation nonsteroidal anti-androgens, such as bicalutamide (Casodex), showed some activity against the disease in early stage trials and have long been common treatments for the condition.

PROSPER and SPARTAN, which both tested second-generation nonsteroidal anti-androgens, have reported better results to date (TABLE).

The double-blind phase III PROSPER trial randomized 1401 men with nonmetastatic CRPC and a PSA doubling time of 10 months or less 2:1 to either enzalutamide and ADT or placebo and ADT. The primary endpoint was metastasis-free survival (MFS), defined as the time from randomization until death or radiographic progression. Secondary endpoints included PSA response rate, time to PSA progression, and OS.

As of June 28, 2017, 219 of 933 patients (23%) treated with enzalutamide and 228 of 468 patients (49%) treated with placebo had either developed metastasis or died. The median MFS was 36.6 months in the enzalutamide group versus 14.7 months in the placebo group (HR for metastasis or death, 0.29; 95% CI, 0.24-0.35;

<.001). Nearly half of all patients on placebo but just 15% of all enzalutamide patients had moved on to subsequent antineoplastic therapy by data cutoff, and the median time to such therapy was 39.6 months for patients treated with enzalutamide/ADT and 17.7 months for patients in the ADT-alone arm (

<.001). PSA progression occurred in 22% of patients in the enzalutamide group versus 69% with placebo. The median time to PSA progression was 37.2 months in patients treated with enzalutamide and 3.9 months in those treated with ADT alone (

Although patients in the placebo arm were far more likely to progress than those treated with enzalutamide, they were not significantly more likely to die as of the data cutoff date. At the first interim OS analysis, 103 patients (11%) who were treated with enzalutamide and 62 (13%) with placebo had died.

These results have so far been similar to those from the double-blind phase III SPARTAN trial.

Investigators randomized 1207 men with nonmetastatic CRPC and PSA doubling times of 10 months or less in a 2:1 ratio to ADT and either apalutamide or placebo. The primary endpoint was MFS, and secondary endpoints included progression-free survival, OS, and time to symptomatic progression, among others.

Current published data come from a planned primary analysis that occurred after 378 instances of metastasis or death. The median MFS was 40.5 months in the apalutamide group and 16.2 months in the placebo group (HR for metastasis or death, 0.28; 95% CI, 0.23-0.35;

<.001). Numbers were almost identical for median time to metastasis and median progression-free survival because most of the events were from the development of metastatic disease, not death. The median time to PSA progression was 3.7 months in the placebo group but it was not reached in the apalutamide group (HR, 0.06; 95% CI, 0.05-0.08).

The preliminary analysis did not show a significant increase in OS, which was a median of 39 months among patients receiving placebo and was not yet reached among patients receiving apalutamide, but the calculation was close (HR for death, 0.70; 95% CI, 0.47-1.04,

The preliminary SPARTAN data were enough for the independent data and safety monitoring committee to unanimously recommended more than a year ago that the trial be unblinded and that the patients in the placebo group be given the option to receive apalutamide.

Subsequent sub-analyses from the trials have been presented at conferences, and the news has been favorable.

For example, several SPARTAN investigators combed their data to see what they could learn about how well MFS predicted OS. They found that patients who developed metastases at 6, 9, and 12 months died significantly earlier than patients without metastasis, even after adjustment for baseline covariants (Spearman&rsquo;s correlation coefficient, 0.62;

<.0001). Fleischer&rsquo;s statistical model confirmed the positive correlation (correlation coefficient, 0.69), with approximately 50% of variability in OS explained by MFS.

Another SPARTAN sub-analysis combined trial data with existing estimates of patients who would progress from high-risk nonmetastatic CRPC to metastatic disease and then death between 2018 and 2024. They extrapolated from study data to estimate that if all such patients used apalutamide, 92,553 deaths would be averted in those 7 years and 88,682 quality-adjusted life-years would be gained.

Of course, both of those analyses are necessarily speculative. It would probably take several large trials that improve both MFS and OS in highly correlated ways to know that the first is a good proxy for the second and to infer deaths prevented from improvements in MFS.

There&rsquo;s also the matter of weighing the benefits against the financial and physical costs. The wholesale cost of each drug is about $130,00 per year.

As for AEs, the SPARTAN trial showed several any-grade AEs that were more common with apalutamide than placebo: fatigue (30.4% vs 21.1%), rash (23.8% vs 5.5%), weight loss (16.1% vs 6.3%) hypothyroidism (8.1% vs 2.0%), and fracture (11.7% vs 6.5%).

Enzalutamide has a similar AE profile, with additional more frequent incidences of hypertension over the placebo group (12% vs 5%).

Of note, both agents show an incidence of mental-impairment disorder of about 5%.

&ldquo;Many people will think these results already justify giving 1 of these 2 medications to patients with nonmetastatic castration-resistant prostate cancer, but there&rsquo;s an argument for taking a more conservative approach,&rdquo; said Julie N. Graff, MD, an investigator on the SPARTAN trial and associate professor of medicine at OHSU Knight Cancer Institute. &ldquo;The studies haven&rsquo;t shown significant benefits yet in overall survival. Until we see a benefit in overall survival, we will not know whether you get the maximum benefit by using these medications on nonmetastatic disease or by waiting for metastases. That&rsquo;s not to say these medicines shouldn&rsquo;t be used in patients with nonmetastatic castration-resistant prostate cancer, but we still have a lot to learn in terms of timing and long-term toxicity.&rdquo;

The Institute for Clinical and Economic Review also advocates a wait-and-see approach. A recent report from the research organization said there aren&rsquo;t enough data yet to choose the proper therapy for nonmetastatic CRPC.

Further data from both PROSPER and SPARTAN should answer some important questions, but those 2 trials aren&rsquo;t the only hope for further clarity on optimal treatment strategies.

The ongoing ARAMIS trial is studying a third second-generation anti-androgen called darolutamide in roughly-1500 men with nonmetastatic CRPC (NCT02200614). Early stage trials suggest that darolutamide penetrates the brain and central nervous system less than enzalutamide or apalutamide and thus may produce fewer AEs. The newer medication also binds with a wider variety of androgen receptors, which has led some to hope that it may work somewhat better.

Another major trial of darolutamide will help answer lingering questions about the efficacy of combining several anti-androgens against prostate cancer while it is still hormone sensitive. The ARASENS trial is testing the combination of darolutamide, ADT, and docetaxel against placebo, ADT, and docetaxel in about 1300 men with newly diagnosed hormone-sensitive metastatic prostate cancer (NCT02799602).

There are also dozens of smaller trials going on, too, testing different treatments in many combinations on patients at every point in prostate cancer progression. For example, the National Cancer Institute currently lists 21 ongoing trials that combine apalutamide with different forms of medication, radiation, and surgery, and another 49 trials using enzalutamide.

There&rsquo;s also increasing interest in using immunotherapies besides sipuleucel-T against CRPC. Investigators made news at this year&rsquo;s ASCO Annual Meeting by announcing some results from a trial of pembrolizumab (Keytruda) in 258 patients with advanced CRPC who had failed all other treatments. In KEYNOTE-199, approximately 40% survived a year and 11% experienced disease control for at least 6 months.

Not many other trials of immunotherapy against advanced prostate cancer have made as many headlines, but dozens of such studies are currently underway.

&ldquo;There&rsquo;s been, and continues to be, true excitement within prostate cancer research,&rdquo; said Neal D. Shore, MD, medical director for the Carolina Urologic Research Center, who was an investigator on the PROSPER trial. &ldquo;After many years of failed combination trials for castration-resistant disease, after the approval of docetaxel, we&rsquo;ve had 7 approved CRPC therapeutics within the last 8 years. Now we have 2 newly approved drugs that have shown the ability, on average, to delay metastases for approximately 2 years.

&ldquo;These 2 newly approved therapeutics, enzalutamide and apalutamide, may also be well suited for combinations with other medications, radiopharmaceuticals, immunotherapies, or other novel oral antineoplastics, such as PARP inhibitors, EZH2 inhibitors, etc. We continue to strive to accomplish survival prolongation, quality-of-life preservation, and complication prevention for our patients [with advanced cancer].

Ritch CR, Cookson MS. Advances in the management of castration resistant prostate cancer. BMJ. 2016;355:i4405. doi: 10.1136/bmj.i4405.

Huggins CB, Hodges CV. Studies on prostate cancer: 1. The effects of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1(4):293-297. cancerres.aacrjournals.org/content/1/4/293.

Huggins C, Stephens RC, Hodges CV. Studies on prostatic cancer II. The effects of castration on advanced carcinoma of the prostate gland. Arch Surg. 1941;43(2):209-223. doi: 10.1001/archsurg.1941.01210140043004.

4. Denmeade SR, Isaacs JT. A history of prostate cancer treatment. Nat Rev Cancer. 2002;2(5):389-396. doi: 10.1038/nrc801.

Tannock IF, de Wit R, Berry WR, et al; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-1512. doi: 10.1056/NEJMoa040720.

de Bono JS, Oudard S, Ozguroglu M, et al; TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747):1147-1154. doi: 10.1016/S0140-6736(10)61389-X.

Liede A, Arellano J, Hechmati G, et al. International prevalence of nonmetastatic (M0) castration-resistant prostate cancer (CRPC). J Clin Oncol. 2013;31(suppl 15):e16052. ascopubs.org/doi/abs/10.1200/jco.2013.31.15_suppl.e16052.

Luo J, Beer TM, Graff JN. Treatment of nonmetastatic castration-resistant prostate cancer. Oncology (Williston Park). 2016;30(4):336-344.

Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378(26):2465-2474. doi: 10.1056/NEJMoa1800536.

Smith MR, Saad F, Chowdhury S, et al; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418. doi: 10.1056/NEJMoa1715546.

Articles

Patients with the localized form of CRPC still have no options that are proven to extend overall survival, but preliminary results from the PROSPER trial of enzalutamide and the SPARTAN trial of apalutamide offer them unprecedented hope.

Pushing Ahead With New Treatments for Nonmetastatic Castration-Resistant Prostate Cancer

Mixed results have occured in recent trials testing immuotherapy in patients with breast cancer. Checkpoint inhibitors have been used as monotherapy in a pair of trials, reporting lackluster overall response rates (ORRs). When immunotherapy was paired with chemotherapy, on the other hand, it usually showed better results, and gave signals that immunotherapies combined with targeted agents could work better than immunotherapy alone.

&ldquo;I think we have enough data at this point to say that monotherapy is not the way forward for checkpoint blockade in breast cancer patients,&rdquo; said Elizabeth A. Mittendorf, MD, PhD, who reviewed data ahead of her presentation at the 2018 Miami Breast Cancer Conference

titled, &ldquo;Breast Cancer Immunotherapy Update."

&ldquo;The tumor types where we have seen the most robust responses to immunotherapies used on their ownmelanoma and lung cancer&mdash;have genetic mutations that occurred during exposure to the sun or tobacco,&rdquo; Mittendorf said. &ldquo;Breast tumors generally have far fewer mutations. They look more like normal tissue, so it&rsquo;s harder to get the immune system to attack them. Immunotherapies such as checkpoint blockade, therefore, need help. If you think of checkpoint blockade as taking the brakes off T cells, if T cells aren&rsquo;t present, what would we be taking the brakes off? We don&rsquo;t quite know which other treatments will help the most by generating an initial immune response, but we&rsquo;re making progress.&rdquo;

Patients with breast cancer enrolled in basket trials of checkpoint blockade monotherapy in many tumor types, indicating that such therapy might work in approximately 20% of patients with breast cancer. Recent findings from subsequent trials with larger numbers of patients with breast cancer suggested the true response rate may be much lower.

In the KEYNOTE-086 study of pembrolizumab (Keytruda) in metastatic triple-negative breast cancers (TNBCs), patients were seperated into 2 cohorts. Cohort A

consisted of 170 women with previously treated disease, only 1 woman who had achieved a complete response, and 8 women who had achieved any sort of response (ORR, 4.7%; 95% CI, 2.3%-9.2%).

ORR did not vary significantly for women whose tumors expressed PD-L1 (ORR, 4.8%) and those whose tumors did not (ORR, 4.7%). Figures were dramatically lower than those in the KEYNOTE-012 basket trial,

reporting responses for 5 of 32 patients with heavily pretreated TNBC (ORR, 18.5%) and stable disease in another 7 patients. For cohort B of KEYNOTE-086,

pembrolizumab was&nbsp;administered as first-line therapy to 84 patients whose metastatic TNBC expressed PD-L1, finding an ORR of 23%.

Similar results from a monotherapy trial of atezolizumab (Tecentriq)

were found, both in actual response rates and in the fact that pretreated patients were far less likely to respond than patients who were previously untreated. In the 115 women with TNBC, ORR was 10%. There were also high levels of PD-L1 expression (defined as &ge;5% positive immune-infiltrating cells) which improved that figure, but the real predictor of response appeared to be previous treatment.

ORR was 26% in the 19 women whose cancers were previously untreated (95% CI, 9%-51%) while the ORR was 7% in the 93 women who had already tried at least 1 other treatment prior (95% CI, 2%-14%). Those who did respond to treatment tended to haver durable responses (median duration, 21.1 months). All responders, with the exception of only 11% as nonresponders, were still alive after 2 years. Median survival for the entire patient population in the trial was only 9.3 months which is about a normal survival rate for untreated patients.

However, trials combining checkpoint blockades with other medications have found higher response rates with a combination of pembrolizumab (Keytruda) while eribulin (Halaven)

has produced a 26.4% ORR in 106 patients with metastatic TNBC who enrolled in the ENHANCE1/KEYNOTE-150 phase Ib/II trial. The ORR was similar among the 65 untreated patients (29.2%; 95% CI, 18.6%-41.8%) and the 41 patients who had received 1 or 2 prior therapies (22.0%; 95% CI, 10.6%-37.6%). Previously treated women responded slightly better than treatment-na&iuml;ve women who responded. There was a total median overall survival (OS) of 17.7 months (95% CI, 13.7-not estimable).

It&rsquo;s possible that some responders have responded to chemotherapy alone rather than with the combination of immunotherapy and chemotherapy, but Mittendorf sees plenty of reason to believe that chemotherapy makes checkpoint blockade more effective.

High doses of strong chemotherapies can severely weaken immune systems, particularly when administered with steroids. However,&nbsp;recent research demonstrates that many chemotherapies have the opposite effect. Many common chemotherapies increase immune response against cancer by altering dying tumor cells in ways that make them visible to the immune system, which reducses the ability of tumors to suppress the immune system and stimulate T cells or other effector cells both directly and indirectly. These effects would, in turn, seem likely to increase the effectiveness of checkpoint blockades and other immunotherapies.

Other types of medications can enhance the effects of immunotherapies, such as PARP inhibitors which can hinder proteins that repair single-strand DNA breaks and are vital to the survival of many fastgrowing cancers. When PARP inhibitors block those repairs, broken DNA gets passed on in cell reproduction and mistakes will multiply. If DNA degrades enough, the tumor cells die on their own, but a smaller increase in DNA mutations might be able to attract a response from the immune system.

This theory is supported by phase II findings from the MEDIOLA trial of the PARP inhibitor olaparib (Lynparza) and the PD-L1 blockade with durvalumab (Imfinzi)

where there was an ORR of 52% (95% CI, 31%-72%) among 25 patients with

-mutated, HER2-negative metastatic breast cancer. The disease control rate (DCR) at 12 weeks was the trial&rsquo;s primary endpoint. A DCR of 75% was considered a predetermined measure of success. The actual DCR was 80%. The data was not mature enough yet at time of analysis to determine progression-free survival, OS, and duration of response.

Combination with immunotherapy and inhibitors of cyclindependent kinases 4 and 6 (CDK4/6) are another option to be looked at. Shom Goel, PhD, MB, and colleagues published a paper in

showing that at least 1 of such compounds increased immunity to breast cancer and other tumor types.

&ldquo;The enhanced antitumor immune response has 2 underpinnings,&rdquo; the authors wrote. &ldquo;First, CDK4/6 inhibitors activate tumor cell expression of endogenous retroviral elements, thus increasing intracellular levels of double-stranded RNA. This in turn stimulates production of type III interferons and hence enhances tumor antigen presentation. Second, CDK4/6 inhibitors markedly suppress the proliferation of regulatory T cells.&rdquo;

The study found that checkpoint blockades rarely work against cold tumors, most likely because there are not enough T cells to do enough damage to the tumor if the medications succeed in making them attack. Research suggests a possible solution which is to make the tumor &ldquo;hot.&rdquo; A hot tumor is surrounded by cells sent out by the immune system a large enough amount of cells to do actual damage if a checkpoint blockade inspired them to attack the tumor. Some chemotherapies have tendencies to do this, which may help explain why chemotherapy combinations produce so many more responses than immunotherapy alone in patients with breast cancer.

A significant interest has been identified in other strategies to initiate an immune response in breast tumors that can subsequently be reinforced with checkpoint blockade agents. Preclinical experiments have shown that radiation can also attract an immune response. Experience in patients has been limited to date, but that&rsquo;s about to change. A meta-analysis published in 2017 reported that there were more than 50 ongoing trials designed to evaluate the combination of radiation and some sort of checkpoint inhibitor.

Cryoablation is another strategy investigators are looking at for making cold tumors hot. Research in the lab has demonstrated that the process of injecting tumors with freezing gas damages surviving cancer cells enough to attract a large number of immune cells. A pilot study of this strategy used a single dose of ipilimumab (Yervoy) and/or cryoablation in 19 patients with breast cancer who planned on having mastectomies.

Preoperative cryoablation was given to 7 patients, ipilimumab to 6 patients, and both to the remaining 6 patients. It was noted that the individual treatments proved safe both as monotherapies and in combination. In regard to the effects of the combination, authors wrote, &ldquo;Potentially favorable intratumoral and systemic immunologic effects were observed with the combination, suggesting the possibility for induced and synergistic antitumor immunity with this strategy.&rdquo;

Investigators are looking at another experimental option for making cold tumors hot: cancer vaccines. As director of the Breast Immuno-Oncology Program at Dana-Farber/Brigham and Women&rsquo;s Cancer Center, Mittendorf is currently working with a HER2-derived peptide vaccine. This vaccine stimulates both a direct immune attack against breast cancer while also increasing the efficacy of immune checkpoint blockade agents. Experimental vaccines are being looked at by a number of research teams.

Some investigators believe that the phase III IMpassion130 trial may realistically change treatment strategies in the next year. This study looks at atezolizumab and nab-paclitaxel (Abraxane) with the expectation of reporting preliminary results later this year. The early-stage trial tested the combination against heavily treated TNBC, but IMpassion130 is using the combination as a first-line therapy, expecting a possible change in the standards of care for patients with newly diagnosed TNBC.

&ldquo;If response in that larger trial matches response in the early-stage trials, it could lead to a change in the therapies we offer patients with metastatic TNBCs,&rdquo; said Mittendorf.

Adams S, Schmid P, Rugo HS, et al. Phase 2 study of pembrolizumab (pembro) monotherapy for previously treated metastatic triple-negative breast cancer (mTNBC): KEYNOTE-086 cohort A.

35, 2017 (suppl; abstr 1008).. meetinglibrary.asco.org/record/153044/abstract.

Nanda R, Chow LQM, Dees EC, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study.

2016;34(21):2460-2467. doi: 10.1200/JCO.2015.64.8931.

Adams S, Loi S, Toppmeyer DL, et al. KEYNOTE-086 cohort B: pembrolizumab monotherapy for PD-L1positive, previously untreated, metastatic triple-negative breast cancer (mTNBC). Abstract presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract PD6-10. 23.

Schmid P, Cruz C, Braiteh FS, et al. Atezolizumab in metastatic triplenegative breast cancer: long-term clinical outcomes and biomarker analyses. Abstract presented at: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. Abstract 2986. cancerres.aacrjournals.org/content/77/13_Supplement/2986.

Encouraging Updated Results from Phase 1b/2 Study Evaluating the Combination of Eribulin Mesylate and Pembrolizumab in Patients with Metastatic Triple-Negative Breast Cancer Presented at the 2017 SABCS [news release]. Woodcliff Lake, NJ: Eisai, PR Newswire; December 8, 2001. https://www.prnewswire.com/news-releases/ encouraging-updated-results-from-phase-1b2-study-evaluating-thecombination-of-eribulin-mesylate-and-pembrolizumab-in-patientswith-metastatic-triple-negative-breast-cancer-presented-at-the2017-sabcs-300568801.html.

Domchek SM, Postel-Vinay S, Bang Y-J, et al. An open-label, multitumor, phase II basket study of olaparib and durvalumab (MEDIOLA): Results in germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer (MBC). Presented at: the 2017 San Antonio Breast Cancer Symposium; Dec. 5-9, 2017. Abstract PD6-11.

Goel S, DeCristo MJ, Watt AC, et al. CDK4/6 inhibition triggers antitumour immunity.

2017;548(7668):471-475. doi: 10.1038/nature23465.

Kang J, Demaria S, Formenti S. Current clinical trials testing the combination of immunotherapy with radiotherapy.

2016;4:51. doi: 10.1186/s40425-016-0156-7.

McArthur HL, Diab A, Page DB, et al. A pilot study of preoperative single-dose ipilimumab and/or cryoablation in women with early-stage breast cancer with comprehensive immune profiling.

Mixed results have occured in recent trials testing immuotherapy in patients with breast cancer. Checkpoint inhibitors have been used as monotherapy in a pair of trials, reporting lackluster overall response rates. When immunotherapy was paired with chemotherapy, on the other hand, it usually showed better results, and gave signals that immunotherapies combined with targeted agents could work better than immunotherapy alone.

Trials Consider Role of Immunotherapy in Breast Cancer

Dendreon has filed for chapter 11 bankruptcy, the company announced Nov. 10. Dendreon is the maker of the first FDA-approved immunotherapy for advanced prostate cancer, sipuleucel-T (Provenge). Sipuleucel-T will remain available after the financial restructuring of the Seattle-based company, Dendreon said in the written statement.

"Whether the restructuring takes the form of a stand-alone recapitalization or a sale of the company or its assets, we are confident that this process will allow Provenge to remain commercially available to the patients and providers who have come to rely on this revolutionary personalized cancer immunotherapy," said W. Thomas Amick, president and chief executive officer of Dendreon, in the statement. "We are pleased to have the support of a substantial majority of our senior noteholders through this restructuring and sale process. We thank our employees for their continued hard work and dedication and for their commitment to help deliver Provenge to patients who are in need of immunotherapy."

Dendreon said the restructuring is based on agreements with the senior noteholders of the company's 2.875% convertible senior notes due in 2016, representing about 84% of the $620 million aggregate principal amount of the 2016 notes. The senior noteholders have agreed to support a plan that will convert all 2016 notes to common equity of the reorganized Dendreon. In addition, the agreements will allow Dendreon to conduct a court-supervised sale for all or most of its assets, or no less than $275 million, to a party that would continue to produce and provide Provenge, the company&rsquo;s statement said.

Under the agreement, the money from a sale of the company would go to noteholders; if no sale occurs, noteholders will assume ownership of Dendreon, an article on the Bloomberg.com explained.

Dendreon does not expect to need to raise any incremental financing in connection with the restructuring process. During the restructuring, the company will not only continue to manufacture and distribute sipuleucel-T, but will pay employees and run patient assistance programs, it said.

The company&rsquo;s stock valuation dropped nearly 81% from 94 cents on November 7 to 18 cents on the morning of Nov. 11.

Philip Kantoff, MD, chief of the Division of Solid Tumor Oncology and director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, in Boston, and a co-author of the phase III study that led to sipuleucel-T&rsquo;s approval, said yesterday that &ldquo;Provenge was an important first step in immunotherapy,&rdquo; and that he and his colleagues will continue to prescribe it as long as it remains available.

&ldquo;To have an effective therapy that goes away completely would be troubling until something took its place, and there&rsquo;s nothing on the immediate horizon that will,&rdquo; he said. &ldquo;So I hope, for the sake of the prostate cancer community, that it remains an option for patients.&rdquo;

Neal D. Shore, MD, of Atlantic Urology Clinics in Myrtle Beach, South Carolina and also a co-author of the phase III study, said he does not think that Dendreon&rsquo;s declaration of bankruptcy will affect &ldquo;the drug or its placement in the armamentarium for metastatic castration-resistant prostate cancer [mCRPC].&rdquo;

&ldquo;There is no reason to think that the ongoing manufacturing process would be affected at all, and no reason to think that anyone would change the NCCN [National Comprehensive Cancer Network] or AUA [American Urological Association] guidelines that offer the highest level of evidence that sipuleucel-T is a very appropriate therapy to discuss with patients who have asymptomatic or minimally symptomatic mCRPC. I don&rsquo;t think that discussion should change for any patient or clinician at the current time.&rdquo;

Kantoff said it could be sipuleucel-T&rsquo;s mechanism of action that caused it to be less frequently used than anticipated.

&ldquo;The challenges that it had were that there was no perceptible change in patients treated with itPSAs [prostate-specific antigens] didn&rsquo;t go down, they didn&rsquo;t feel better, and there was no change in measurable progression-free survival [PFS]. But it did meet a very high bar, which is prolonging overall survival, and since then there have been very strong biological studies supporting the fundamental concept of how it works.

Dendreon has filed for chapter 11 bankruptcy, the company announced Nov. 10. Dendreon is the maker of the first FDA-approved immunotherapy for advanced prostate cancer, sipuleucel-T (Provenge).

Dendreon Files for Bankruptcy, Provenge Still Available

Debu Tripathy, MD, Co-Leader, Women's Cancer Program, Norris Comprehensive Cancer Center, University of Southern California, discusses two important trials in breast cancer looking at extended hormonal therapy.

It is understood now that 10 years of tamoxifen is superior to 5 years in premenopausal patients with high-risk, early-stage disease. However, Tripathy says, most patients are postmenopausal and see benefit when treated with aromatase inhibitors. The question remains as to whether these patients could see benefit when treated with 10 years of an aromatase inhibitor compared to 5 years.

While these results may not be the most scientifically interesting, Tripathy says, they will surely affect many patients.

For patients who are premenopausal with high-risk, early-stage breast cancer, 10 years of tamoxifen has shown superiority to 5 years of tamoxifen

In postmenopausal women, aromatase inhibitors have demonstrated superiority and a better side effect profile

Two large studies look to answer the question as to whether extended use (10 years) of aromatase inhibitors will show benefit compared to 5 years

MM-003: A phase III, multicenter, randomized, open-label study of pomalidomide plus low-dose dexamethasone (LoDEX) versus high-dose dexamethasone (HiDEX) in relapsed/refractory multiple myeloma (RRMM)

Pomalidomide + LoDEX significantly extended PFS and overall survival vs. HiDEX in patients who failed lenalidomide and bortezomib. Pomalidomide + LoDEX should become a standard of care in relapsed/refractory multiple myeloma patients who have exhausted treatment with lenalidomide and bortezomib.

PrECOG 0105: Final efficacy results from a phase II study of gemcitabine and carboplatin plus iniparib (BSI-201) as neoadjuvant therapy for triple-negative and BRCA1/2 mutation-associated breast cancer

Preoperative gemcitabine and carboplatin plus iniparib is active in the treatment of early-stage triple-negative and BRCA1/2 mutation-associated breast cancer.

Results of a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas with PET and CA19-9 correlates

Developmental Therapeutics - Immunotherapy

MPACT was a large, international study performed at community and academic centers. nab-paclitaxel + gemcitabine was superior to gemcitabine across all efficacy endpoints, had an acceptable toxicity profile, and is a new standard for the treatment of metastatic PC that could become the backbone for new regimens.

A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors

MPDL3280A was well tolerated, with no pneumonitis-related deaths. Durable responses were observed in a variety of tumors. PD-L1 tumor status appears to correlate with responses to MPDL3280A.

Nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with advanced solid tumors: Survival and long-term safety in a phase I trial.

Nivolumab produced sustained survival with a manageable long-term safety profile in advanced melanoma, NSCLC and renal cell carcinoma, supporting its ongoing clinical development in controlled phase III trials with survival endpoints.

A phase II study of NPC-1C: A novel therapeutic monoclonal antibody (mab) to treat pancreatic and colorectal cancers

Preliminary results with NPC-1C show signs of clinical activity based on stable disease in heavily pretreated patients with pancreating and colorectal cancer. Safety has been established at the 1.5 mg/kg dose. A new lot of NPC-1C, produced with improved sterility and purification procedures and demonstrating no red cell agglutination, has been manufactured under GMP conditions. We plan to introduce this new lot at the current 1.5 mg/kg dose level. If there are no dose limiting toxicities, we plan to dose escalate to a higher MTD at which we will re-evaluate clinical efficacy.

A phase III study of pemetrexed (Pem) plus carboplatin (Cb) plus bevacizumab (Bev) followed by maintenance pem plus bev versus paclitaxel (Pac) plus cb plus bev followed by maintenance bev in stage IIIb or IV nonsquamous non-small cell lung cancer (NS-NSCLC): Overall and age group results

Overall survival was not significantly different in any of the age subgroups. PFS was significantly longer in pemetrexed arm overall and for patients &le;70, but was similar for patients >70, >75 yrs. Toxicity profiles differed; subgroup safety data paralleled overall data.

Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC)

Treatment with MPDL3280A was well tolerated, with no pneumonitis-related deaths. Rapid and durable responses were observed. PD-L1 tumor status correlated with response to MPDL3280A.

CA184-095: A randomized, double-blind, phase III trial to compare the efficacy of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer

The primary endpoint is overall survival; secondary endpoints include progression-free survival, time to pain progression, time to non-hormonal systemic therapy and safety characterization. The accrual goal is 600 patients randomized.

Outcomes in patients with liver or lung metastatic castration-resistant prostate cancer treated with the androgen receptor inhibitor enzalutamide: Results from the phase III AFFIRM trial.

In the phase III AFFIRM trial, patients with lung mCRPC had higher median overall survival than patients with liver mCRPC. Enzalutamide resulted in higher response rates in both liver and lung mCRPC patients. Overall survival and radiographic progression-free survival were also improved in both patient groups treated with enzalutamide.

Design of the AFFINITY study: A randomized phase III study of a novel clusterin inhibitor, custirsen, plus cabazitaxel/prednisone (CbzP) versus CbzP alone as second-line chemotherapy in metastatic castration-resistant prostate cancer (mCRPC)

The primary efficacy measure is overall survival. The secondary measure is proportion of patients alive without disease progression at Day 140 post-randomization.

Rates of dose adjustment in patients treated with tivozanib versus sorafenib in the phase III TIVO-1 study.

Lower rates of dose adjustment due to related AEs were observed in patients with metastatic RCC who received tivozanib compared to sorafenib

Phase III randomized sequential open-label study to evaluate the efficacy and safety of sorafenib followed by pazopanib versus pazopanib followed by sorafenib in the treatment of advanced/metastatic renal cell carcinoma (SWITCH-2 study).

The primary endpoint of this study is to evaluate if total PFS of sorafenib followed by pazopanib is non-inferior to pazopanib followed by sorafenib.

A phase III comparative study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus everolimus in patients with advanced or metastatic renal cell carcinoma previously treated with antiangiogenic therapy.

The primary endpoint is overall survival. Secondary endpoints include PFS, ORR, OR duration, adverse events, overall survival in PD-L1 positive or negative subgroups, and patient-reported outcomes. The trial is open and enrolling patients.

A randomized double-blind phase III trial comparing vintafolide plus pegylated liposomal doxorubicin (PLD) versus PLD plus placebo in patients with platinum-resistant ovarian cancer (PROCEED).

The primary objective is to assess PFS based on investigator assessment (RECIST v1.1) in folate receptor positive patients. Secondary objectives include overall survival, safety/tolerability, overall response rate, and disease control rate. Enrollment to the study is currently ongoing.

Exploratory analysis of nibrin in advanced ovarian cancer (AOC) patients treated in the phase III OVA-301 trial.

The results point out the potential importance of nibrin expression in the clinical outcome of patients with advanced ovarian cancer. In particular, high protein expression of nibrin seems to be associated with a worse clinical outcome. Prospective clinical trials evaluating the clinical usefulness of this marker with other standard of care treatments are warranted.

The nationâ€™s leading cancer centers continue to unveil ambitious new clinical programs and research projects that will change the way every cancer specialist practices.

Andrew D. Smith | Authors

Articles

Pushing Ahead With New Treatments for Nonmetastatic Castration-Resistant Prostate Cancer

Trials Consider Role of Immunotherapy in Breast Cancer

Dendreon Files for Bankruptcy, Provenge Still Available

The Genetic Complexity of Cancer: Cancer Centers Take Varying Approaches to Solving the Puzzle