By Jay Grisolano, PhD and Emily Benesh, PhD
Today was an exciting day for physicians and patients experiencing newly-diagnosed metastatic prostate cancer. At the ASCO 2017 meeting, data were presented on LATITUDE, a randomized Phase III trial comparing Zytiga (abiraterone acetate, Janssen)/prednisone plus androgen deprivation therapy (ADT) versus placebos plus ADT in newly-diagnosed high-risk metastatic hormone-naive prostate cancer (mHSPC), concurrent with a publication in the New England Journal of Medicine1, which will transform the prostate cancer treatment landscape.
The prostate cancer competitive landscape is one of the most highly dynamic and complex in all of oncology. In both early stage high-risk and treatment-naïve metastatic disease, hormone therapies are the mainstay systemic treatments for newly-diagnosed patients. In fact, ADT has been standard of care for newly diagnosed mHSPC patients for decades. Despite the durable efficacies and minimal side effects of hormonal agents, some patients fail treatment and become castrate-resistant.
Zytiga improved the treatment options for metastatic castrate resistant prostate cancer (mCRPC) patients when it was initially approved by the FDA as a second-line therapy in 2011. The label was expanded in late 2012 to include front-line treatment in the mCRPC space. Zytiga is a second-generation hormone therapy that inhibits androgen-production in the microenvironment by blocking CYP17A1 protein production in the testes, adrenal glands, and the tumor itself2.
Since their initial approvals, Zytiga and its second-generation hormone therapy competitor, Xtandi (enzalutamide, Astellas/Medivation; approved in April 2012), an androgen receptor antagonist, have eaten up mCRPC market-share. According to Kantar Health’s CancerMPact, Treatment Architecture module, in 2016, Zytiga and Xtandi captured over 70% share of the United States, EU5, and Japanese first-line mCRPC markets for both asymptomatic and symptomatic diseases2; Zytiga sees utilization in over 100 other countries across the world3.
Having demonstrated efficacy in the mCRPC setting, Janssen now aims to move Zytiga even earlier in the treatment paradigm: into the metastatic, hormone-naïve setting. No other next-generation hormone therapies or cutting-edge systemic therapies have been approved for use in this space2.
In 2016, nearly 70% of mHSPC patients in the U.S. were treated with traditional hormone therapies [Luteinizing Hormone Releasing Hormone (LHRH) agonists or anti-androgens]2. Importantly, roughly 20% of patients received off-label second-generation hormone therapy (namely, Zytiga or Xtandi), either as a monotherapy or in combination with traditional hormone treatments2. This suggests that awareness about the utility of second-generation hormone therapies is high and that uptake of these agents in the hormone-sensitive metastatic prostate cancer space will be rapid upon approval.
Janssen has strong previous data supporting the use of second-generation hormone therapies in the metastatic hormone-sensitive space. In a Phase II study, Zytiga and prednisone were added to a first-generation LHRH agonist in 37 patients with high-risk localized prostate cancer4. High-risk was defined as patients with Stage T1c/T2 disease and a Gleason score of at least eight, or patients with at least Stage T2b/T2c disease with a Gleason score of at least 7 and a PSA level > 10 ng/mL. Patients were randomized 2:1 to receive either: Zytiga/prednisone/LHRH agonist or LHRH agonist alone. The percentage of patients with preoperative prostate-specific antigen (PSA) less than 0.1 ng/mL was significantly increased in the Zytiga/prednisone/LHRH agonist arm compared to the control arm (68% versus 0%, p<0.0001). In addition, there was a numerical increase and decrease, respectively, in the percent of patients with near complete cytoreductions (< 6 mm scattered cells; 24% versus 8%, p=0.10) and lymph node infiltration (25% versus 50%, p=0.10) in the Zytiga/prednisone/LHRH agonist arm compared to controls. The safety profile was similar to what has been observed in the mCRPC setting. These results showed that the addition of Zytiga and prednisone to standard hormonal therapy can add significant efficacy even in a hormone-sensitive population.
In February 2013, Janssen initiated a randomized, double-blind, global (including Japan) Phase III trial (LATITUDE, CR100900; NCT01715285) of Zytiga in newly-diagnosed, high-risk metastatic patients who are hormone-naïve. Patients must have been diagnosed within three months of randomization and have not yet received any treatment for their prostate cancer [with the exception of fewer than three months of ADT received since diagnosis]. Patients were considered high-risk if they met at least two of the following requirements: Gleason score of at least 8, presence of at least three lesions on a bone scan, or presence of measurable visceral metastasis.
Patients were randomized 1:1 to receive either: Zytiga/prednisone/ADT (either LHRH agonists or surgical castration) or placebo/ADT. Co-primary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS); secondary endpoints included time to next skeletal-related event, time to prostate-specific androgen progression, time to next therapy, time to initiation of chemotherapy, changes in mRNA and miRNA levels, and safety. The trial intended to accrue 1,200 patients and have three analyses: interim one – after 50% of total projected events (426 events), interim two – after 65% of events (554 events) and a final analysis – after a total of 852 events. The trial would be considered positive if P values for overall survival were lower than 0.011, 0.022 and 0.049 for interim one, two and the final analysis, respectively.
Data from the first interim analysis of the LATITUDE trial were reported in a plenary session on June 4, 2017 at the 53rd annual meeting of the American Society for Clinical Oncology (ASCO) held in Chicago, Illinois5. The trial had accrued 1,199 patients. At the first interim analysis 406 events had occurred: 169 occurred in the Zytiga arm, while 237 events occurred in the placebo controls. The median follow-up time was 30.4 months.
As the discussant, Eric Small, MD, stated, “LATITUDE was a profoundly positive study.”
The Zytiga/prednisone/ADT arm had a 38% reduction in risk of death when compared to the control (OS: not reached vs. 34.7 months, HR: 0.62, 95% CI: 0.51-0.76; P<0.0001). The 3-year OS rate was 66% in the Zytiga arm versus 49% in the placebo arm. Overall survival benefit persisted across all of the pre-specified subgroups (e.g., ECOG status and visceral disease).
Additionally, patients in the Zytiga arm experienced a 53% reduction in the risk of radiographic progression (rPFS: 33.0 vs. 14.8 months, HR: 0.47, 95% CI: 0.39-0.55; P<0.001). All secondary endpoints were statistically improved in the Zytiga arm. Zytiga patients had an astounding 70% reduced risk of time to PSA progression (33.2 vs. 7.4 months, HR: 0.30, 95% CI: 0.26-0.35; P<0.0001). As mentioned by the discussant, given the concern of patients regarding PSA levels, this finding is expected to greatly improve quality of life for this population. Patients in the Zytiga arm receive fewer subsequent, post-study, life-prolonging therapies, suggesting that OS benefit was due to Zytiga and not subsequent treatment. Adverse events in the Zytiga arm were manageable and consistent with studies in mCRPC patients. Elevated rates of hypertension, hypokalemia, ALT and AST increases, and cardiac disorders were observed with Zytiga use. Taken together, these data were sufficiently positive to support early termination of the trial, un-blinding of participants and cross-over of placebo receiving patients to the Zytiga arm.
On May 26, 2017 Janssen announced that they filed for approval of Zytiga for mHSPC to the Ministry of Health Labor and Welfare in Japan3. Given the unmet need of development of resistance to ADT in mHSPC patients, the previous enthusiastic global uptake of Zytiga in metastatic CRPC, and the current off-label use of second-generation hormones in hormone-sensitive disease, it is expected that Zytiga will have rapid uptake upon approval for mHSPC patients.
The approval of Zytiga will have practice-altering effects on the metastatic prostate cancer landscape; Zytiga will likely become the new standard of care for high-risk mHSPC patients. Furthermore, data presented yesterday from the Phase III STAMPEDE trial suggest that Zytiga will soon move into early-stage/low-risk disease, as well. In a population that was 48% low-risk (N0M0 or N+M0) overall survival was significantly improved (HR: 0.63, 95% CI: 0.52-0.76; P=0.00000015)6. Thus, the reach of Zytiga is expected to continue expanding in earlier settings of the prostate cancer treatment landscape.
It is important to note that data reported from the Phase III CHAARTED study showed that addition of docetaxel to ADT in castration-naïve metastatic prostate cancer significantly improved survival outcomes in the overall population of patients (51.2 versus 34.4 months, HR: 0.73, P<0.0001) as well as in those with high-volume disease7, providing evidence for use of docetaxel in this setting Questions remain about how physicians will use Zytiga versus docetaxel in metastatic prostate cancer patients. Cross-trial comparisons between LATITUDE and CHAARTED show nearly identical improvements in risk of death for patients receiving Zytiga versus docetaxel with ADT (HR of 0.62 versus 0.63, respectively). Physicians may prefer the improved toxicity profile of Zytiga over docetaxel, but may also consider cost in treatment choice. Notably, duration of therapy with Zytiga has a median of 33 months in LATITUDE, while docetaxel was given for 6 cycles, or 4.5 months, in CHAARTED, potentially impacting cost as well as convenience to the patient. Another concern is that if Zytiga is used in an earlier setting, what will be used for subsequent treatment if the patient becomes mCRPC. Only time will tell regarding whether physicians will re-treat with the same general mechanism of action, the sequencing of the agents, and whether a space will open for another novel mechanism of action for use with progressed patients.
While Zytiga is poised to be first-to-market, several other second-generation agents have ongoing Phase III trials for use in first-line hormone-sensitive metastatic prostate cancer. Phase III trials testing combinations of androgen-deprivation therapy plus either apalutamide (ARN-509/JNJ-927, Aragon Pharmaceuticals/Janssen; TITAN/NCT02489318 initiated November, 2015), Xtandi (NCT02677896 initiated March 2016), and darolutamide (ODM-201, Bayer; ARASENS/NCT02799602 initiated June 2016) have the promise of bringing several competitors to the market in the near future. Competition in this space is likely to be intense, but Zytiga may have an advantage by being first-to-market.
In any case, today was a bright day for the field of prostate cancer and for prostate cancer patients.
The 2017 Genitourinary Cancers Symposium takes place in Orlando, FL, on February 16 – 18, and a press cast held in advance of the meeting featured 3 important abstracts, with these key findings:
Early Discontinuation of PD-1/PD-L1 Blockers May Not Compromise Efficacy
In a small study of 19 patients with metastatic renal cell carcinoma (RCC), discontinuation of anti-PD-1/PD-L1 immune checkpoint inhibitors due to side effects did not always lead to poor outcomes. The findings may challenge the current practice of continuing these drugs until (and sometimes after) the patient’s disease progresses.
Among 19 patients who initially responded to nivolumab but discontinued because of immune-related side effects, 42% had a durable response lasting for 6 months or longer, according to Rana R. McKay, MD, of the University of California San Diego School of Medicine.
“In medicine, we are constantly balancing the benefits and risks of any given treatment. This is a small study, and our findings need to be validated in a larger group of patients, but it underscores that in some cases, immunotherapy can have lasting benefits even after treatment discontinuation,” she said.
Two thirds of patients had received nivolumab as a single agent and the remainder received it in combination with other systemic treatments. The median time on immunotherapy was 5.5 months. All 19 discontinued treatment because of immune-related side effects, such as joint pain, rash, eye problems, diarrhea, and inflammation of the pituitary gland, muscle, heart, liver, pancreas, kidney or lung. Steroids were administered to 84% of patients and additional immunosuppressive agents were required for 11%. More than half the group had ongoing toxicity at the time of the analysis.
In 3 (16%) patients, the tumor progressed immediately after stopping treatment, but 8 (42%) patients had a continued response after being off treatment for at least 6 months. The remaining 8 (42%) were off treatment for 4 to 6 months or had follow-up for less than 6 months. The durable responders spent a median of 11 months on treatment and 20 months off treatment, reported Dr. McKay.
“We demonstrated that responders to anti-PD1/PD-L1 agents can have persistent clinical benefit despite treatment discontinuation for immune-related adverse events,” said Dr. McKay.
The prospective OMINIVORE study (Phase 2 study of Optimized Management of NIVOlumab based on Response) will further explore the efficacy of immunotherapy treatment discontinuation in treatment responders.
Press cast moderator and ASCO Expert Sumanta Pal, MD, reiterated the study’s message: that while the “unintended consequences of a reinvigorated immune response,” ie, immune-related adverse events, can be “serious,” patients with these side effects “can still have tangible benefit from these drugs.”
Recent Antibiotic Use May Negate Immunotherapy Benefits
In a retrospective analysis, patients with metastatic RCC who were treated with antibiotics within 1 month of starting treatment with immune checkpoint inhibitors had a significantly shorter progression-free survival, versus patients not taking antibiotics, according to French investigators.
The researchers attribute this to the ability of antibiotics to wipe out “good bacteria” in the gut, based on preclinical studies showing that certain microorganisms in the gut interact with the immune system in a way that facilitates the effect of immune checkpoint inhibitors.
The study is the first to analyze the impact of antibiotics on immune checkpoint inhibitors, and provides the first evidence of a relationship between the gut microbiome and patients’ response to immunotherapy.
The study included 80 patients with metastatic RCC enrolled in a trial of anti-PD-1/PD-L1 agents. Of these, 16 (20%) had been treated with broad-spectrum antibiotics (mostly beta-lactamases and fluoroquinolones) from baseline up to 1 month prior to the first injection.
Compared with patients not taking antibiotics, antibiotic users had significantly worse progression-free survival: 2.3 months vs 8.1 months, respectively (P< .001); their response rates to the checkpoint inhibitors were also lower.
This statistical association was maintained in a multivariate analysis that adjusted for age, gender, disease risk group, tumor burden and use of proton pump inhibitors. Antibiotic users’ risk for progression was increased more than four-fold vs non-users.
“Although it’s too early to conclude about overall survival, with median follow up of less than 6 months, there is already a negative trend in the antibody-positive group,” reported Lisa Derosa, MD, MD, a PhD candidate at the Gustave Roussy Cancer Institute, Paris-Sud University in Villejuif, France.
Dr. Derosa suggested that the findings may be applicable to other tumor types, since antibiotics are frequently used in cancer patients in general to prevent and treat treatment-related infections. At this time, she does not recommend withholding antibiotics from patients taking checkpoint inhibitors.
Dr. Pal agreed, stating, “While Dr. Derosa’s findings are very intriguing, they were retrospectively generated and therefore are hypothesis-generating. Having said that, the observations are consistent with preclinical observations. With further prospective validation, we may gain insight as to whether the bacterial composition of the gut affects clinical outcomes, and this could help guide us in our antibiotic usage. Meanwhile, we must consider that antibiotics are used under circumstances that are medically necessary.”
In Prostate Cancer, Liquid Biopsy Reveals Potential New Treatment Targets
Analysis of cancer DNA from blood samples is yielding some new leads for potential prostate cancer treatment targets. With a commercially available liquid biopsy — which examines cell-free circulating tumor DNA (ctNDA) in the bloodstream — researchers identified new genetic mutations in prostate cancers, some of which were associated with poor prognosis.
Cell-free DNA reveals a tumor’s genetic profile, for which targeted treatments can be designed. The genetic landscape, however, changes over time, rendering some drugs ineffective because resistance develops.
If the ctDNA can identify the evolving mutations, clinicians could discontinue futile treatments and switch therapies, explained Guru Sonpavde, MD, of the University of Alabama in Birmingham.
The study included blood samples from 514 patients with metastatic castration-resistant prostate cancer (mCRPC). The test, Guardant360, examined changes in 73 cancer-related genes.
In 163 patients, researchers explored associations between DNA changes and clinical outcomes, and in 64 patients they documented genetic changes over time through serial testing.
“Almost all the patients (94%) had some change detected, and most changes were associated with worse poor outcomes,” reported Dr. Sonpavde.
Higher number of ctDNA alterations was associated with shorter time to treatment failure (P=0.026). Patients with prior treatment for mCRPC had significantly more alterations in the androgen receptor gene (AR) than untreated patients (56% vs 37%; P=0.028).
Genes most often mutated were TP53, AR, APC, and NF1. Increased copy numbers were most common with AR, MYC and BRAF; increased cancer gene copy number can lead to proliferation of proteins that drive tumor growth.
Serial testing revealed that changes in AR over time were common. Importantly, patients with these mutations also trended toward shorter remissions (P=0.053) and shorter survival time (P=0.09).
“This indicates that developing salvage therapy with agents targeting AR alterations holds promise,” commented Dr. Sonpavde.
The findings via ctDNA were consistent with changes observed through traditional tissue biopsy, suggesting that noninvasive liquid biopsy may be a viable alternative. While there are currently no approved drugs targeting the most common mutations observed, some are in clinical trials noted investigators.
Dr. Sonpavde acknowledged that a controlled, prospective clinical trial is needed to confirm that treatment based on the molecular information from ctDNA improves patient outcomes.
Dr. Pal remarked that the study offers “one of the largest clinically annotated datasets describing features of ctDNA in advanced prostate cancer, which is a simple and convenient way to assess DNA composition and can reveal new mutations that clinicians can use to personalize therapy… The development of new agents targeting the androgen receptor is a good future direction of research.”