June 02, 2019 - 09:06 pm Posted in ASCO Conference Coverage Posted in Pancreatic Posted in Policy and Value (includes Cost, Quality, Reimbursement, Guidelines, Pathways, Insurance) Posted in Prostate Posted in Sarcoma 0 Comments
Today, four plenary sessions dropped at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting featured results from three phase 3 trials: ENZAMET, ANNOUNCE, and POLO as well as encouraging data about the impact of Medicaid expansion under the Affordable Care Act (ACA).
Medicaid Expansion Closes Racial Disparities Gap (Abstract LBA1)
When the ACA was implemented in 2010, states were permitted to expand Medicaid access. A retrospective study found that states that expanded Medicaid had a reduction in racial disparities in time to cancer treatment.
Using data from electronic health records, researchers observed timely treatment (ie, treatment initiation within 30 days of diagnosis) for adult patients younger than 65 with a diagnosis of advanced or metastatic cancer. The study population included more than 30,000 patients, and depending on the Medicaid expansion status of the state in which they lived, patients were labeled as participating in Medicaid expansion or not.
When Medicaid was not expanded, a significantly lower percentage of African American patients received timely treated compared with white patients (43.5% vs 48.3%; P<0.001). When Medicaid was expanded, this racial disparity gap did not exist (49.6% vs 50.3%; P=0.63).
“The disparities disappeared under the expansion,” summed up study presenter Amy Davidoff, PhD, Yale University.
Enzalutamide for the Win in Metastatic Prostate Cancer (Abstract LBA2)
Enzalutamide outperformed standard non-steroidal anti-androgens for men with metastatic hormone-sensitive prostate cancer, according to data from an interim analysis of the randomized, phase 3 ENZAMET trial.
Patients (n=1,125) received a testosterone-suppressing medicine followed by treatment with enzalutamide or a standard of care non-steroidal anti-androgen: bicalutamide, nilutamide, or flutamide.
For the overall patient population, the 3-year overall survival (OS) rate was 79% for men treated with enzalutamide; 72% for men treated with bicalutamide, nilutamide, or flutamide. This resulted in a 33% reduced likelihood in risk of death for men treated with enzalutamide (HR=0.67; 95% CI, 0.52-0.86; P=0.002).
In particular, an OS benefit for enzalutamide was seen among men with high volume disease (HR=0.74; 95% CI, 0.55-1.01) or no planned early docetaxel (HR=0.51; 95% CI, 0.36-0.73), but not for those with planned early docetaxel (HR=0.90; 95% CI, 0.62-1.31).
“There is a delay in progression with an improvement in overall survival, but there is toxicity,” cautioned study presenter Christopher Sweeney, MBBS, a medical oncologist at the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute. “Ezalutamide actually increased the docetaxel-related toxicity.”
Olaratumab Flops in Phase 3 for Advanced Soft Tissue Sarcomas (Abstract LBA3)
Despite encouraging survival data in the previous phase 1b/2 trial, olaratumab in combination with doxorubicin failed to improve survival in patients with advanced soft tissue sarcomas in the phase 3 ANNOUNCE trial. Olaratumab in combination with doxorubicin was granted accelerated approval in 2016, but in light of the ANNOUNCE trial results, olaratumab is in the process of being withdrawn from the market.
No clear reason was offered for the failure of olaratumab in the phase 3 trial, but a few possibilities were floated, such as the control arm having a particularly high OS and not limiting study entry to treatment-naïve patients.
Offering a partial explanation for the initial survival benefit seen in the early-phase trial, study discussant Jaap Verweij, MD, PhD, Erasmus University Medical Center, said, “A critical issue in phase 2 studies, certainly in a group of diseases as heterogenous as soft tissue sarcomas, are small numbers of patients.”
Olaparib Hits its Target in BRCA-Positive Metastatic Pancreatic Cancer (Abstract LBA4)
Maintenance therapy with olaparib, a PARP inhibitor, after first-line, platinum-based chemotherapy extended progression-free survival (PFS) for patients with germline BRCA-positive metastatic pancreatic cancer, according to the results of the phase 3 POLO trial. Final OS results are still maturing.
The trial included metastatic pancreatic cancer patients with a BRCA1 or BRCA2 germline mutation who received chemotherapy for at least 16 months and then were randomly assigned maintenance therapy with either olaparib or placebo.
The median PFS was 7.4 months for the olaparib arm and 3.8 months for the placebo arm, resulting in a 47% reduced risk of progression for patients receiving olaparib (HR=0.53; 95% CI, 0.35 – 0.82; P=0.0038).
The objective response rate was 23.1% (18 of 78 patients) for the olaparib arm and 11.5% (6 of 52 patients) for the placebo arm, with two patients on olaparib achieving a complete response; both complete responses are ongoing. The median duration of response was 24.9 months for the olaparib arm and 3.7 months for the placebo arm.
“We conclude that a strategic approach of first-line, platinum-based chemotherapy followed by maintenance olaparib treatment should become a new standard of care for patients with metastatic pancreatic cancer who have a germline BRCA mutation,” said the study presenter Hedy Kindler, MD, Professor of Medicine, University of Chicago Medicine.
by Christina Bennett, MS
May 29, 2019 - 11:05 am Posted in ASCO Conference Coverage Posted in Breast Posted in Cervical Posted in Immuno-oncology (includes cancer vaccines) Posted in Liver (includes HCC, Billiary Tract) Posted in Lung (includes NSCLC, SCLC, Mesothelioma) Posted in Multiple Myeloma Posted in Pancreatic Posted in Prostate Posted in Stomach (Gastric) Cancer 0 Comments
One of biggest challenges in attending an annual ASCO meeting is time management. With over 2,000 abstracts submitted this year and a wide variety of new drugs and therapeutic targets, ASCO 2019 will be no different.
During a webinar last week sponsored by E-Squared Communications (a Conisus company), OBR and three renowned cancer experts helped identify some of the “high impact studies” that are sure to gain a lot of attention at this year’s ASCO Annual Meeting. For those of you who missed this increasingly popular annual webinar, the experts not only covered the important data but also provided some suggestions on where to go if you happen to play hooky for a day at ASCO. Don Sharpe, President and Founder of OBR, moderated the session, and the primary areas of focus included cervical, prostate, pancreatic, breast, lung, and advanced gastric/gastroesophageal junction cancers as well as multiple myeloma and hepatocellular carcinoma (HCC).
Pending its final outcome, the first trial highlighted in the webinar could well be a practice-changing study. This phase 3 Intergroup trial (E3A06) in patients with asymptomatic intermediate- or high-risk smoldering multiple myeloma is the largest randomized trial in this setting to date. The 182 patients who participated in this study were randomized to either receive lenalidomide alone or observation, with progression-free survival (PFS) being the primary endpoint. At a median of 28 months of follow-up, the 3-year PFS rate in the lenalidomide arm seems to be numerically trending in the right direction (91% vs. 66%). This data will be highlighted in an oral abstract (8001) session on Sunday, June 2nd.
Following an interesting review of a phase 2 study highlighting the use of LN-145 tumor infiltrating lymphocytes in patients with cervical cancer, the next phase 3 study highlighted by the experts was a late-breaking abstract. This Australian and New Zealand Urogenital (ANZUP) Cooperative Group trial (ENZAMET) evaluated enzalutamide as first-line androgen-deprivation therapy for metastatic hormone-sensitive prostate cancer. The abstract LBA2 will be presented at the plenary session on Sunday, June 2nd and is sure to draw comparisons to the earlier LATITUDE study of abiraterone in this setting.
Pancreatic cancer seems to be climbing into the spotlight as well this year, as the OBR experts identified the Adjuvant Treatment in Pancreatic Cancer Study (APACT) as an important one to watch. This study evaluated nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with surgically resected pancreatic cancer. With 866 patients enrolled, this large clinical trial had a primary endpoint of disease-free survival; however, the authors noted that the overall survival (OS) results seen in this study may better support the rationale of using this combination in the adjuvant setting, especially for patients who are ineligible for FOLFIRINOX.
The PARP inhibitor olaparib was also discussed in the webinar as a potentially new therapeutic option for patients with pancreatic cancer. The phase 3 POLO trial of olaparib versus placebo as maintenance therapy in patients with germline BRCA-mutated metastatic pancreatic cancer whose disease had not progressed following first-line platinum-based chemotherapy will be highlighted during the plenary session on Sunday, June 2nd (LBA4). This study is the first positive phase 3 trial of any PARP inhibitor in germline BRCA-mutated metastatic pancreatic cancer.
Pembrolizumab was highlighted as well in two studies looking at gastric cancer and GEJ adenocarcinoma (KEYNOTE-062) and advanced HCC (KEYNOTE-240). In KEYNOTE-062, pembrolizumab met its primary endpoint by demonstrating OS noninferiority compared to chemotherapy in the intent-to-treat population. In KEYNOTE-240, pembrolizumab showed positive numerical trends but did not meet statistical significance for its co-primary endpoints of OS and PFS; however, it did show an improved response rate versus placebo (ORR 16.9% vs. 2.2%), and it will be interesting to see what impact this might have going forward.
Another important KEYNOTE study is KEYNOTE-189: Updated OS and progression after the next line of therapy (PFS2) with pembrolizumab (pembro) plus chemo with pemetrexed and platinum vs placebo plus chemo for metastatic nonsquamous NSCLC. KEYNOTE-001 is also a late-breaking abstract looking at 5-year long-term OS for patients with advanced non-small cell lung cancer treated with pembrolizumab.
There are certainly other important abstracts at this year’s ASCO Annual Meeting, but at the very least, this review should help narrow down your choices.
By Adrian Barfield, President, Medallion Healthcare
As the Genitourinary Cancers (GU) Symposium gets under way in San Francisco February 13-16 2019, at a pre-meeting Presscast, ASCO experts singled out three abstracts to be presented at the meeting as of special interest: two on prostate cancer and one on kidney cancer. As would be expected, these three abstracts are just the tip of the iceberg among many important studies to be discussed at the 3-day meeting.
Prostate Cancer – Racial Disparity in Survival?
A large retrospective study to be presented at the meeting suggests that African-American men with chemotherapy-naïve metastatic castrate-resistant prostate cancer (mCRPC) have improved survival on the newer androgen-directed therapies abiraterone or enzalutamide compared with Caucasians (Abstract 212). This is the first study to suggest a survival benefit for both drugs in African-American men, and further study is needed to validate this finding.
“We’ve historically seen that prostate cancer is more common, more aggressive, and more lethal in African Americans compared with men of other racial groups. Balancing against other health-related risks, we found that treatment with newer hormonal medicines led to a significantly greater survival for African-American men in this analysis, compared with white men,” said lead study author Megan Ann McNamara, MD, Assistant Professor of Medicine, Duke University School of Medicine, Durham, NC.
“These findings provide important evidence that African-American men with metastatic prostate cancer, who have long had among the highest incidence and poorest outcomes of this disease, may now have better survival when treated with newer prostate cancer medications as compared with other men,” said ASCO Expert Robert Dreicer, MD, moderator of the Presscast.
The study was based on the Veterans Health Administration database from April 1, 2013 to March 31, 2018. Researchers identified 787 African American men and 2123 Caucasians aged 18 or older with prostate cancer and disease progression after surgical or medical castration; all men received either abiraterone or enzalutamide, but no chemotherapy. Patients were followed until death or disenrollment in their VA health plan. Median follow-up was 570 days for African-American men and 561 days for Caucasians.
African-American men were more likely than Caucasians to have the following co-morbidities: hypertension (77.1% versus 67.1%, respectively, P<.0001); type II diabetes (38.1% versus 29.3%, respectively, P<.0001); and liver damage or abnormality (8.8% versus 5.2%, respectively, P=.0003).
In an analysis adjusted for demographic and clinical characteristics, median overall survival was 30 months for African-American men compared with 26 months for Caucasians.
“This study was conducted in men with access to care through a single-payer system. The evidence suggests that African-American men have improved survival on standard of care treatments. Prospective trials are needed to validate these findings,” Dr. McNamara said.
Prostate Cancer – Radioligand Therapy
A novel approach using a tumor-specific radioligand therapy that binds to prostate specific membrane antigen (LuPSMA) had a strong showing in an expanded Phase II study of men with metastatic castrate-resistant prostate cancer (mCRPC) who progressed on standard therapies (Abstract 228). The study showed high rates of PSA response with low toxicity, and high response rates were also seen in men who subsequently progressed on LuPSMA and were treated with further LuPSMA, the authors said.
Moreover, men treated with LuPSMA lived a median of 13.3 months after treatment, surpassing expected survival of 9 months for this stage of disease.
The study, the first prospective study of LuPSMA, is based on an expanded cohort of 50 patients; results in the first 30 patients treated were reported previously in The Lancet Oncology in June of 2018. The present study confirms earlier findings using LuPSMA, and two randomized controlled trials will compare LuPSMA versus cabazitaxel and LuPSMA versus best standard of care, respectively.
“For men with localized prostate cancer, brachytherapy, or radioactive seeds implanted by needle directly into the tumor, as well as external beam radiotherapy, have been effective forms of treatment. However, for men in this trial with cancer cells spread throughout the body, LuPSMA provides a new approach to a form of the disease that has been difficult to treat,” said lead author Michael Hofman, MBBS, professor of nuclear medicine at the Peter MacCallum Cancer Centre, Melbourne, Australia.
“In this trial, we treated men who would have otherwise been directed to palliative care. It’s exciting to see that LuPSMA can potentially offer benefits for many men with these very aggressive cancers, with few side effects and significant improvements in quality of life. Importantly, we saw continued benefit with LuPSMA retreatment in some men whose cancer progressed,” Dr. Hofman said.
Patients enrolled in the Phase II study were diagnosed with PSMA-positive mCRPC by upfront PET scan and were treated with up to 4 cycles of LuPSMA every 6 weeks. The primary endpoints were PSA response and toxicity. In the 50 patients enrolled in the trial, median PSA doubling time was 2.6 months. The majority of patients received prior treatment (docetaxel, 84%; cabazitaxel (48%), and abiraterone or enzalutamide (90%).
A PSA decline of >50% was observed in 32 of 50 patients (64%), including 22 patients (44%) with a PSA decline >80%. Among 27 patients with soft tissue disease at baseline, 56% had a partial or complete response according to RECIST criteria. Fourteen patients who progressed on LuPSMA received a median of 2 more cycles of LuPSMA; PSA >50% decline was observed in 9 patients (64%).
Adverse events were similar to those reported earlier in 30 patients: transient grades 1-2 dry mouth (68%), nausea (48%),and fatigue (36%).
Grades 3 to 4 toxicities were thrombocytopenia and anemia (10% for each). Median PSA progression-free survival was 6.9 months and median overall survival was 13.3 months.
“Survival rates are low for patients with prostate cancer that has spread to distant parts of the body, and providing effective treatments for this type of cancer has been an ongoing challenge. For this group of patients in dire need of new options, using an entirely new approach provides hope that we can start to change their outcomes,” said ASCO Expert Robert Dreicer, MD, Presscast moderator.
Immunotherapy Combo in RCC
Immunotherapy is making inroads in the treatment of metastatic renal cell carcinoma (mRCC), according to promising results of the phase III KEYNOTE-426 study. The global, open-label phase III study demonstrated the superiority of the combination of pembrolizumab plus axitinib versus standard of care sunitinib as first-line therapy for mRCC (Abstract 543).
Pembrolizumab plus axitinib showed significant improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) at a median follow-up of 12.8 months (P<.0001 for all three comparisons with suninitib). Twelve-month OS was 89.9% for the combination versus 78.3% for sunitinib (P= .0001). Median PFS was 15.1 months versus 11.1 months, respectively, and ORR was 59.3% versus 35.7%, respectively. Duration of response was not yet reached for the combination therapy arm versus a median of 15 months for sunitinib.
“These results are exciting. By adding pembrolizumab to a VEGF-targeted TKI we are seeing powerful anticancer responses, including improved survival, and importantly, results are seen across broad subgroups of patients. These data suggest that pembrolizumab plus axitinib should be a new standard of care for this population, in my opinion,” said lead author Thomas Powles, MD, Professor of Urology Oncology, Barts Cancer Institute, London, U.K.
Following promising results of a phase Ib study, the phase III KEYNOTE-426 trial randomized 861 patients with clear-cell RCC and no previous systemic therapy for mRCC to either arm. Pembrolizumab was given 200 mg IV every 3 weeks for a maximum of 35 cycles plus oral axitinib 5 mg b.i.d. versus oral sunitinib 50 mg every day on a 4 week on/2 week off schedule. Patients were treated until disease progression, unacceptable toxicity, or investigator’s decision.
“There have been few significant advances in treating this advanced form of disease. These findings may help provide an important new option for patients with mRCC,” said ASCO Expert Robert Dreicer, MD, Presscast moderator.
By Adrian Barfield, President, Medallion Healthcare
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.