The FDA has granted a breakthrough device designation to the Avenda Health Focal Therapy System, a male “lumpectomy” product under development to treat patients with prostate cancer in office while preserving quality of life (QoL), according to an announcement from Avenda Health, the developer of the artificial intelligence (AI)–enabled focal therapy system.

The regulatory designation is only granted to devices that possess the potential to transform the field, providing a new way to treat serious diseases that could be more effective than existing approaches.

The system was designed to spare healthy tissue and minimize toxicity. By using patient-specific data and AI, the device delivers a precise and individualized treatment that only targets the tumor. The treatment can be delivered in a physician’s office with local anesthesia, thus minimizing the downtime of the patient and potentially cutting healthcare costs.

“We are working to advance the treatment of prostate cancer by giving patients and their doctors more options,” Shyam Natarajan, cofounder and chief executive officer of Avenda Health, stated in a press release. “We see our approach as similar to that of a lumpectomy for breast cancer—if the cancerous tumor and appropriate treatment margins can be identified, the standard approach of removing the entire prostate gland and surrounding tissue may not be necessary.”

With the device, physicians are able to precisely ablate tissue and monitor treatment progress in real time.

 They utilize diagnostic data to create an individualized treatment plan. Targeted therapy is then administered through focal laser ablation in the physician’s office with anesthesia. Treatment progress is monitored in real time using sensors to reduce the impact on healthy tissue and preserve QoL.

“Using large datasets of imaging and pathology, Avenda uses AI to calculate precisely where treatment should be applied, sparing healthy tissue so men can maintain urinary and sexual function,” Natarajan stated in a prior release on the device.

 “Diagnosis and treatment can be done in-office by a urologist, rather than multiple specialists and procedures, saving time and costs and offering potentially quick recovery.”

Previously, the FDA granted 510(k) clearance to the device for ablation of soft tissue.

A grant from the National Cancer Institute helped to fund a phase 1 study done in 10 patients, which has recently completed enrollment. Data indicate that the device is safe, with no decline in urinary or sexual function observed in patients over the follow-up period.

Avenda Health granted FDA breakthrough device designation for technology to treat prostate cancer. News release. Avenda Health. May 11, 2021. Accessed May 11, 2021. https://bwnews.pr/2Rbzybl

Focal therapy made easy. Avenda Health. 2020. Accessed May 11, 2021. https://bit.ly/3fgWJcu

Avenda Health uses artificial intelligence to improve prostate cancer treatment. News release. Avenda Health. May 30, 2019. Accessed May 11, 2021. https://bit.ly/3f5djvG

This article was originally published on OncLive as, "

FDA Grants Breakthrough Device Designation to AI-Based Focal Therapy System in Prostate Cancer.

Articles

The FDA has granted a breakthrough device designation to the Avenda Health Focal Therapy System, a male “lumpectomy” product under development to treat patients with prostate cancer in office while preserving quality of life.

AI-Based Focal Therapy System Get a Breakthrough Device Designation for Prostate Cancer Treatment

Although the standard-of-care treatment for patients with metastatic pancreatic cancer remains largely unchanged with multi-agent chemotherapy, the role for multidisciplinary care has expanded significantly in recent years, said Andrew E. Hendifar, MD, who added that such an approach to treatment can improve quality of life, alleviate cancer-related complications, and lead to the discovery of relevant genetic predispositions.

“The treatment of [patients with] advanced pancreas cancer, fortunately, is very straightforward. We’ve made some progress; however, when we use multi-agent chemotherapy regimens, some people feel that [we haven’t made] that much progress,” said Hendifar.

“It takes a village to take care of patients with pancreatic cancer; we need medical oncologists, palliative care physicians, dietitians, and genetic counselors involved. That [multidisciplinary] care extends to multiple facets [including] the cancer itself to associated complications, such as diabetes, pain, and weight loss,” Hendifar added.

® during an Institutional Perspectives in Cancer webinar on gastrointestinal malignancies, Hendifar, medical director of Pancreatic Cancer and an assistant professor of medicine at the Samuel Oschin Cancer Center at Cedars-Sinai, discussed considerations for selecting frontline treatment in pancreatic cancer, the growing role of biomarker-driven therapies, and the importance of multidisciplinary care.

®: How are you selecting between the available frontline chemotherapy regimens FOLFIRINOX and gemcitabine plus nab-paclitaxel (Abraxane)?

: The easiest scenario is in the adjuvant setting where FOLFIRINOX has demonstrated superiority to single-agent gemcitabine. In patients who have completed definitive surgery and are medical candidates for FOLFIRINOX, [FOLFIRINOX] would definitely be the way to go. If patients are not medical candidates [for FOLFIRINOX], we have many options.

Choosing between the 2 regimens shouldn’t cause somebody too much grief or consternation because we just don’t have the data to know whether one regimen is superior to the other. When you have a gemcitabine-based or 5-fluorouracil [5-FU]–based first-line regimen, the second-line regimen will be the [alternative].

A lot of times in the clinic, I will discuss the available data and the pros and cons of each regimen with the patient so that we can make the decision together. [I’m] often surprised by how important it is for some patients to not have a port placed or how a continuous infusion is not feasible for some patients based on their social situation.

I try not to get too focused on which regimen we start first. In certain patient subtypes, including the 

-mutant population, we have the same questions about whether we should give gemcitabine plus cisplatin, or FOLFIRINOX.

Fortunately, several clinical trials [are ongoing] to definitively answer that question. One [study] is looking at nanoliposomal irinotecan [nal-IRI], 5-FU and oxaliplatin vs gemcitabine and nab-paclitaxel. The other [study is called] Precision Promise [NCT04229004] and is looking at modified FOLFIRINOX vs gemcitabine plus nab-paclitaxel. Therefore, we have 2 registration clinical trials [ongoing] that will be able to answer that question [of which regimen should be sequenced first].

My guess is that there won’t be much of a long-term survival difference between the 2 [regimens]. We may see a progression-free survival change, but once we switch to a second-line regimen, I can’t imagine it would make a difference.

How could the results of the NAPOLI-3 trial affect the treatment of patients with pancreatic cancer? Do you foresee this regimen being integrated into clinical practice by providers?

NAPOLI-1 firmly places 5-FU plus nal-IRI as the optimal choice for second-line therapy in patients who have received gemcitabine as first-line treatment.

NAPOLI-3 is a registration trial comparing the frontline combination of 5-FU plus nal-IRI and oxaliplatin vs gemcitabine and nab-paclitaxel. This trial is very interesting because it [utilizes] modified oxaliplatin, and the nal-IRI dose has been modified. This is a regimen we would feel very comfortable using in the clinic and is kind of the way we actually manage patients [in this population]. In that sense, it is a very timely trial. It could possibly change the way that we treat patients with pancreatic cancer if [the data] show an improvement with the triplet therapy vs the doublet therapy in terms of survival, as well as tolerability.

What does the future of pancreatic cancer management hold regarding perioperative therapy and biomarker-driven approaches?

As we understand the role of multi-agent first- and second-line treatments, we are also trying to understand the perioperative setting. What is the optimal [perioperative] approach with the current tools available? We are trying to better understand different subgroups of patients and biomarker-related subgroups, such as the DNA damage repair deficient [population], to better understand what we should do.

We are trying to better understand [other populations], such as the 

-mutant groups. Finding those 1 in 100 alterations that are not 

 mutations [is an ongoing challenge, but], that 

 wild-type [population] is a very interesting group of patients to look at.

 mutations go, of course, KRAS inhibitors are on the rise. We have one 

 inhibitor that is [close to being] approved and there are several in development. Unfortunately, 

 G12C is a very rare mutation in pancreatic cancer, but 

 G12D is very common. There are treatments being developed [specifically for 

 G12D mutations]. We are trying to find the right KRAS-directed therapy for these patients.

In the meantime, treatments targeting tumor metabolism is something that should be looked at. We have several in development, including devimistat [CPI-613]. [Pancreas cancer tumors] seem to cause so much weight loss and muscle mass loss, so it makes sense that a treatment targeting tumor metabolism could be the way forward.

Could you elaborate on the rationale to evaluate tumor metabolism–targeting therapies in pancreatic cancer?

 mutations have specific effects on tumor metabolism, specifically regarding the tricarboxylic acid cycle [TCA]. Any therapy that targets TCA cycle metabolism makes a lot of sense to [evaluate] and pancreatic cancer is the perfect test-case for the principle behind this medication. We are very excited about the clinical trial [evaluating this approach] that has completed, and we are eagerly awaiting the results.

Knowing that pancreatic cancer can cause significant complications, such as weight loss, how important is supportive care for these patients?

Therapies for pancreatic cancer are typically intense, multi-agent chemotherapies. They can cause problems such as weight loss, fatigue, and deconditioning, which are inherent in that patient population already. It’s essential that we jump on [supportive care measures, including getting dietitians involved, supplementing pancreatic enzymes, managing pain in effective ways, and using anti-inflammatory agents.

From our understanding, anti-inflammatory agents play a big role in cancer-associated inflammation and cachexia. Also, getting physical therapy involved to get our patients less deconditioned if possible is difficult, but we have to do that in order for patients to be able to receive systemic therapy.

With that in mind, why is integrating a multidisciplinary approach to patient care important in pancreatic cancer?

When we are treating patients with pancreatic cancer, that is the time to rally the troops as much as possible. We want to get everyone involved because this patient group needs help and support [from a multidisciplinary team. Beyond] the medical oncologist, nurses can help explain to patients how to handle their treatments, dietitians can help them with weight loss, and palliative care doctors can help with pain. It may also be appropriate to get genetic counselors involved to make sure patients do not have any predispositions.

It seems like a lot of work, and it is. However, it is what we need to do right now for this patient group until therapies [improve]. One day in the future, I know we are going to say, “Wow, pancreatic cancer is easy [to treat]; we just give this medication, and everything is going to get better.” However, until that happens, the morbidity associated with this disease is immense, so we really need to rally the troops to get everybody together and help our patients.

Multidisciplinary Care Is Paramount as New Therapies Emerge in Metastatic Pancreatic Cancer.

Multidisciplinary care is key to improve quality of life, lessen cancer-related complications, and improve outcomes for patients with pancreatic cancer.

Team-Based Approach Is Key Moving Forward in Pancreatic Cancer Care

Two studies conducted at NYU Grossman School of Medicine and NYU Langone’s Perlmutter Cancer Center found that misinformatoin and bias is prevalent in YouTube videos about prostate and bladder cancer. 

A massive amount of misinformation and bias is being spread in YouTube videos on bladder and prostate cancer, according to 2 studies conducted at NYU Grossman School of Medicine and NYU Langone’s Perlmutter Cancer Center.1

Investigators on the bladder cancer study,2 led by Stacy Loeb, MD, MSc, ranked the overall quality of over two-thirds of the YouTube videos they assessed as poor to moderate. A moderate to high amount of misinformation was noted in 21% of the videos and a commercial bias was found in 17% of the videos.

In the prostate cancer study,3 also led by Loeb, it was discovered that over three-fourths of the videos included content that was potentially misinformative in the video itself or in the comments section. Further, while treatment benefits were highlighted in 75% of the videos, the risks of the treatments were only adequately described in 50%.

For the bladder cancer study, the investigators used these 2 validated instruments to score the quality of the videos: the Patient Education Materials Assessment Tool (PEMAT) and the DISCERN quality criteria for consumer health information.

The researchers found that there were 242,000 bladder cancer videos on YouTube and then used the 2 instruments to evaluate the first 150 of these. Overall, 67% of the 150 videos ranked as poor to moderate using DISCERN. Of concern, over 1 million (1,289,314) viewers watched the 21% of videos that were noted to have a moderate to high amount of misinformation, and 324,287 viewers watched the 17% of videos found by Loeb et al to contain commercial bias.

“Bladder cancer is the second most common urologic cancer worldwide, but evidence is lacking on the accuracy of information available on YouTube, the most popular social network,” Loeb, professor of Urology and Population Health at NYU Grossman School of Medicine and NYU Langone’s Perlmutter Cancer Center, stated in a press release.

“Our findings highlight an urgent need for more accurate, patient-friendly social media content,” added Loeb, who is also the incoming chair of the American Urological Association Public Media Committee.

Loeb et al used the same instruments—DISCERN and PEMAT—for the prostate cancer study that were used in the bladder cancer assessment. The investigators found that there were more than 600,000 videos about prostate cancer on YouTube and assessed the first 150 of these for their study.

Overall, 77% (n = 115) of the videos contained content that was potentially misinformative in the video itself or in the comments section. According to Loeb et al, these 115 videos reached more than 6 million viewers.

The potential benefits of treatments were highlighted in 75% of the 150 videos, while only 53% explained potential side effects and other risks. Further, only half of the videos advocated shared decision-making despite it being a key recommendation in current guidelines. Loeb et al’s analysis also determined that there was a significant negative correlation between the scientific quality of the videos and viewer engagement.

Summarizing her advice to providers on these findings, Loeb said, “Having lots of ‘likes’ and views does not mean that a video is medically accurate. As health-care providers, we can help counter this trend by better communicating with patients and guiding them to trustworthy sources for additional information.”

In the press release highlighting the findings of the studies, Loeb provider several tips for providers:

“Engage in shared decision-making, clearly outlining the benefits and risks of treatment and offering actionable steps for patients.

Encourage patients to learn how to spot medical misinformation.

Arm patients with trustworthy sources of information, such as the Bladder Cancer Advocacy Network, Prostate Cancer Foundation, the Urology Care Foundation, and the National Cancer Institute.

Actively participate in social media to disseminate accurate, evidence-based content.”

1. Many Popular YouTube Videos Spread Misinformation on Bladder & Prostate Cancer, Studies Find. Published online April 27, 2021. Accessed May 5, 2021. https://bit.ly/3xNYXID.

2. Loeb S, Reines K, Abu-Salha Y, et al. Quality of bladder cancer information on YouTube. 

. 2021;79(1):56-59. doi: 10.1016/j.eururo.2020.09.014

3. Loeb S, Sengupta S, Butaney M, et al. Dissemination of misinformative and biased information about prostate cancer on YouTube. 

. 2019;75(4):564-567. doi: 10.1016/j.eururo.2018.10.056

This article was originally published on Urology Times as, "

Studies spotlight misinformation in YouTube bladder and prostate cancer videos

Studies found that misinformation and bias is prevalent in YouTube videos about prostate and bladder cancer. 

YouTube Videos Spread Cancer Misinformation

The novel oral TKI masitinib in combination with docetaxel and prednisone resulted in improved progression-free survival compared with docetaxel plus prednisone in patients with metastatic castration-resistant prostate cancer (CRPC), meeting the predefined primary end point of the phase 2b/3 AB12003 trial (NCT03761225).1

Patents associated with the data from the study are being filed. Once submitted, detailed findings will be shared during a webcast with key opinion leaders, according to the pharmaceutical company AB Science.

Masitinib was developed to target mast cells and macrophages, which are both key players in cell immunity; the drug does this by hindering a small number of kinases. The mechanism of action of the TKI allows for its use in many conditions within the field of oncology, in inflammatory diseases, and in select central nervous system (CNS) diseases.

Because masitinib has an immunotherapy effect, the agent is hypothesized to favorably impact survival when used either alone or in combination with chemotherapy in patients with cancer. Masitinib has showcased activity on mast cells and microglia, which inhibits the activation of the inflammatory process. As such, the drug is able to impact symptoms experienced with select inflammatory and CNS diseases and the deterioration of such diseases.

In the international, multicenter, randomized, double-blind, placebo-controlled, 2-parallel group, phase 3 trial, investigators enrolled chemotherapy-eligible patients with metastatic CRPC.

To be eligible for enrollment, patients had to have histologically or cytologically confirmed metastatic CRPC that was either pretreated with abiraterone acetate (Zytiga) and had documented disease progression or indicated for the initiation of docetaxel treatment.2 Patients also had to have evidence of progressive metastatic disease per Prostate Cancer Clinical Trials Working Group 2 recommendations and have acceptable organ function per the study protocol. If patients had previously received chemotherapy, they were excluded.

Those in the investigative arm received masitinib at a dose of 6.0 mg/kg/day twice daily, in combination with docetaxel at 75 mg/m2 once every 3 weeks for 6 cycles, plus prednisone per standard clinical practice. Patients in the control arm were given placebo plus docetaxel and prednisone at the same dosing and schedule.

The primary end point of the trial is PFS, while overall survival (OS) serves as a secondary end point.

Patient enrollment to the trial was given the green light by the FDA in January 2020, after the company’s investigational new drug application was cleared for the agent’s use in patients with metastatic CRPC who were eligible for chemotherapy.3

In June 2018, an interim analysis was conducted by an independent data monitoring committee. Based on the rules for the assessment, the committee recommended to continue the study in a prespecified subgroup of patients who had been identified by a biomarker.

The probability of success of the trial was projected to exceed 80% in this subgroup per the statistical rule of the protocol at the time of the analysis, with the assumption that patients yet to be enrolled at the time would behave like those who had been analyzed. The subgroup was expected to account for about two-thirds of the population.

Previously, the agent was evaluated in a phase 1/2 trial, which evaluated its use in combination with docetaxel in patients with hormone refractory prostate cancer who experienced disease progression following first-line treatment.4

Results indicated that the doublet resulted in a median OS of 18.4 months, with a lower bound of the corresponding one-sided 75% CI of 17.8 months. This finding compared favorably with a meta-analysis that showcased an OS of 14.4 months, following the emergence of enzalutamide (Xtandi).

AB Science today announced that its masitinib phase 2B/3 study (AB12003) in metastatic castration-resistant prostate cancer (mCRPC) met its predefined primary endpoint. News release. AB Science. April 29, 2021. Accessed April 30, 2021. 

Masitinib plus docetaxel in metastatic castration-resistant prostate cancer. ClinicalTrials.gov. Updated November 10, 2020. Accessed April 30, 2021. 

https://clinicaltrials.gov/ct2/show/NCT03761225

FDA green-lights US patient enrollment in masitinib phase 3 study following IND clearance in metastatic castration-resistant prostate cancer eligible to chemotherapy. News release. AB Science. August 1, 2020. Accessed April 30, 2021. 

Masitinib in oncology. AB Science website. Accessed April 30, 2021. 

Masitinib Plus Docetaxel Improves PFS in Metastatic Castration-Resistant Prostate Cancer."

The novel oral TKI masitinib in combination with docetaxel and prednisone resulted in improved progression-free survival compared with docetaxel plus prednisone in patients with metastatic castration-resistant prostate cancer, meeting the predefined primary end point of the phase 2b/3 AB12003 trial.

Drug Combo Improves PFS in mCRPC

The FDA has granted a priority review designation to a supplemental biologics license application for nivolumab (Opdivo) for use as an adjuvant treatment in patients with surgically resected, high-risk, muscle-invasive urothelial carcinoma.1

The decision was based on data from the phase 3 CheckMate-274 trial (NCT02632409), which demonstrated that giving the PD-1 inhibitor after surgery resulted in improved disease-free survival (DFS) in this patient population.2 This is the first positive phase 3 trial of an immunotherapy in this setting, according to Bristol Myers Squibb.

Results indicated that adjuvant nivolumab nearly doubled the median DFS in the intent-to-treat (ITT) population vs placebo, at 21.0 months vs 10.9 months, respectively (HR, 0.70; 98.31% CI, 0.54-0.89; 

 <.001). A subset of patients with PD-L1–positive disease also experienced an improvement in DFS vs placebo. The median DFS had not yet been reached in the investigative arm, while it was 10.8 months in the control arm (HR, 0.53; 98.87% CI, 0.34-0.84; 

Under the Prescription Drug User Fee Act, the FDA must make a decision on the application by September 3, 2021. If approved, the PD-1 inhibitor will be the first adjuvant immunotherapy option available to patients with this disease in the United States.

“After patients undergo surgery for muscle-invasive urothelial carcinoma, they continue to face uncertainties given the high rate of disease recurrence and the lack of safe and effective treatment options,” Dana Walker, MD, MSCE, vice president, development program lead, genitourinary cancers, at Bristol Myers Squibb, stated in a press release. “Based on the groundbreaking DFS results from CheckMate-274, we believe [nivolumab] has the potential to change the future of treatment for muscle-invasive urothelial carcinoma.”

CheckMate-274 evaluated the safety and efficacy of adjuvant nivolumab vs placebo in patients with high-risk muscle-invasive urothelial carcinoma after radical surgery. The trial enrolled 709 patients who were randomized 1:1 to nivolumab at 240 mg once every 2 weeks (n = 353) or placebo (n = 356) for up to 1 year of adjuvant treatment.

Patients must have undergone radical surgery within 120 days with or without neoadjuvant cisplatin or that they must not have been eligible for, or declined, cisplatin-based chemotherapy. Patients also needed to be free of disease on imaging.

The primary end point of the trial was DFS in the ITT population and those with a PD-L1 expression of 1% or higher. For nivolumab, the median follow-up was 20.9 months, while it was 19.5 months for placebo. Additionally, 53.3% and 56.3% of patients in the investigative and control arms discontinued treatment, respectively. Recurrence was the most frequently cited reason for discontinuation.

In the investigative arm, 79% had their tumor of origin be urinary bladder carcinoma and 21% had upper tract disease; in the control arm, these rates were 78.9% and 21.1%, respectively. About 40% of patients in both treatment arms had PD-L1–positive disease and just under half, or 43%, had prior neoadjuvant cisplatin-based chemotherapy.

Notably, no differences in DFS benefit with nivolumab were reported in a subgroup analysis of the ITT population, regardless of age, sex, or performance status.

The PD-1 inhibitor also improved the median non–urothelial tract recurrence-free survival (NUTRFS) and distant metastasis-free survival in the ITT population and the subgroup of patients with PD-L1 positivity. In the ITT population, the NUTRFS with adjuvant nivolumab was 24.6 months, while it was 13.7 months with placebo (HR, 0.72; 95% CI, 0.58-0.89). In the subgroup of patients with PD-L1–positive disease, the NUTRFS was not reached with the PD-1 inhibitor vs 10.9 months with placebo (HR, 0.54; 95% CI, 0.38-0.77).

Safety findings with nivolumab were consistent with prior data of the agent in patients with solid tumors. Results indicated that 17.9% of patients in the adjuvant nivolumab arm had treatment-related adverse effects (TRAEs) compared with 7.2% of those on the placebo arm.

Additionally, 12.8% and 2% of patients on the investigative and control arms, respectively, experienced any-grade TRAEs. Pruritis, fatigue, diarrhea, and rash, were among the most commonly experienced TRAEs in the adjuvant nivolumab arm.

European Medicines Agency validated a type II variation application for nivolumab as an adjuvant treatment

 for patients with surgically resected, high-risk muscle-invasive urothelial carcinoma based on data from CheckMate-274.

Previously, in July 2014, nivolumab was the first PD-1 inhibitor to received regulatory approval anywhere in the world. The agent is now approved for use in over 65 countries. The immunotherapy agent was given the green light in October 2015 for use in combination with ipilimumab (Yervoy) in patients with metastatic melanoma and this indication has since been approved in over 50 countries.

US Food and Drug Administration accepts for priority review Bristol Myers Squibb’s application for Opdivo (nivolumab) as adjuvant treatment for patients with muscle-invasive urothelial carcinoma. News release. Bristol Myers Squibb. April 30, 2021. Accessed April 30, 2021. 

Bajorin DF, Witjes JA, Gschwend J, Schenker M. First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab vs placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC). 

. 2021;39(suppl 6):391. doi:10.1200/JCO.2021.39.6_suppl.391

FDA Grants Priority Review to Adjuvant Nivolumab for Muscle-Invasive Urothelial Carcinoma

The FDA has granted a priority review designation to a supplemental biologics license application for nivolumab for use as an adjuvant treatment in patients with surgically resected, high-risk, muscle-invasive urothelial carcinoma.

Adjuvant Nivolumab Granted Priority Review for Muscle-Invasive Urothelial Carcinoma

The FDA granted an accelerated approval to sacituzumab govitecan (Trodelvy) for patients with locally advanced or metastatic urothelial cancer (mUC) who previously had a platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor.

The approval is based off findings from the single-arm TROPHY (IMMU-132-06; NCT03547973) trial, which involved 112 patients with mUC who received 10 mg/kg of intravenous sacituzumab govitecan — the recommended dose — on days 1 and 8 of 21-day treatment cycles.

Overall response rate (ORR) in the trial was 27.7%, with 5.4% complete responses and 22.3% partial response. Average duration of response (DOR) was 7.2 months in the 31 patients who responded to therapy (range, 1.4+13.7).

Common adverse events from sacituzumab govitecan, which occurred in more than 25% of patients, were neutropenia, nausea, diarrhea, fatigue, alopecia, anemia, vomiting, constipation, decreased appetite, rash, and abdominal pain.

The FDA recommends sacituzumab govitecan be given until disease progression or unacceptable toxicity.

The FDA granted an accelerated approval to sacituzumab govitecan (Trodelvy) for patients with locally advanced or metastatic urothelial cancer (mUC) who previously had a platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor. 

FDA Approves Sacituzumab Govitecan for Previously Treated Metastatic Urothelial Cancer

The FDA approvals of olaparib (Lynparza) and rucaparib (Rubraca) for the treatment of men with 

-mutant metastatic castration-resistant prostate cancer (mCRPC) shifted the paradigm away from sequential antiandrogen therapy with enzalutamide (Xtandi) and abiraterone acetate (Zytiga), said Tanya Dorff, MD, who added that genetic and genomic testing should be considered a key step in the continuum of care for patients.

“[We know that] going from abiraterone to enzalutamide or enzalutamide to abiraterone is less successful [vs a PARP inhibitor because] phase 3 data have shown us that patients with an applicable alteration can do better with a PARP inhibitor,” said Dorff. “We need to refer our patients for genetic testing, perform genetic testing ourselves as medical oncologists if we are comfortable with that, and think about genomic sequencing [in men with mCRPC].”

However, Dorff explained that the utility of these agents could be further enhanced by identifying additional biomarkers of response to PARP inhibitors, seeing confirmatory phase 3 data with rucaparib, and comparing PARP inhibition with chemotherapy.

® during an Institutional Perspectives in Cancer webinar on prostate cancer, Dorff, a medical oncologist and an associate clinical professor in the Department of Medical Oncology and Therapeutics Research at City of Hope, discussed how the FDA approvals of olaparib and rucaparib have paved the way for additional research with PARP inhibitors in mCRPC.

®: How have the approvals of olaparib and rucaparib affected the treatment paradigm of men with mCRPC?

: [Olaparib and rucaparib] are approved for 

-mutant mCRPC, and [the approvals] have done two things. One is [the approvals have] increased the need for genomic sequencing. We have always pushed for genetic testing of our patients with prostate cancer, but we also need to do somatic testing to ensure we don’t miss any patients who could benefit from [PARP inhibitors]. Therefore, a companion diagnostic was approved as part of the approval of olaparib so that we can use liquid genomics [to test for 

 mutations]. Liquid genomics are much more convenient in the setting of bone metastases where we can’t always get tissue DNA. That’s the first major thing: We can’t treat patients if we don’t identify them as being eligible.

The second thing is that [the approvals] gave us confidence in the fact that there was a progression-free survival [PFS] advantage and an overall survival [OS] advantage [with PARP inhibition vs antiandrogen agents]. These trials were not placebo-controlled, but [the PARP inhibitors] were compared head-to-head with enzalutamide or abiraterone after failure on the other agent. That [yielded] really strong, level 1 evidence.

The rucaparib approval was based on phase 2 [data], but we know phase 3 data are coming. Based on the very strong response rates we’ve seen with rucaparib, it is very much expected that we will see positive phase 3 data.

mutations needed in mCRPC? Do any look promising?

The approvals came through for both agents for 

-mutant mCRPC. [BRCA] testing can be done by tissue genomics, liquid genomics, or genetic testing to find a germline alteration.

However, other biomarkers are more questionable. Very rare mutations may predict sensitivity to PARP inhibitors, but so few patients have been treated that it is hard to have confidence in terms of the likelihood of an objective response or whether the median PFS would look similar to the cohorts presented.

Cohort B in the [PROfound] trial [with olaparib] included patients with a variety of mutations, such as 

. [Patients] may have some mutations that are strong predictors for benefit and others that are weaker. Mixed together, the data don’t look as strong [in those subgroups], but we need more of these patients to be treated [with PARP inhibitors] to determine which of the other alterations [beyond 

In the meantime, we are starting to cast a wider net to look beyond DNA sequencing and try to understand what other factors impact DNA repair where there could be the synthetic lethality effect that we see with clear DNA repair alterations. [Perhaps we can] even just leverage the other actions of the PARP inhibitor and the crosstalk with an androgen receptor [AR].


For instance, at City of Hope, we are looking at the triplicate repeats in the AR in all-comers to see whether that is a potential biomarker for who might benefit from PARP inhibitor therapy.

How have the phase 3 data with olaparib solidified the role of PARP inhibitors in patients with

The PROfound study was done in patients with mCRPC who had already been exposed to enzalutamide or abiraterone and had progressed. Patients were allowed to have been treated with chemotherapy, but it wasn’t required. Patients were randomized in an open-label [design] to olaparib at 300 mg twice daily or enzalutamide if they had prior abiraterone, or abiraterone if they had prior enzalutamide. The primary end point was radiographic PFS [rPFS], which was almost doubled in the olaparib arm. [The improvement in rPFS] was a strong indicator [of the benefit of PARP inhibition] in cohort A, [which included patients with] 

[mutations]. Although more than 80% of patients crossed over after radiographic progression, OS was still positive, favoring olaparib in cohort A. Of course, when we sensor for the crossover design, we see an even stronger survival benefit [with olaparib. Olaparib demonstrated] really strong efficacy in this population.

Cohort B with the other alterations was a little bit more mixed. [The cohort demonstrated] an rPFS benefit [with olaparib], but the OS wasn’t significant. If we had looked at smaller subsets of patients, we might have gotten a different answer.

How could phase 3 data supplement the phase 2 data observed with rucaparib?

If we look at the publication by [Wassim Abida, MD, PhD, of Memorial Sloan Kettering Cancer Center] and colleagues [that was published] last year in the 

, we see a strong response rate with rucaparib in 

-mutant [mCRPC]. A second study published in Clinical Cancer Research [demonstrated responses rates] with [rucaparib in patients with] other alterations, such as 

. Again, we see really strong prostate-specific antigen responses and strong objective response signals [in those patients]. We can’t determine whether [there is] a more significant benefit [with rucaparib vs an approved agent] the same way we can in a phase 3 trial, although I predict based on the efficacy signals that we would see much less durable and less frequent responses with the second AR-targeted agent [vs rucaparib].

Although cross-trial comparisons are not reliable, how are you choosing between olaparib and rucaparib in the clinical setting?

It is challenging to choose between [olaparib and rucaparib] because the data look really strong in both cases. Olaparib does have the advantage of [having] phase 3 data that show a survival benefit, as well as the broader FDA label that includes other genetic alterations [beyond 

In terms of safety, we don’t want to do cross-trial comparisons. However, the adverse effect [AE] profiles look very much like class effects, with the majority of grade 3 and higher toxicities falling into the category of myelosuppression, such as anemia. Anemia is very common in these patients. In my practice, [anemia] is one of the reasons I might need to hold dosing for a time or even dose reduce. [The PARP inhibitors] can also cause some gastrointestinal AEs or fatigue; however, the toxicity profiles look similar, and it would be hard to choose one or the other based on that.

Where does chemotherapy fit into sequencing with PARP inhibitors and antiandrogen agents?

We don’t know whether PARP inhibitors would be better compared with chemotherapy because that wasn’t the trial design. Patients who are progressing on abiraterone or enzalutamide could also be considered for chemotherapy. We don’t yet know optimal sequencing when it comes to PARP inhibitors vs chemotherapy.

PARP Inhibitors Could Help Craft Better Personalized Medicine in Prostate Cancer

Tanya Dorff, MD, discusses how the FDA approvals of olaparib and rucaparib have paved the way for additional research with PARP inhibitors in metastatic castration-resistant prostate cancer.

PARP Inhibitors Lay Groundwork for Personalized Care in Prostate Cancer

The National Comprehensive Cancer Network (NCCN) has updated its Clinical Practice Guidelines to include tivozanib (Fotivda) as a recommended regimen for subsequent therapy in patients with clear cell renal cell carcinoma (RCC), according to an announcement from AVEO Oncology.

The current NCCN guidelines for RCC categorically make treatment recommendations for frontline or subsequent options of patients with the disease. Specifically, the network now recommends tivozanib as a subsequent treatment for patients with clear cell RCC who have previously received 2 or more systemic therapies (category 2a).

The addition of the agent to the guidelines follows the March 2021 FDA approval of tivozanib for the treatment of adult patients with relapsed/refractory advanced RCC, after 2 or more previous systemic therapies. The regulatory decision was based primarily on data from the phase 3 TIVO-3 trial (NCT02627963), which examined tivozanib vs sorafenib (Nexavar), showed that the final hazard ratio (HR) for overall survival (OS) was 0.97 (95% CI, 0.75-1.24; 

 At a median follow-up of 38 months for tivozanib and 40 months for sorafenib, the median OS was 16.4 months (95% CI, 13.4-22.2) and 19.2 months (95% CI, 15.0-24.2), respectively.

Prior data showed that the next-generation VEGF TKI significantly improved progression-free survival (PFS) over sorafenib in patients who had received 2 or 3 prior regimens.

 The median PFS with tivozanib was 5.6 months (95% CI, 5.3-7.3) vs 3.9 months (95% CI, 3.9-5.6) with sorafenib (HR, 0.73; 95% CI, 0.56-0.94; 

“[Tivozanib’s] addition to the NCCN Guidelines provides further validation for its potential to serve as an important evidence-based, well-tolerated treatment option for patients with relapsed or refractory advanced RCC,” Michael Bailey, president and chief executive officer of AVEO, stated in a press release. “As previously announced, launch efforts are now underway, and we are committed to bringing this promising therapy to as many appropriate patients as possible.”

Tivozanib is a potent and highly selective VEGF inhibitor that targets VEGFRs 1, 2, and 3 and was designed to have a long half-life to improve tolerability and efficacy. In the phase 3 TIVO-3 trial, investigators set out to compare the use of tivozanib with sorafenib in patients with relapsed/refractory RCC.

To be eligible for enrollment, patients needed to have histologically or cytologically confirmed recurrent or metastatic disease; an ECOG performance status of 0 or 1; and have progressed on at least 2 previous regimens, including a VEGFR TKI. Patients were stratified by International Metastatic RCC Database risk and prior TKI regimen.

A total of 350 patients were randomized 1:1 to receive either tivozanib (n = 170) or sorafenib (n = 159). Patients received treatment until disease progression. The primary end point of the trial was PFS, while secondary end points included OS, objective response rate (ORR), and duration of response, as well as safety and tolerability.

Overall, 18% of those (n = 31) on the tivozanib arm experienced a partial response to treatment vs 8% in the sorafenib arm (n = 14). The ORR in the investigative arm was 34.0% vs 24.0% in the control arm.

Additional data presented during the 2021 Genitourinary Cancers Symposium showed that among a subset of patients who received 2 prior VEGFR TKIs, the median PFS in the investigative and control arms was 5.5 months (95% CI, 3.6-7.4) and 3.7 months (95% CI, 3.6-3.9), respectively (HR, 0.57; 95% CI, 0.39-0.83; 

 = .003).4 The ORRs in this subset were 15.2% and 7.5%, respectively.

Moreover, the HR for PFS in patients who were in the third line and received prior axitinib (Inlyta) was 0.73, while the ORRs were 18% vs 8% in the investigative and control arms. The HR for PFS in those who were in the fourth line and previously received axitinib was 0.64, and the ORR was 11% with tivozanib vs 10% with sorafenib. Lastly, in third- and fourth-line populations with any prior axitinib, the HR for PFS was 0.68; ORRs in the investigative and control arms were 13% and 8%, respectively.

Regarding safety, treatment-related toxicities were experienced by 84.0% of those in the tivozanib arm vs 94.0% of those in the sorafenib arm. Serious treatment-related adverse effects (AEs) were reported in 11.0% of those in the investigative arm and 10.0% of those on the control arm. The most frequently experienced AE that were grade 3 or 4 in severity in the tivozanib and sorafenib arms was hypertension, which was reported in 21.0% vs 14.0% of patients, respectively. The most common any-grade toxicities linked with tivozanib included hypertension (38.0%), diarrhea (33.0%), fatigue (29.0%), and reduced appetite (27.0%).

Significantly reduced dose reductions and interruptions because of toxicities were reported with tivozanib vs sorafenib, at 48.0% and 63.0%, respectively (

 = .0164), despite almost double the average time of cycles initiated for the tivozanib arm, at 11.9 months vs 6.7 months, respectively. Eight percent of patients on the investigative arm experienced treatment-related toxicities that resulted in permanent discontinuation of treatment vs 15.0% in the control arm.

AVEO Oncology announces addition of FOTIVDA (tivozanib) into National Comprehensive Cancer Network Clinical Practice Guidelines. News release. AVEO Oncology. March 29, 2021. Accessed March 30, 2021. 

AVEO Oncology Announces U.S. FDA Approval of FOTIVDA® (tivozanib) for the Treatment of Adult Patients with Relapsed or Refractory Advanced Renal Cell Carcinoma. AVEO Oncology. News release. March 10, 2021. Accessed March 30, 2021. 

Pal SK, Escudier B, Atkins MB, et al. TIVO-3: Final OS analysis of a phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with metastatic renal cell carcinoma (RCC). 

. 2020;38(suppl 15):5062. doi:10.1200/JCO.2020.38.15_suppl.5062

Rini BI, Pal SK, Escudier B, et al. TIVO-3: tivozanib in patients with advanced renal cell carcinoma (aRCC) who have progressed after treatment with axitinib. 

. 2021;39(suppl 6):278. doi:10.1200/JCO.2021.39.6_suppl.278

NCCN Updates Guidelines to Include Tivozanib as Recommended Regimen in Clear Cell RCC

The National Comprehensive Cancer Network has updated its Clinical Practice Guidelines to include tivozanib as a recommended regimen for subsequent therapy in patients with clear cell renal cell carcinoma.

NCCN Updates Clear Cell RCC Guidelines

Although the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) has become the standard frontline treatment for patients with advanced hepatocellular carcinoma (HCC), whether immunotherapy could play a role in earlier lines of treatment remains the subject of ongoing research, said David J. Pinato, MD, PhD, who added that immune-based therapy could improve cure rates in early-stage HCC and overcome the survival plateau associated with transarterial chemoembolization (TACE) in intermediate-stage HCC.

“It often happens in drug development that you take the knowledge that you have consolidated in advanced disease and move it earlier to other, less advanced stages of disease. However, doing so is accompanied by new treatment goals and new challenges,” said Pinato, clinical senior lecturer in medical oncology, clinician scientist, and consultant medical oncologist in the Department of Surgery and Cancer at Imperial College London, in a virtual presentation during the 2021 HCC-TAG Conference.

In early-stage HCC, patients have an estimated median overall survival (OS) of over 60 months, and standard of care therapies include resection, local ablation, and transplant, Pinato said. Notably, cure remains the main treatment goal in this setting.

In intermediate-stage disease, patients have an estimated median OS of approximately 24 months. Prolonged survival with TACE, which remains the standard of care, is the main treatment intervention.

However, in both settings, factors such as the severity of cirrhosis, anti-viral control, microvascular invasion, serum alpha-fetoprotein, focality, and tumor size contribute to a heterogenous tumor environment that can be difficult to treat. Moreover, up to 70% of patients relapse within 2 years.

In the past few years, many studies evaluating systemic therapy for non-advanced HCC have yielded negative results.

Although the combination of atezolizumab and bevacizumab has become the standard frontline treatment for patients with advanced hepatocellular carcinoma, whether immunotherapy could play a role in earlier lines of treatment remains the subject of ongoing research.

Genitourinary Cancer