Highlights • Bladder cancer incidence and mortality have changed little over the past 20 years. • Immunotherapy offers improved efficacy and tolerability over other modalities. • Checkpoint ...inhibitors offer an effective alternative for patients with few options. • Recent data on PD-L1 inhibitors have proven their benefit in bladder cancer.
In this trial, the addition of six cycles of docetaxel to androgen-deprivation therapy resulted in longer median progression-free and overall survival than that with ADT alone in patients with ...metastatic prostate cancer.
Regressions of metastatic prostate cancer were first documented in the 1940s and were achieved with surgical castration; subsequently, androgen-deprivation therapy (ADT) became the mainstay of therapy.
1
Attempts to improve the efficacy or decrease the treatment burden of ADT have included the use of antiandrogens alone, intermittent dosing of ADT, and the use of an antiandrogen combined with medical or surgical castration.
2
–
4
A meta-analysis revealed an increase in survival of 3 percentage points at 5 years with concurrent use of a nonsteroidal antiandrogen at the time of initiation of ADT.
2
However, resistance to ADT occurs in most patients, with the . . .
Purpose Docetaxel added to androgen-deprivation therapy (ADT) significantly increases the longevity of some patients with metastatic hormone-sensitive prostate cancer. Herein, we present the outcomes ...of the CHAARTED (Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) trial with more mature follow-up and focus on tumor volume. Patients and Methods In this phase III study, 790 patients with metastatic hormone-sensitive prostate cancer were equally randomly assigned to receive either ADT in combination with docetaxel 75 mg/m
for up to six cycles or ADT alone. The primary end point of the study was overall survival (OS). Additional analyses of the prospectively defined low- and high-volume disease subgroups were performed. High-volume disease was defined as presence of visceral metastases and/or ≥ four bone metastases with at least one outside of the vertebral column and pelvis. Results At a median follow-up of 53.7 months, the median OS was 57.6 months for the chemohormonal therapy arm versus 47.2 months for ADT alone (hazard ratio HR, 0.72; 95% CI, 0.59 to 0.89; P = .0018). For patients with high-volume disease (n = 513), the median OS was 51.2 months with chemohormonal therapy versus 34.4 months with ADT alone (HR, 0.63; 95% CI, 0.50 to 0.79; P < .001). For those with low-volume disease (n = 277), no OS benefit was observed (HR, 1.04; 95% CI, 0.70 to 1.55; P = .86). Conclusion The clinical benefit from chemohormonal therapy in prolonging OS was confirmed for patients with high-volume disease; however, for patients with low-volume disease, no OS benefit was discerned.
Summary Background Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone ...metastases with high-energy, short-range α-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases. Methods In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2:1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov , number NCT00699751. Findings Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15·6 months 95% CI 13·5–18·0 vs 9·8 months 7·3–23·7; hazard ratio HR=0·66, 95% CI 0·52–0·83; p=0·00037). The risks of external beam radiation therapy for bone pain (HR 0·67, 95% CI 0·53–0·85) and spinal cord compression (HR=0·52, 95% CI 0·29–0·93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0·62, 95% CI 0·35–1·09), or the need for tumour-related orthopaedic surgical intervention (HR 0·72, 95% CI 0·28–1·82). Interpretation Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases. Funding Algeta and Bayer HealthCare Pharmaceuticals.
Genomic alterations in DNA damage repair (DDR) genes other than
may confer synthetic lethality with PARP inhibition in metastatic castration-resistant prostate cancer (mCRPC). To test this ...hypothesis, the phase II TRITON2 study of rucaparib included patients with mCRPC and deleterious non-
DDR gene alterations.
TRITON2 enrolled patients who had progressed on one or two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy for mCRPC. Key endpoints were investigator-assessed radiographic response per modified RECIST/PCWG3 and PSA response (≥50% decrease from baseline).
TRITON2 enrolled 78 patients with a non-
DDR gene alteration
(
= 49),
(
= 15),
(
= 12), and other DDR genes (
= 14). Among patients evaluable for each endpoint, radiographic and PSA responses were observed in a limited number of patients with an alteration in
2/19 (10.5%) and 2/49 (4.1%), respectively,
0/10 (0%) and 1/15 (6.7%), respectively, or
1/9 (11.1%) and 2/12 (16.7%), respectively, including no radiographic or PSA responses in 11 patients with confirmed biallelic
loss or 11 patients with
germline mutations. Responses were observed in patients with alterations in the DDR genes
, and
.
In this prospective, genomics-driven study of rucaparib in mCRPC, we found limited radiographic/PSA responses to PARP inhibition in men with alterations in
, or
. However, patients with alterations in other DDR-associated genes (e.g.,
) may benefit from PARP inhibition.
.
Docetaxel (D) at the time of starting androgen deprivation therapy (ADT) for metastatic castrate naive prostate cancer shows a clear survival benefit for patients with high-volume (HV) disease. It is ...unclear whether patients with low-volume (LV) disease benefit from early D.
To define the overall survival (OS) of aggregate data of patient subgroups from the CHAARTED and GETUG-AFU15 studies, defined by metastatic burden (HV and LV) and time of metastasis occurrence (at diagnosis or after prior local treatment PRLT).
Data were accessed from two independent phase III trials of ADT alone or ADT+D—GETUG-AFU15 (N=385) and CHAARTED (N=790), with median follow-ups for survivors of 83.2 and 48.2 mo, respectively. The definition of HV and LV disease was harmonized.
The primary end point was OS.
Meta-analysis results of the aggregate data showed significant heterogeneity in ADT+D versus ADT effect sizes between HV and LV subgroups (p=0.017), and failed to detect heterogeneity in ADT+D versus ADT effect sizes between upfront and PRLT subgroups (p=0.4). Adding D in patients with HV disease has a consistent effect in improving median OS (HV-ADT: 34.4 and 35.1 mo, HV-ADT+D: 51.2 and 39.8 mo in CHAARTED and GETUG-AFU15, respectively; pooled average hazard ratio or HR (95% confidence interval CI) 0.68 (95% CI 0.56; 0.82, p<0.001). Patients with LV disease showed much longer OS, without evidence that D improved OS (LV-ADT: not reached NR and 83.4; LV-ADT+D: 63.5 and NR in CHAARTED and GETUG-AFU15, respectively; pooled HR (95% CI) 1.03 (95% CI 0.77; 1.38). Aggregate data showed no evidence of heterogeneity of early D in LV and HV subgroups irrespective of whether patients had PRLT or not. Post hoc subgroup analysis was based on aggregated data from two independent phase III randomized trials.
There was no apparent survival benefit in the CHAARTED and GETUG-AFU15 studies with D for LV. Across both studies, early D showed consistent effect and improved OS in HV patients.
Patients with a higher burden of metastatic prostate cancer starting androgen deprivation therapy (ADT) have a poorer prognosis and are more likely to benefit from early docetaxel. Low-volume patients have longer overall survival with ADT alone, and the toxicity of docetaxel may outweigh its benefits.
The aggregate data of two phase 3 trials show that patients with a high volume of metastatic castrate naive prostate cancer have poorer overall survival (OS) and benefit from androgen deprivation therapy (ADT)+docetaxel. Low-volume patients have longer OS with ADT alone and no clear benefit with adding docetaxel.
Summary Background In previous clinical trials of patients with metastatic renal-cell carcinoma, patients treated with axitinib as second-line therapy had longer median progression-free survival than ...those treated with sorafenib. We therefore undertook a phase 3 trial comparing axitinib with sorafenib in patients with treatment-naive metastatic renal-cell carcinoma. Methods In this randomised, open-label, phase 3 trial, patients with treatment-naive, measurable, clear-cell metastatic renal-cell carcinoma from 13 countries were stratified by Eastern Cooperative Oncology Group performance status, and then randomly assigned (2:1) by a centralised registration system to receive axitinib 5 mg twice daily, or sorafenib 400 mg twice daily. The primary endpoint was progression-free survival, assessed by masked independent review committee in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov , NCT00920816. Findings Between June 14, 2010, and April 21, 2011, we randomly assigned 192 patients to receive axitinib, and 96 patients to receive sorafenib. The cutoff date for this analysis was July 27, 2012, when 171 (59%) of 288 patients died or had disease progression, as assessed by the independent review committee. There was no significant difference in median progression-free survival between patients treated with axitinib or sorafenib (10·1 months 95% CI 7·2–12·1 vs 6·5 months 4·7–8·3, respectively; stratified hazard ratio 0·77, 95% CI 0·56–1·05). Any-grade adverse events that were more common (≥10% difference) with axitinib than with sorafenib were diarrhoea (94 50% of 189 patients vs 38 40% of 96 patients), hypertension (92 49% vs 28 29%), weight decrease (69 37% vs 23 24%), decreased appetite (54 29% vs 18 19%), dysphonia (44 23% vs ten 10%), hypothyroidism (39 21% vs seven 7%), and upper abdominal pain (31 16% vs six 6%); those more common with sorafenib than with axitinib included palmar-plantar erythrodysaesthesia (PPE; 37 39% of 96 patients vs 50 26% of 189), rash (19 20% vs 18 10%), alopecia (18 19% vs eight 4%), and erythema (18 19% vs five 3%). The most common grade 3 or 4 adverse events in patients treated with axitinib included hypertension (26 14% of 189 patients), diarrhoea (17 9%), asthenia (16 8%), weight decrease (16 8%), and PPE (14 7%); common grade 3 or 4 adverse events in patients treated with sorafenib included PPE (15 16% of 96 patients), diarrhoea (five 5%), and asthenia (five 5%). Serious adverse events were reported in 64 (34%) of 189 patients receiving axitinib, and 24 (25%) of 96 patients receiving sorafenib. Interpretation Axitinib did not significantly increase progression-free survival in patients with treatment-naive metastatic renal-cell carcinoma compared with those treated with sorafenib, but did demonstrate clinical activity and an acceptable safety profile. Funding Pfizer Inc.
Lenvatinib is a multikinase inhibitor of VEGFR1, VEGFR2, and VEGFR3, and other receptor tyrosine kinases. Pembrolizumab, an antibody targeting PD-1, has moderate efficacy in biomarker-unselected ...endometrial cancer. We aimed to assess the combination of lenvatinib plus pembrolizumab in patients with advanced endometrial carcinoma, after establishing the maximum tolerated dose in a phase 1b study.
In this open-label, single-arm, phase 2 study done at 11 centres in the USA, eligible patients were aged 18 years or older and had metastatic endometrial cancer (unselected for microsatellite instability or PD-L1), had an Eastern Cooperative Oncology Group performance status of 0 or 1, had received no more than two previous systemic therapies, had measurable disease according to the immune-related Response Evaluation Criteria In Solid Tumors (irRECIST), and had a life expectancy of 12 weeks or longer. Patients received 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks. Treatment continued until disease progression, development of unacceptable toxic effects, or withdrawal of consent. The primary endpoint of this interim analysis was the proportion of patients with an objective response at week 24 as assessed by investigators according to irRECIST in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT02501096.
Between Sept 10, 2015, and July 24, 2017, 54 patients were enrolled, 53 of whom were included in the analysis. At the cutoff date for anti-tumour activity data (Dec 15, 2017), median study follow-up was 13·3 months (IQR 6·7–20·1). 21 (39·6% 95% CI 26·5–54·0) patients had an objective response at week 24. Serious treatment-related adverse events occurred in 16 (30%) patients, and one treatment-related death was reported (intracranial haemorrhage). The most frequently reported any-grade treatment-related adverse events were hypertension (31 58%), fatigue (29 55%), diarrhoea (27 51%), and hypothyroidism (25 47%). The most common grade 3 treatment-related adverse events were hypertension (18 34%) and diarrhoea (four 8%). No grade 4 treatment-related adverse events were reported. Five (9%) patients discontinued study treatment because of treatment-related adverse events.
Lenvatinib plus pembrolizumab showed anti-tumour activity in patients with advanced recurrent endometrial cancer with a safety profile that was similar to those previously reported for lenvatinib and pembrolizumab monotherapies, apart from an increased frequency of hypothyroidism. Lenvatinib plus pembrolizumab could represent a new potential treatment option for this patient population, and is being investigated in a randomised phase 3 study.
Eisai and Merck.
Summary Background Primary results from the phase 3 ALSYMPCA trial showed that radium-223 dichloride (radium-223), a targeted α-emitter, improved overall survival compared with placebo and was well ...tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases. We did a prespecified subgroup analysis from ALSYMPCA to assess the effect of previous docetaxel use on the efficacy and safety of radium-223. Methods In the phase 3, randomised, double-blind ALSYMPCA trial, patients with symptomatic castration-resistant prostate cancer, at least two symptomatic bone metastases, no known visceral metastases, and who were receiving best standard of care were randomly assigned (2:1) via an interactive voice response system to receive six injections of radium-223 (50 kBq/kg intravenously) or matching placebo, with one injection given every 4 weeks. Patients had either received previous docetaxel treatment or were unsuitable for or declined docetaxel; previous docetaxel use (yes or no) was a trial stratification factor. We investigated the effect of previous docetaxel use on radium-223 treatment for the primary endpoint of overall survival, the main secondary efficacy endpoints, and safety. Efficacy analyses were done for the intention-to-treat population; safety analyses were done for the safety population. The trial has been completed and is registered with ClinicalTrials.gov , number NCT00699751. Findings Randomisation took place between June 12, 2008, and Feb 1, 2011. 526 (57%) of 921 randomly assigned patients had received previous docetaxel treatment (352 in the radium-223 group and 174 in the placebo group) and 395 (43%) had not (262 in the radium-223 group and 133 in the placebo group). Radium-223 prolonged median overall survival compared with placebo, irrespective of previous docetaxel use (previous docetaxel use, hazard ratio HR 0·70, 95% CI 0·56–0·88; p=0·002; no previous docetaxel use, HR 0·69, 0·52–0·92; p=0·01). The benefit of radium-223 compared with placebo was seen in both docetaxel subgroups for most main secondary efficacy endpoints; risk for time to time to first symptomatic skeletal event was reduced with radium-223 versus placebo in patients with previous docetaxel use, but the difference was not significant in those with no previous docetaxel use. 322 (62%) of 518 patients previously treated with docetaxel had grade 3–4 adverse events, compared with 205 (54%) of 383 patients without docetaxel. Patients who had previously been treated with docetaxel had a higher incidence of grade 3–4 thrombocytopenia with radium-223 than with placebo (31 9% of 347 patients vs five 3% of 171 patients), whereas the incidence was similar between treatment groups among patients with no previous docetaxel use (seven 3% of 253 patients vs one 1% of 130 patients). The incidences of grade 3–4 anaemia and neutropenia were similar between the radium-223 and placebo groups within both docetaxel subgroups. Interpretation Radium-223 is effective and well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases, irrespective of previous docetaxel use. Funding Algeta ASA and Bayer HealthCare Pharmaceuticals.
Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune ...checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients.
We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0–1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov (NCT02501096) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants.
Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3–28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8–89·3) of 22 treatment-naive patients, seven (41·2%, 18·4–67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7–65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 21% of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia).
Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC.
Eisai and Merck Sharp & Dohme.
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